Alzheimer Disease

Updated: May 09, 2022
Author: Shaheen E Lakhan, MD, PhD, MS, MEd, FAAN; Chief Editor: Jasvinder Chawla, MD, MBA 

Overview

Practice Essentials

Alzheimer disease (AD) is a neurodegenerative disorder marked by cognitive and behavioral impairment that significantly interferes with social and occupational functioning. It is an incurable disease with a long preclinical period and progressive course. In AD, plaques develop in the hippocampus, a structure deep in the brain that helps to encode memories, and in other areas of the cerebral cortex that are involved in thinking and making decisions. Whether plaques themselves cause AD or whether they are a by-product of the AD process remains unknown. The following image depicts one of the cardinal neuroimaging findings in AD – hippocampal atrophy.

Coronal T1-weighted magnetic resonance imaging (MR Coronal T1-weighted magnetic resonance imaging (MRI) scan in a patient with moderate Alzheimer disease. Brain image reveals hippocampal atrophy, especially on the right side.

Signs and symptoms

Preclinical Alzheimer disease

A patient with preclinical AD may appear completely normal on physical examination and mental status testing. Specific regions of the brain (eg, entorhinal cortex, hippocampus) are likely to be affected decades before any signs or symptoms appear.

Mild Alzheimer disease

Signs of mild AD can include the following:

  • Memory loss

  • Confusion about the location of familiar places

  • Taking longer to accomplish normal, daily tasks

  • Trouble handling money and paying bills

  • Compromised judgment, often leading to bad decisions

  • Loss of spontaneity and sense of initiative

  • Mood and personality changes; increased anxiety

Moderate Alzheimer disease

The symptoms of this stage can include the following:

  • Increasing memory loss and confusion

  • Shortened attention span

  • Problems recognizing friends and family members

  • Difficulty with language; problems with reading, writing, working with numbers

  • Difficulty organizing thoughts and thinking logically

  • Inability to learn new things or to cope with new or unexpected situations

  • Restlessness, agitation, anxiety, tearfulness, wandering, especially in the late afternoon or at night

  • Repetitive statements or movement; occasional muscle twitches

  • Hallucinations, delusions, suspiciousness or paranoia, irritability

  • Loss of impulse control: Shown through behavior such as undressing at inappropriate times or places or vulgar language

  • Perceptual-motor problems: Such as trouble getting out of a chair or setting the table

Severe Alzheimer disease

Patients with severe AD cannot recognize family or loved ones and cannot communicate effectively. They are completely dependent on others for care, and all sense of self seems to vanish.

Other symptoms of severe AD can include the following:

  • Weight loss

  • Seizures, skin infections, difficulty swallowing

  • Groaning, moaning, or grunting

  • Increased sleeping

  • Lack of bladder and bowel control

In end-stage AD, patients may be in bed much or all of the time. Death is often the result of other illnesses, frequently aspiration pneumonia.

See Clinical Presentation for more detail.

Diagnosis

Means of diagnosing AD include the following:

  • Clinical examination: The clinical diagnosis of AD is usually made during the mild stage of the disease, using the above-listed signs

  • Lumbar puncture: levels of tau and phosphorylated tau in the cerebrospinal fluid are often elevated in AD, whereas amyloid levels are usually low; at present, however, routine measurement of CSF tau and amyloid is not recommended except in research settings

  • Imaging studies: Imaging studies are particularly important for ruling out potentially treatable causes of progressive cognitive decline, such as chronic subdural hematoma or normal-pressure hydrocephalus.[1]  Moreover, volumetric studies of the hippocampus and 2-[18F]fluoro-2-Deoxy-D-glucose positron emission tomography (FDG-PET) with or without amyloid imaging have been employed for early detection and differentiating dementia etiologies.[2]

See Clinical Presentation and Workup for more detail.

Management

All drugs approved by the US Food and Drug Administration (FDA) for the treatment of AD are symptomatic therapies that modulate neurotransmitters, either acetylcholine or glutamate. The standard medical treatment for AD includes cholinesterase inhibitors (ChEIs) and a partial N-methyl-D-aspartate (NMDA) antagonist.[3, 4]  They do not treat the underlying cause of AD nor halt the rate of decline.

The following classes of psychotropic medications have been used to treat the secondary symptoms of AD, such as depression, agitation, aggression, hallucinations, delusions, and sleep disorders[5] :

  • Antidepressants

  • Anxiolytics

  • Antiparkinsonian agents

  • Beta-blockers

  • Antiepileptic drugs

  • Neuroleptics

  • Amyloid-directed antibody

Prevention

There are no proven modalities for preventing AD,[3] but evidence, largely epidemiologic, suggests that healthy lifestyles can reduce the risk of developing the disease; the following may be protective[6, 7] :

  • Physical activity

  • Exercise

  • Cardiorespiratory fitness

  • Diet: Although no definitive dietary recommendations can be made, in general, nutritional patterns that appear beneficial for AD prevention fit the Mediterranean diet

See Treatment and Medication for more detail.

Background

Alzheimer disease (AD) is the most common form of dementia. In the United States alone, approximately 6.08 million Americans had either clinical AD or mild cognitive impairment due to AD in 2017. That number is expected to grow to 15 million by 2060.[8]  AD is the sixth leading cause of death in the United States, accounting for 3.6% of all deaths in 2014.[9] The percentage of Alzheimer’s decedents who died in a medical facility (e.g., hospital) declined from 14.7% in 1999 to 6.6% in 2014, whereas the percentage who died at home increased from 13.9% in 1999 to 24.9% in 2014.[9] Economically, AD is a major public health problem. Total payments in 2017 for health care and long-term care for all individuals with AD or other dementias are estimated at $259 billion. By 2050, these costs could rise as high as $1.1 trillion.[10]

Currently, an autopsy or brain biopsy is the only way to make a definitive diagnosis of AD. In clinical practice, the diagnosis is usually made on the basis of the history and findings on Mental Status Examination (see Presentation).

Symptomatic therapies are the only treatments available for AD. The standard medical treatments include cholinesterase inhibitors and a partial N -methyl-D-aspartate (NMDA) antagonist. Psychotropic medications are often used to treat secondary symptoms of AD, such as depression, agitation, and sleep disorders. (See Treatment.)

For additional information, see Alzheimer’s Disease: Slideshow.

Historical background

In 1901, a German psychiatrist named Alois Alzheimer observed a patient at the Frankfurt Asylum named Mrs. Auguste D. This 51-year-old woman suffered from a loss of short-term memory, among other behavioral symptoms that puzzled Dr. Alzheimer. Five years later, in April 1906, the patient died, and Dr. Alzheimer sent her brain and her medical records to Munich, where he was working in the lab of Dr. Emil Kraeplin. By staining sections of her brain in the laboratory, he was able to identify amyloid plaques and neurofibrillary tangles.[11]

A speech given by Dr. Alzheimer on November 3, 1906, was the first time the pathology and the clinical symptoms of the disorder, which at the time was termed presenile dementia, were presented together. Alzheimer published his findings in 1907.[12]

In the past 15-20 years, dramatic progress has been made in understanding the neurogenetics and pathophysiology of AD (see Pathophysiology and Etiology). Four different genes have been definitively associated with AD, and others that have a probable role have been identified. The mechanisms by which altered amyloid and tau protein metabolism, inflammation, oxidative stress, and hormonal changes may produce neuronal degeneration in AD are being elucidated, and rational pharmacologic interventions based on these discoveries are being developed.

Anatomy

Healthy neurons have an internal support structure partly made up of structures called microtubules. These microtubules act like tracks, guiding nutrients and molecules from the body of the cell down to the ends of the axon and back. A special kind of protein, tau, binds to the microtubules and stabilizes them.

In AD, tau is changed chemically. It begins to pair with other threads of tau, which become tangled together. When this happens, the microtubules disintegrate, collapsing the neuron’s transport system (see the image below). The formation of these neurofibrillary tangles (NFTs) may result first in malfunctions in communication between neurons and later in the death of the cells.

Healthy neurons. Image courtesy of NIH. Healthy neurons. Image courtesy of NIH.

In addition to NFTs, the anatomic pathology of AD includes senile plaques (SPs; also known as beta-amyloid plaques) at the microscopic level and cerebrocortical atrophy at the macroscopic level (see the image below). The hippocampus and medial temporal lobe are the initial sites of tangle deposition and atrophy.[13] This can be seen on brain magnetic resonance imaging early in AD and helps support a clinical diagnosis.

Cortical atrophy with hydrocephalus ex vacuo is se Cortical atrophy with hydrocephalus ex vacuo is seen in Alzheimer disease.

SPs and NFTs were described by Alois Alzheimer in his original report on the disorder in 1907.[12] They are now universally accepted as the pathological hallmark of the disease.

Pathophysiology

A continuum exists between the pathophysiology of normal aging and that of AD.[14] Pathologic hallmarks of AD have been identified; however, these features also occur in the brains of cognitively intact persons. For example, in a study in which neuropathologists were blinded to clinical data, they identified 76% of brains of cognitively intact elderly patients as demonstrating AD.[15]

AD affects the 3 processes that keep neurons healthy: communication, metabolism, and repair. Certain nerve cells in the brain stop working, lose connections with other nerve cells, and finally die. The destruction and death of these nerve cells causes the memory failure, personality changes, problems in carrying out daily activities, and other features of the disease.

The accumulation of SPs primarily precedes the clinical onset of AD. NFTs, loss of neurons, and loss of synapses accompany the progression of cognitive decline.[14]

Considerable attention has been devoted to elucidating the composition of SPs and NFTs to find clues about the molecular pathogenesis and biochemistry of AD. The main constituent of NFTs is the microtubule-associated protein tau (see Anatomy). In AD, hyperphosphorylated tau accumulates in the perikarya of large and medium pyramidal neurons. Somewhat surprisingly, mutations of the tau gene result not in AD but in some familial cases of frontotemporal dementia.

Since the time of Alois Alzheimer, SPs have been known to include a starchlike (or amyloid) substance, usually in the center of these lesions. The amyloid substance is surrounded by a halo or layer of degenerating (dystrophic) neurites and reactive glia (both astrocytes and microglia).

One of the most important advances in recent decades has been the chemical characterization of this amyloid protein, the sequencing of its amino acid chain, and the cloning of the gene encoding its precursor protein (on chromosome 21). These advances have provided a wealth of information about the mechanisms underlying amyloid deposition in the brain, including information about the familial forms of AD. (See Amyloid Hypothesis Versus Tau Hypothesis, below.)

Alzheimer disease biomarkers may follow a sequential pattern in the brain, according to a study of AD biomarker trajectories. The study included both symptomatic and asymptomatic carriers of autosomal dominant gene mutations linked to AD, including APP, PSEN1, and PSEN2. Researchers did not address tauopathy. Results show that amyloid deposition in the brain occurs first, followed by a decline in glucose metabolism and then structural brain atrophy. The rate of Ab accumulation was significantly higher in mutation carriers compared to noncarriers, and was found to begin more than 2 decades before the expected onset of dementia. In carriers, metabolism began to decrease at a mean of 14.1 years before expected symptom onset, and structural changes in the brain began 4.7 years before expected symptom onset. It is important to note that only about 1% of patients with AD have an autosomal dominant mutation, so results may not be generalizable to sporadic AD.[16]

Although the amyloid cascade hypothesis has gathered the most research financing, other interesting hypotheses have been proposed. Among these are the mitochondrial cascade hypothesis.[17]

In addition to NFTs and SPs, many other lesions of AD have been recognized since Alzheimer’s original papers were published. These include the granulovacuolar degeneration of Shimkowicz; the neuropil threads of Braak et al[17] ; and neuronal loss and synaptic degeneration, which are thought to ultimately mediate the cognitive and behavioral manifestations of the disorder.

In 2019, researchers identified a new type of dementia that mimics AD but that is caused by another mechanism in the brain. This new classification is limbic-predominant age-related TDP-43 encephalopathy, (LATE). TDP-43 is a protein that helps regulate gene expression in the brain and other tissues, and when it misfolds it causes problems in the brain. According to researchers, misfolded TDP-43 protein is very common in older adults; about 25% of people aged 85 and older have enough misfolded TDP-43 protein to affect their memory and thinking skills.[18]

Neurofibrillary tangles and senile plaques

Plaques are dense, mostly insoluble deposits of protein and cellular material outside and around the neurons. Plaques are made of beta-amyloid (Ab), a protein fragment snipped from a larger protein called amyloid precursor protein (APP). These fragments clump together and are mixed with other molecules, neurons, and non-nerve cells (see the images below).

APP is associated with the cell membrane, the thin APP is associated with the cell membrane, the thin barrier that encloses the cell. After it is made, APP sticks through the neuron's membrane, partly inside and partly outside the cell. Image courtesy of NIH.
Enzymes (substances that cause or speed up a chemi Enzymes (substances that cause or speed up a chemical reaction) act on the APP and cut it into fragments of protein, one of which is called beta-amyloid. Image courtesy of NIH.
The beta-amyloid fragments begin coming together i The beta-amyloid fragments begin coming together into clumps outside the cell, then join other molecules and non-nerve cells to form insoluble plaques. Image courtesy of NIH.

In AD, plaques develop in the hippocampus, a structure deep in the brain that helps to encode memories, and in other areas of the cerebral cortex that are used in thinking and making decisions. Plaques may begin to develop as early as the fifth decade of life.[19] Whether Ab plaques themselves cause AD or whether they are a by-product of the AD process is still unknown. It is known that changes in APP structure can cause a rare, inherited form of AD.

Tangles are insoluble twisted fibers that build up inside the nerve cell. Although many older people develop some plaques and tangles, the brains of people with AD have them to a greater extent, especially in certain regions of the brain that are important in memory. There are likely to be significant age-related differences in the extent to which the presence of plaques and tangles are indicative of the presence of dementia.

NFTs are initially and most densely distributed in the medial aspect and in the pole of the temporal lobe; they affect the entorhinal cortex and the hippocampus most severely (however, Braak et al found that in sporadic AD, tauopathy may appear first in the lower brainstem rather than in the transentorhinal region[19] ). As AD progresses, NFTs accumulate in many other cortical regions, beginning in high-order association regions and less frequently in the primary motor and sensory regions.

SPs also accumulate primarily in association cortices and in the hippocampus. Plaques and tangles have relatively discrete and stereotypical patterns of laminar distribution in the cerebral cortex, which indicate predominant involvement of corticocortical connections.

Although NFTs and SPs are characteristic of AD, they are not pathognomonic. NFTs are found in several other neurodegenerative disorders, including progressive supranuclear palsy and dementia pugilistica (chronic traumatic encephalopathy). SPs may occur in normal aging.

Therefore, the mere presence of these lesions is not sufficient to support the diagnosis of AD. These lesions must be present in sufficient numbers and in a characteristic topographic distribution to fulfill the current histopathologic criteria for AD. There is consensus that the presence of even low numbers of NFTs in the cerebral neocortex with concomitant SPs is characteristic of AD.

Some authorities believed that NFTs, when present in low densities and essentially confined to the hippocampus, were part of normal aging. However, the histologic stages for AD that Braak et al formulated include an early stage in which NFTs are present at a low density in the entorhinal and perirhinal (ie, transentorhinal) cortices.[20] Therefore, even small numbers of NFTs in these areas of the medial temporal lobe may be abnormal.

Amyloid hypothesis versus tau hypothesis

A central but controversial issue in the pathogenesis of AD is the relationship between amyloid deposition and NFT formation. Evidence shows that abnormal amyloid metabolism plays a key pathogenic role. At high concentrations, the fibrillar form of Ab has been shown to be neurotoxic to cultured neurons.

Cultured cortical and hippocampal neurons treated with Ab protein exhibit changes characteristic of apoptosis (self-regulated cell destruction), including nuclear chromatin condensation, plasma membrane blebbing, and internucleosomal DNA fragmentation. The fibrillar form of Ab has also been shown to alter the phosphorylation state of tau protein.

The identification of several point mutations within the APP gene in some patients with early-onset familial AD and the development of transgenic mice exhibiting cognitive changes and SPs also incriminate Ab in AD. The apolipoprotein E (APOE) E4 allele, which has been linked with significantly increased risk for developing AD, may promote inability to suppress production of amyloid, increased production of amyloid, or impaired clearance of amyloid with collection outside of the neuron.

Autopsies have shown that patients with 1 or 2 copies of the APOE E4 allele tend to have more amyloid. Additional evidence comes from recent experimental data supporting the role of presenilins in Ab metabolism, as well as findings of abnormal production of Ab protein in presenilin-mutation familial Alzheimer disease.

Although very popular, the amyloid hypothesis is not uniformly accepted. On post-mortem analysis, amyloid plaques may be undetectable in the brains of patients who had severe AD but may be present in the brains of elderly patients who did not have dementia.[21]

Dementia severity correlates better with the number of neocortical NFTs than with SPs. The tau protein stabilizes neuronal microtubules. Destabilization of the microtubular system is speculated to disrupt the Golgi apparatus, in turn inducing abnormal protein processing and increasing production of Ab. In addition, this destabilization may decrease axoplasmic flow, generating dystrophic neurites and contributing to synaptic loss.

For more information, see the Medscape Reference article Alzheimer Disease and APOE-4.

Granulovacuolar degeneration and neuropil threads

Granulovacuolar degeneration occurs almost exclusively in the hippocampus. Neuropil threads are an array of dystrophic neurites diffusely distributed in the cortical neuropil, more or less independently of plaques and tangles. This lesion suggests neuropil alterations beyond those merely due to NFTs and SPs and indicates an even more widespread insult to the cortical circuitry than that visualized by studying only plaques and tangles.

Cholinergic neurotransmission and Alzheimer disease

The cholinergic system is involved in memory function, and cholinergic deficiency has been implicated in the cognitive decline and behavioral changes of AD. Activity of the synthetic enzyme choline acetyltransferase (CAT) and the catabolic enzyme acetylcholinesterase are significantly reduced in the cerebral cortex, hippocampus, and amygdala in patients with AD.

The nucleus basalis of Meynert and diagonal band of Broca provide the main cholinergic input to the hippocampus, amygdala, and neocortex, which are lost in patients with AD. Loss of cortical CAT and decline in acetylcholine synthesis in biopsy specimens have been found to correlate with cognitive impairment and reaction-time performance. Because cholinergic dysfunction may contribute to the symptoms of patients with AD, enhancing cholinergic neurotransmission constitutes a rational basis for symptomatic treatment.

Oxidative stress and damage

Oxidative damage occurs in AD. Studies have demonstrated that an increase in oxidative damage selectively occurs within the brain regions involved in regulating cognitive performance.[22]

Oxidative damage potentially serves as an early event that then initiates the development of cognitive disturbances and pathological features observed in AD. A decline in protein synthesis capabilities occurs in the same brain regions that exhibit increased levels of oxidative damage in patients with mild cognitive impairment (MCI) and AD. Protein synthesis may be one of the earliest cellular processes disrupted by oxidative damage in AD.[23]

Oxidative stress is believed to be a critical factor in normal aging and in neurodegenerative diseases such as Parkinson disease, amyotrophic lateral sclerosis, and AD. Formation of free carbonyls and thiobarbituric acid-reactive products, an index of oxidative damage, are significantly increased in AD brain tissue compared with age-matched controls. Plaques and tangles display immunoreactivity to antioxidant enzymes.

Multiple mechanisms exist by which cellular alterations may be induced by oxidative stress, including production of reactive oxygen species (ROS) in the cell membrane (lipid peroxidation). This in turn impairs the various membrane proteins involved in ion homeostasis such as N -methyl-D-aspartate receptor channels or ion-motive adenosine triphosphatases.

The subsequent increase in intracellular calcium, along with the accumulation of ROS, damages various cellular components such as proteins, DNA, and lipids and may result in apoptotic cellular death. Increased intracellular calcium may also alter calcium-dependent enzyme activity such as the implication of protein kinase C in amyloid protein metabolism and the phosphorylation of tau.

The involvement of calcium in AD has suggested that blocking the increase in free intracellular calcium may diminish neuronal injury. However, clinical trials of nimodipine, a lipophilic calcium channel blocker that is mediated through inactivation of voltage-dependent L-type (long-lasting) calcium channels, have yielded generally disappointing results in patients with AD.

The apoptotic pattern of cellular death seen in oxidative stress is similar to that produced by Ab peptide exposure, and Ab neurotoxicity is attenuated by antioxidants such as vitamin E. Ab may induce toxicity by engaging several binding sites on the membrane surface. The receptor for advanced glycation end products (RAGE) may be one of these receptors. RAGE is a member of the immunoglobulin superfamily of cell surface molecules known for its capacity to bind advanced glycation end products.

RAGE is also expressed in a variety of other cell types, including endothelial cells and mononuclear phagocytes. Activation of this receptor is believed to trigger cellular oxidative reactions. In addition, RAGE has been shown to mediate the interaction of Ab with glial cells, which may be one of the first steps in the inflammatory cascade.

Inflammatory reactions

Inflammatory and immune mechanisms may play a role in the degenerative process in AD. Reactive microglia are embedded in neuritic plaques. Increased cytokine levels are seen in the serum, cortical plaques, and neurons of patients with AD, as compared with aged-matched control patients. Interestingly, transforming growth factor beta 1 (TGF-β1), which is an anti-inflammatory cytokine, has been found to promote or accelerate the deposition of amyloid.

Classical complement pathway fragments are also found in the brains of patients with AD, and amyloid may directly activate the classical complement pathway in an antibody-independent fashion.

Whether markers of immune and inflammatory processes actively participate in the neurodegenerative process or instead represent an epiphenomenon remains unclear. Brain specimens from elderly patients with arthritis treated with nonsteroidal anti-inflammatory drugs (NSAIDs) have similar numbers of senile plaques as do control brains.

However, less microglial activation is seen in the brains of the patients with arthritis. This suggests that although NSAIDs may not impede senile plaque formation, they may delay or prevent clinical symptoms by limiting the associated inflammation.

As mentioned above, RAGE has been shown to mediate the interaction of amyloid and glial cells, producing cellular activation and an inflammatory response with cytokine production, chemotaxis, and haptotaxis. The expression of this receptor appears to be upregulated in neurons, vasculature, and microglia in affected regions of AD brains.

The unrelated class A scavenger receptor (class A SR) also mediates the adhesion of microglial cells to amyloid fibrils. SPs contain high concentrations of microglia that express class A SRs. RAGE and class A SRs may represent novel pharmacologic targets for diminishing the inflammatory and oxidative reactions associated with AD.

Clusterin

Clusterin, a plasma protein, plays an important role in the pathogenesis of AD. In one study, clusterin was associated with atrophy of the entorhinal cortex, baseline disease severity, and rapid clinical progression in AD. This important study suggests that alterations in amyloid chaperone proteins could be a relevant peripheral signature of AD.[24] A study by Schrijvers et al notes that although plasma clusterin levels are significantly associated with baseline prevalence and severity of AD, they are not related to the risk for AD.[25]

Presenilins

A significant proportion of early-onset autosomal-dominant AD cases have been linked to a candidate gene on chromosome 14 (14q24.3) called presenilin-1 (PS1) and a candidate gene on chromosome 1 called presenilin-2 (PS2). The 2 putative products of these candidate genes, PS1 and PS2, share substantial amino-acid and structural similarities, suggesting that they may be functionally related. In addition, the expression patterns of PS1 and PS2 in the brain are similar, if not identical.

Both PS1 messenger RNA (mRNA) and PS2 mRNA are detectable only within neuronal populations. Immunochemical analyses indicate that PS1 localizes to intracellular compartments, such as the endoplasmic reticulum and the Golgi complex, that are involved in similar functions. Evidence supports the role of presenilins in Ab metabolism. Mice deficient in the expression of PS1 exhibit a dramatic decrease in proteolytic cleavage of the transmembrane domain of amyloid precursor protein (APP) by secretase.

PS1 is immunoreactive with the neuritic component of SPs. Both asymptomatic and demented subjects carrying the PS1 mutation have increased production of the amyloidogenic Ab 42/43 isoform in skin fibroblasts and plasma. Prominent deposition of Ab 42/43 is found in many brain regions of patients with PS1 mutations. These findings, in suggesting that inhibiting presenilin function might decrease Ab amyloid production, offer new therapeutic avenues.

Estrogen loss

Postmenopausal women are at higher risk than men for AD. Some studies have shown that estrogen loss may lead to cognitive decline and neuronal degeneration, and the expression of nerve growth factor and brain-derived neurotrophic factor mRNA is also decreased.

Estrogen has also been shown to exert cytoprotective effects and to prevent amyloid toxicity in human neuroblastoma cell cultures. However, a randomized clinical trial of estrogen in cognitively normal women aged 65 years and older with a first-degree relative with AD showed that estrogen therapy might actually increase the risk of stroke and dementia.[26]

Etiology

The cause of AD is unknown. Several investigators now believe that converging environmental and genetic risk factors trigger a pathophysiologic cascade that, over decades, leads to Alzheimer pathology and dementia.[27]

The following risk factors for Alzheimer-type dementia have been identified:[28, 29, 30, 31]

  • Advancing age

  • Family history

  • APOE 4 genotype

  • Obesity

  • Insulin resistance

  • Vascular factors

  • Dyslipidemia

  • Hypertension

  • Inflammatory markers

  • Down syndrome

  • Traumatic brain injury

Midlife hypertension is an established risk factor for late-life dementia, of which AD is the most common type. A brain autopsy study evaluating the link between hypertension and AD found that patients using beta-blockers to control blood pressure had fewer Alzheimer's-type brain lesions on autopsy compared to patients taking no drug therapy or those taking other medications.[32]

In addition, epidemiologic studies have suggested some possible risk factors such as aluminum[33, 34]  and previous depression[35] . Other studies have suggested protective factors (e.g.,education[36, 37] , long-term use of nonsteroidal anti-inflammatory drugs[38] ). 

Genetic causes

Although most cases of AD are sporadic (ie, not inherited), familial forms of AD do exist. Autosomal dominant AD, which accounts for less than 5% of cases, is almost exclusively early onset AD; cases occur in at least 3 individuals in 2 or more generations, with 2 of the individuals being first-degree relatives.[39]

Familial clustering represents approximately 15–25% of late-onset AD cases and most often involves late-onset AD. In familial clustering, at least 2 of the affected individuals are third-degree relatives or closer.[39]

Mutations in the following genes unequivocally cause early-onset autosomal dominant AD:

  • The amyloid precursor protein (APP) gene on chromosome 21

  • The presenilin-1 (PS1) gene on chromosome 14

  • The presenilin-2 (PS2) gene on chromosome 1

All 3 of these genes lead to a relative excess in the production of the stickier 42-amino acid form of the Ab peptide over the less sticky 40-amino-acid form.

This beta-pleated peptide is postulated to have neurotoxic properties and to lead to a cascade of events (as yet incompletely understood) that results in neuronal death, synapse loss, and the formation of NFTs and SPs, among other lesions. Nonetheless, the mutations that have been found to date account for less than half of all cases of early-onset AD.

Other than the apolipoprotein E epsilon 4 (APOE E4) genotype, no polymorphisms in other genes have been consistently found to be associated with late-onset AD. However, genome-wide association studies have identified the following additional susceptibility loci[40] :

  • Clusterin (CLU) gene

  • Phosphatidylinositol-binding clathrin assembly protein (PICALM) gene

  • Complement receptor 1 (CR1) gene

  • ATP-binding cassette sub-family A member 7 gene (ABCA7)

  • Membrane-spanning gene cluster (MS4A6A/MS4A4E)

  • Ephrin receptor A1 (EPHA1)

  • CD33

  • CD2AP

APP mutations

The observation that patients with Down syndrome (trisomy 21) develop cognitive deterioration and typical pathological features of AD by middle age led to the discovery of the APP gene on chromosome 21. Simultaneously, a locus segregating with a minority of early-onset familial AD kindreds was mapped to this chromosome, in the same region as the APP gene. For more information, see the Medscape Reference article Alzheimer Disease in Down Syndrome.

Subsequently, several missense mutations within the APP gene that resulted in amino acid substitutions in APP were identified in these familial AD kindreds. Such mutations appear to alter the previously described proteolytic processing of APP, generating amyloidogenic forms of Ab.

Skin fibroblasts from individuals carrying APP mutations produce increased Ab 42/43. Increased plasma concentration of Ab 42/43 is also seen in these patients, regardless of age, sex, or clinical status. Interestingly, some patients with sporadic AD may exhibit similar elevations of plasma Ab 42/43.

PS1 and PS2 mutations

Approximately 50-70% of early-onset autosomal-dominant AD cases appear to be associated with a locus (AD3) mapped by genetic linkage to the long arm of chromosome 14 (14q24.3). Numerous missense mutations have been identified on a strong candidate gene, called PS1.

At the same time, another autosomal dominant locus responsible for early-onset AD was localized to chromosome 1. Two mutations were identified on the candidate gene, designated PS2. The physiological role of presenilins and the pathogenic effects of their mutations are not yet well understood.

APOE

The gene encoding the cholesterol-carrying apolipoprotein E (APOE) on chromosome 19 has been linked to increased risk for AD, principally late-onset but also some early-onset cases. The gene is inherited as an autosomal codominant trait with 3 alleles. The APOE E2 allele, the least prevalent of the 3 common APOE alleles, is associated with the lowest risk of developing AD,[41] with a lower rate of annual hippocampal atrophy and higher cerebrospinal fluid Aβ and lower phosphotau, suggesting less AD pathology.[42]

The E3 allele confers intermediate risk of developing AD, with less risk than the E4 allele. The E3 allele, which is more common than the E2 allele, may protect tau from hyperphosphorylation, and the E2 allele’s effect on tau phosphorylation is complex.

APOE E4 gene “dose” is correlated with increased risk and earlier onset of AD.[43] Individuals who are genetically predisposed to AD are advised to closely control their blood pressure closely. Hypertension has been shown to interact with APOE E4 genotype to increase amyloid deposition in cognitively healthy middle-aged and older adults; controlling hypertension may significantly decrease the risk of developing amyloid deposits, even in those with genetic risk.[44, 45]

Persons with 2 copies of the APOE E4 allele (4/4 genotype) have a significantly greater risk of developing AD than persons with other APOE subtypes. Mean age at onset is significantly lower in the presence of 2 APOE E4 copies. A collaborative study has suggested that APOE E4 exerts its maximal effect before the age of 70 years.

Many APOE E4 carriers do not develop AD, and many patients with AD do not have this allele. Therefore, the presence of an APOE E4 allele does not secure the diagnosis of AD, but instead, the APOE E4 allele acts as a biologic risk factor for the disease, especially in those younger than 70 years.

According to one study, exposure to particulate matter (PM) in the ambient air and its interactions with APOE alleles may contribute to the acceleration of brain aging and the pathogenesis of AD. In addition to examining experimental mouse models, researchers analyzed data on more than 3,600 US women between the ages of 65 and 79 years from 48 states. None of the women had dementia when the study began. Data show that residing in places with fine PM exceeding EPA standards increased the risks for global cognitive decline and all-cause dementia respectively by 81 and 92%, with stronger adverse effects in APOE ε4/4 carriers. These joint data from humans and mice provide the first evidence that neurodegenerative effects of airborne PM may involve gene-environment interactions with APOE ε4.[46]

Insulin resistance

A small study by Baker et al implies that insulin resistance, as evidenced by decreased cerebral glucose metabolic rate measured by a specific type of positron emission tomography (PET) scan, may be useful as an early marker of AD risk, even before the onset of MCI.[47] The PET scan revealed a qualitatively different activation pattern in patients with prediabetes or type 2 diabetes mellitus during a memory encoding task, as compared with healthy individuals who were not insulin resistant.

Although the study by Baker et al had too few subjects (n=23) for the results to reach statistical significance, a study by Schrijvers et al in a much larger population (3,139 subjects) found a similar association between insulin resistance and AD over 3 years, which then disappeared after that time.[48] These researchers used a different measure of insulin resistance, the homeostasis model assessment. Disturbances in insulin metabolism may not cause neurological changes but may influence and accelerate these changes, leading to an earlier onset of AD.

Infection

An emerging field of research suggests a significant association between AD and chronic infection with various species of spirochetes, including the periodontal pathogen Treponemas and Borrelia burgdorferi, as well as pathogens such as herpes simplex virus type 1.[49] In vitro and animal studies support the concept of infection resulting in chronic inflammation and neuronal destruction. Ab has been shown to be an antimicrobial peptide, so its accumulation might represent a response to infection.

Depression

Depression has been identified as a risk factor for AD and other dementias. Recent Framingham data have helped bolster the epidemiological association. The study showed a 50% increase in AD and dementia in those who were depressed at baseline.[50] During a 17-year follow-up period, a total of 21.6% of participants who were depressed at baseline developed dementia, as compared with 16.6% of those who were not depressed.

In another related study, recurrent depression was noted to be particularly pernicious. One episode of depression conferred an 87–92% increase in dementia risk, while having 2 or more episodes nearly doubled the risk.[51]

According to the results of a meta-analysis of 23 population-based, prospective cohort studies, late-life depression is associated with an increased risk for all-cause dementia, vascular dementia, and AD.[52, 53] The risk for vascular dementia appeared to be significantly higher than the risk for AD. The analysis included data on patients 50 years and older who were free of dementia at baseline. The total sample included in the pooled analysis for all-cause dementia was 49,612 participants, 5116 of whom had late-life depression.

Alternatively, a large, longitudinal study found that depression that starts early in life increases the risk for AD. Researchers used data from the Prospective Population Study of Women in Gothenburg Sweden, which began in 1968. The study sample included 800 women (mean age, 46 years), born between 1914 and 1930, who were followed up with in 1974, 1980, 1992, 2000, 2009, and 2012. Data show those women who experienced the onset of depression before age 20 years were three times more likely to develop AD (adjusted HR, 3.41; 95% CI, 1.78 - 6.54).[35]

Head trauma

Moderate to severe head trauma has been documented as a risk factor for the development of AD as well as other forms of dementia later in life.[54] Chen et al have proposed that traumatic brain injury leads to accumulation of amyloid precursor protein with its proteolytic enzymes at sites of axonal injury, increased intracellular production of Ab, release of Ab from injured axons into the extracellular space, and deposition of Ab into extracellular plaques.[55]

A study that followed over 7,000 US veterans of World War II showed that those who had sustained head injuries had twice the risk of developing dementia later in life, with veterans who suffered more severe head trauma being at an even higher risk. The study also found that the presence of the APOE gene and sustaining head trauma seemed to act additively to increase the risk of developing AD, although there was no direct correlation.[56]

Epigenetics

Epigenetics is a change in gene expression that results from gene-environment interactions. This is mediated by DNA methylation, RNA editing, and RNA interference without changes in the DNA sequence. Epigenetic elements in AD are suggested by facts that the majority of cases of AD are sporadic, occur in patients without a family history of the disease, and have onset late in life.

One environmental factor that has shown damage in laboratory animals consistent with human AD is lead. Early exposure to lead in monkeys resulted in plaque formation as they aged.[57] One aspect of early lead exposure appears to be increased oxidative stress in brain cells. Oxidative stress is the accumulation of excess free radicals that alter methylation patterns in the cells.

Early oxidative stress other than lead has been postulated as one cause of sporadic AD. Brain cells in AD exhibit overexpression and repression of AD genes, suggesting hypomethylation and hypermethylation, which are associated with oxidative stress.[58]

Given that lead exposure to animals in early life does not produce manifestations until later in life, continued environmental stress may contribute to expression. Consequently, it is possible that the use of antioxidant supplements starting in childhood might decrease long-term oxidative stress and decrease the incidence of AD. The work of Harman indicates that antioxidants may decrease cell damage and aging by decreasing excess oxidative stress.[59]

The only major study of one antioxidant, vitamin E, yielded disappointing results. However, the study involved a very limited time usage. At present no other changes in environmental exposures have been studied for prevention of AD, but this area will be critical in future long-term studies.

Epidemiology

United States statistics

According to a 2017 report, AD affects an estimated 6.08 million people in the United States, and approximately 200,000 people younger than 65 years with AD constitute the younger-onset US population with AD.[10, 8]  A larger number of individuals have decreased cognitive function (eg, mild cognitive impairment); this condition frequently evolves into full-blown dementia, thereby increasing the number of affected persons. By the year 2050, AD could affect 13.8 million persons in the United States.[10]

Using data from Rochester, Minnesota, Genin et al calculated that at the age of 85 years, the lifetime risk of AD without reference to APOE genotype was 11% in males and 14% in females; for APOE 4/4 carriers, risk ranged from 51% for males to 60% for females. For APOE 3/4 carriers, risk ranged from 23% for males to 30% for females. In French incidence data, lifetime risk for females at age 85 was 68% for APOE 4/4 carriers and 35% for APOE 3/4 carriers.[60]

In the United States, AD is a leading cause of death. While deaths from other major causes have been decreasing, deaths from of AD have been rising.[10] AD was the sixth leading cause of death in 2017.[10, 61, 62] Moreover, AD as an underlying cause of death is frequently underreported.[63]

International statistics

Prevalence rates of AD similar to those in the United States have been reported in industrialized nations. The prevalence of dementia in persons 65 years of age and older in North America is approximately 6-10%, with AD accounting for two-thirds of these cases. If milder cases are included, the prevalence rates double. Countries experiencing rapid increases in the elderly segments of their population have rates approaching those in the United States.

The World Health Organization’s review in 2000 on the Global Burden of Dementia,[64] which was an integrative analysis of 47 surveys across 17 countries, suggested that approximate rates for dementia from any cause are under 1% in persons aged 60-69 years, rising to about 39% in persons 90-95 years old. The prevalence doubles with every 5 years of age within that range, with few differences taking into account secular changes, age, gender, or place of living.

AD has become nearly twice as prevalent as vascular dementia (VaD) in Korea, Japan, and China since the early 1990s. American and European studies consistently reported AD to be more prevalent than VaD. The dementia prevalence rate was found to be 11.2 per 1,000 among Chinese aged 50 years and older on the islet of Kinmen. AD accounted for 64.6% and VaD for 29.3%. These results, together with previous studies in Chinese populations, suggest that the rates of AD in the Chinese are low compared with those in whites.

In Nigeria, the prevalence of dementia was found to be low. Indian studies have been contradictory, with both AD and VaD being more prevalent in different studies.

Age distribution for Alzheimer disease

The prevalence of AD increases with age. AD is most prevalent in individuals older than 60 years. Some forms of familial early-onset AD can appear as early as the third decade, but familial cases constitute less than 10% of AD overall.

More than 90% of cases of AD are sporadic and occur in individuals older than 60 years. Of interest, however, results of some studies of nonagenarians and centenarians suggest that the risk may decrease in individuals older than 90 years. If so, age is not an unqualified risk factor for the disease, but further study of this matter is needed.

Savva et al found that in the elderly population, the association between dementia and the pathological features of AD (eg, neuritic plaques, diffuse plaques, tangles) is stronger in persons 75 years of age than in persons 95 years of age. These results were achieved by assessing 456 brains donated to the population-based Medical Research Council Cognitive Function and Ageing Study from persons 69-103 years of age at death.[65]

Studies have demonstrated that the relationship between cerebral atrophy and dementia persist into the oldest ages but that the strength of association between pathological features of AD and clinical dementia diminishes. It is important to take age into account when assessing the likely effect of interventions against dementia.

Sexual differences in incidence

Some studies have reported a higher risk of AD in women than in men; other studies, however, including the Aging, Demographics, and Memory Study, found no difference in risk between men and women.[66] Almost two thirds of Americans with AD are women.[10] Among AD patients overall, any sexual disparity may simply reflect women’s higher life expectancy. Among those who are heterozygous for the APOE E4 allele, however, Payami et al found a twofold increased risk in women.[67]

Race-related differences in incidence

AD and other dementias are more common in African Americans than in whites. According to the Alzheimer’s Association, in the population aged 71 years and older, African Americans are almost twice as likely to have AD and other dementias as whites (21.3% of African Americans vs 11.2% of whites). The number of Hispanic patients studied in this age group was too small to determine the prevalence of dementia in this population.

Based on data for Medicare beneficiaries age 65 and older, 6.9% of whites, 9.4% of African Americans, and 11.5% of Hispanics have AD or other dementias, and the prevalence of AD and other dementias is higher in older age groups.[10]

In a study of 1255 people, including both African American (N=173) and Caucasian participants, researchers found that cerebrospinal fluid from African Americans tended to contain lower levels of brain protein tau, a biomarker associated with AD. However, this did not seem to protect them from the disease; they were just as likely as Caucasians to be cognitively impaired in this study. These results suggest that analysis of biomarkers for AD should be adjusted for race.[68]

Prognosis

AD is initially associated with memory impairment that progressively worsens. Over time, patients with AD can also display anxiety, depression, insomnia, agitation, and paranoia. As their disease progresses, patients with AD come to require assistance with basic activities of daily living, including dressing, bathing, and toileting. Eventually, difficulties with walking and swallowing may develop. Feeding may be possible only by gastrointestinal tube, and difficulty swallowing may lead to aspiration pneumonia.

The time from diagnosis to death varies from as little as 3 years to as long as 10 or more years. Patients with early-onset AD tend to have a more aggressive, rapid course than those with late-onset AD. The primary cause of death is intercurrent illness, such as pneumonia.

Patient Education

When counseling patients following a diagnosis of AD, it is essential to involve the patient’s family and others who will play a supporting role in the discussion. It is important to emphasize that not only the patient but also those who support the patients will likely experience reactions of sadness and anger and that these are normal reactions to such a diagnosis.

As the patient’s symptoms become more pronounced, a dialogue must be opened regarding the patient’s wishes for care when he or she is no longer able to make the necessary choices. Durable power of attorney should be discussed, with particular attention to who will make decisions for both medical and financial issues. Medical advance directives should be considered while the patient is still able to participate in the decision-making process.

Throughout the course of the disease, family members should be careful to select qualified and trustworthy individuals to be involved in the day-to-day management of the patient. Caregivers need to balance attention to the patient’s physical needs with maintaining respect for the patient as a competent adult, to the extent allowed by the progression of the disease. Any suspicions of elder abuse should be immediately addressed.

Above all, counseling of AD patients and families should emphasize that patients should continue to engage in activities that they enjoy doing. Maintaining an optimal quality of life is key.

The following resources may be helpful to share with patients and their families:

  • MedlinePlus -Alzheimer’s Disease

  • The National Institute on Aging -General Information on Alzheimer’s Disease

  • Caring for Someone with Alzheimer’s (video series)

  • The National Alzheimer’s Association

For patient education information, see the Dementia Center ,as well as Alzheimer Disease, Alzheimer Disease in Individuals With Down Syndrome, Dementia Overview, and Dementia Medication Overview

 

Presentation

History

Patients with Alzheimer disease (AD) most commonly present with insidiously progressive memory loss, to which other spheres of cognition are impaired over several years. This loss may be associated with slowly progressive behavioral changes. After memory loss occurs, patients may also experience language disorders (eg, anomic aphasia or anomia) and impairment in their visuospatial skills and executive functions.

Patients with mild AD usually have somewhat less obvious executive, language, and/or visuospatial dysfunction. In atypical presentations, dysfunction in cognitive domains other than memory may be most apparent. In later stages, many patients develop extrapyramidal dysfunction including akathisia, parkinsonism, dystonia, bradykinesia, tremor, and tardive dyskinesia.

Substantially less common, but biopsy or autopsy-proven, presentations include right parietal lobe syndrome, progressive aphasia, spastic paraparesis, and impaired visuospatial skills, which is subsumed under the visual variant of AD.

It is important to obtain a complete history not only from the patient but also from someone who knows the patient well. In addition, a family history of AD or other forms of dementia should be noted.

Here are some key points to keep in mind when taking history of a patient with suspected AD:

  • Many patients with AD lack insight into impairments and may even deny deficits.
  • Early in the course of AD, patients may have preserved insight into the course of their ailment with preserved social and occupational functioning.
  • It is important to characterize the onset and early symptoms to differentiate other pathologies that are more abrupt, such as vascular dementia.
  • Obtaining a good assessment of the patient's functional abilities often is aided by a knowledgeable informant.
  • One may divide functional abilities into basic and instrumental activities of daily living (ADLs). Basic ADLs (BADLs) include activities for self-mantainence such as grooming, whereas instrumental ADLs (IADLs) are more complex tasks such as paying bills.

Physical Examination

At the time of initial diagnosis, a complete physical examination, including a detailed neurologic examination and a mental status examination, should be performed to evaluate disease stage and rule out comorbid conditions. Initial mental status testing should include evaluation of the following:

  • Attention and concentration

  • Recent and remote memory

  • Language

  • Praxis (ie, ability to perform skilled motor tasks without nonverbal prompting)

  • Executive function

  • Visuospatial function

Cognitive features of early AD include memory loss, mild anomic aphasia, and visuospatial dysfunction. At all subsequent follow-up visits, a full mental status examination should be performed to evaluate disease progression and identify the development of any new neuropsychiatric symptoms.

Brief standardized examinations, such as the Mini-Mental Status Examination (MMSE), are less sensitive and specific than longer batteries that are specifically tailored to individual patients. Other examples include the Montreal Cognitive Assessment (MoCA) and the Saint Louis University Mental Status (SLUMS) examination. Nonetheless, screening exams have a role, particularly as a baseline. For more information, see the Medscape Reference article Screening for Cognitive Impairment.

A complete neurologic examination is performed to look for signs of other diseases that could cause dementia, such as Parkinson disease or multiple strokes. In patients with AD, the neurologic exam is generally normal but may reveal minor abnormalities such as hyposmia or anosmia.

Stages of Alzheimer Disease

AD can be classified into the following stages:

  • Preclinical

  • Mild

  • Moderate

  • Severe

Preclinical Alzheimer disease

The pathologic changes associated with AD begin in the entorhinal cortex, which is near the hippocampus and directly connected to it. AD then proceeds to the hippocampus, which is the structure that is essential to the formation of short-term and long-term memories (see the images below). Affected regions begin to atrophy. These brain changes occur decades before any signs or symptoms appear.

Memory loss, the first visible sign, is the main feature of amnestic mild cognitive impairment (MCI). Many scientists think MCI is often an initial, transitional clinical phase between normal brain aging and AD. For more information, see the Medscape Reference article Mild Cognitive Impairment.

Preclinical Alzheimer disease. Image courtesy of N Preclinical Alzheimer disease. Image courtesy of NIH.
Preclinical Alzheimer disease. Image courtesy of N Preclinical Alzheimer disease. Image courtesy of NIH.

A patient with preclinical AD may appear completely normal on physical examination and mental status testing. At this stage, there is normally no alteration in judgment or the ability to perform activities of daily living.

Mild Alzheimer disease

As AD begins to affect the cerebral cortex, memory loss continues and impairment of other cognitive abilities emerges. This stage is referred to as mild AD. The clinical diagnosis of AD is usually made during this stage. Signs of mild AD can include the following:

  • Memory loss

  • Confusion about the location of familiar places (getting lost begins to occur)

  • Taking longer to accomplish normal daily tasks

  • Trouble handling money and paying bills

  • Compromised judgment often leading to bad decisions

  • Loss of spontaneity and sense of initiative

  • Mood and personality changes; increased anxiety

The growing number of plaques and tangles first damage areas of the brain that control memory, language, and reasoning (see the images below). Later in the disease, physical abilities decline. This leads to a situation in mild AD in which a person seems to be healthy but is actually having more and more trouble making sense of the world around him or her. The realization that something is wrong often comes gradually because the early signs can be confused with changes that can happen normally with aging.

Mild Alzheimer disease. The disease begins to affe Mild Alzheimer disease. The disease begins to affect the cerebral cortex, memory loss continues, and changes in other cognitive abilities emerge. The clinical diagnosis of AD is usually made during this stage. Image courtesy of NIH.
Mild-to-moderate Alzheimer disease. Image courtesy Mild-to-moderate Alzheimer disease. Image courtesy of NIH.

Acknowledging these signs of AD and deciding to seek diagnostic testing can be a hurdle for patients and their families to cross. In many cases, the family has a more difficult time handling the diagnosis than the patient does, probably because of apathy from the AD. Following the initial diagnosis, patients should be carefully monitored for depressed mood. Although it is common for patients with early AD to be depressed about the diagnosis, they rarely become suicidal.

Moderate Alzheimer disease

By the time AD reaches the moderate stage, damage has spread further to the areas of the cerebral cortex that control language, reasoning, sensory processing, and conscious thought. Affected regions continue to atrophy, and signs and symptoms of the disease become more pronounced and widespread. Behavior problems, such as wandering and agitation, can occur. More intensive supervision and care become necessary, and this can be difficult for many spouses and families.

The symptoms of this stage can include the following:

  • Increasing memory loss and confusion

  • Shortened attention span

  • Problems recognizing friends and family members

  • Difficulty with language; problems with reading, writing, working with numbers

  • Difficulty organizing thoughts and thinking logically

  • Inability to learn new things or to cope with new or unexpected situations

  • Restlessness, agitation, anxiety, tearfulness, wandering, especially in the late afternoon or at night

  • Repetitive statements or movement; occasional muscle twitches

  • Hallucinations, delusions, suspiciousness or paranoia, irritability

  • Loss of impulse control (shown through behavior such as undressing at inappropriate times or places or vulgar language)

  • Perceptual-motor problems (such as trouble getting out of a chair or setting the table)

Behavior is the result of complex brain processes, all of which take place in a fraction of a second in the healthy brain. In AD, many of these processes are disturbed, and this is the basis for many distressing or inappropriate behaviors. For example, patients may angrily refuse to take a bath or get dressed because they do not understand what the caregiver has asked them to do. If they do understand, they may not remember how to do what was asked.

This anger is a mask for underlying confusion and anxiety. Consequently, the risk for violent and homicidal behavior is highest at this stage of disease progression. Patients should be carefully monitored for any behavior that may compromise the safety of those around them.

For a person who cannot remember the past or anticipate the future, the world around them can be strange and frightening. Staying close to a trusted and familiar caregiver may be the only thing that makes sense and provides security. A person with AD may constantly follow his or her caregiver and fret when the person is out of sight.

Judgment and impulse control continue to decline at this stage. For example, taking off clothes may seem reasonable to a person with AD who feels hot and does not understand or remember that undressing in public is not acceptable.

Severe Alzheimer disease

In the last stage, severe AD, plaques and tangles are widespread throughout the brain, and areas of the brain have atrophied further (see the images below). Patients cannot recognize family and loved ones or communicate in any way. They are completely dependent on others for care. All sense of self seems to vanish.

Severe Alzheimer disease. In the last stage of AD, Severe Alzheimer disease. In the last stage of AD, plaques and tangles are widespread throughout the brain, and areas of the brain have atrophied further. Patients cannot recognize family and loved ones or communicate in any way. They are completely dependent on others for care. All sense of self seems to vanish. Image courtesy of NIH.
Severe Alzheimer disease. Image courtesy of NIH. Severe Alzheimer disease. Image courtesy of NIH.

Other symptoms can include the following:

  • Weight loss

  • Seizures, skin infections, difficulty swallowing

  • Groaning, moaning, or grunting

  • Increased sleeping

  • Lack of bladder and bowel control

In end-stage AD, patients may be in bed much or all of the time. Death is often the result of other illnesses, frequently aspiration pneumonia.

Clinical Guidelines for Diagnosis

Clinical guidelines for the diagnosis of AD have been formulated by the National Institutes of Health-Alzheimer’s Disease and Related Disorders Association (NIH-ADRDA); the American Psychiatric Association, in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM5); and the Consortium to Establish a Registry in Alzheimer’s Disease (CERAD). In 2011, the National Institute on Aging (NIA) and the Alzheimer’s Association (AA) workgroup released new research and clinical diagnostic criteria for AD.[69]

The NIH-ADRDA criteria for the diagnosis of AD require the finding of a slowly progressive memory loss of insidious onset in a fully conscious patient. AD cannot be diagnosed in patients with clouded consciousness or delirium. Toxic metabolic conditions and brain neoplasms must also be excluded as potential causes of the patient’s dementia.

The focus of the 2011 NIA-AA criteria is the need to create a more accurate diagnosis of preclinical disease so that treatment can begin before neurons are significantly damaged, while they are more likely to respond. Therefore, the report includes criteria for diagnosis of the following:

  • Asymptomatic, preclinical AD (for purposes of research, not clinical diagnosis)[70]

  • Mild cognitive impairment (MCI), an early symptomatic but predementia phase of AD[71]

  • AD dementia[72]

The Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, released in 2013, replaces the term dementia with major neurocognitive disorder and mild neurocognitive disorder. The new terms focus on a decline, rather than a deficit, in function.

In order to meet the DSM5 criteria for AD, the individual must meet the criteria for major or mild neurocognitive disorder and there should be insidious onset and gradual progression of impairment in one or more cognitive domains (for major neurocognitive disorder, at least two domains must be impaired). The individual must also meet criteria for either probable or possible AD as outlined in the DSM5.[73]

 

DDx

Diagnostic Considerations

Depression

Depression is an important consideration in the differential diagnosis of Alzheimer disease (AD). The clinical manifestations of depression overlap with those of AD. The term pseudodementia refers to the appearence of cognitive dysfunction (dementia) due to depression. In addition, an estimated 30–50% of AD patients have comorbid depression.[74]

Depression in patients with AD appears to differ from depression in cognitively intact elderly patients. Depression in AD more often features motivational disturbances (eg, fatigue, psychomotor slowing, apathy), whereas depression in geriatric patients without cognitive impairment tends to feature mood symptoms (eg, depressed mood, anxiety, suicidality, sleep and appetite disturbances).[74]

Commonly used instruments for assessing depression (eg, Hamilton Scale for Depression, Beck Depression Inventory, Geriatric Depression Scale) were designed for use in other patient populations and may be less reliable in patients with AD. Consequently, the National Institute of Mental Health has developed provisional diagnostic criteria for depression in AD.[74]

Chronic traumatic encephalopathy

Repetitive head trauma has long been recognized as a cause of brain degeneration in boxers (ie, dementia pugilistica). More recently, progressive degenerative brain disease (chronic traumatic encephalopathy [CTE]) has been recognized in athletes with a history of multiple concussions, as well as milder blows to the head that do not cause concussion.[75] Neuropathologically confirmed CTE has been reported in retired professional football and hockey players and other athletes with a history of repeated head injuries.

Pathological hallmarks of CTE, which may not appear until long after the end of active athletic involvement, include the following[76] :

  • Tau-positive neurofibrillary tangles (NFTs) in the neocortex, concentrated around penetrating parenchymal vessels

  • Neuropil threads

  • Neocortical diffuse amyloid plaques, with or without neuritic plaques

  • Sparing of the hippocampus

The distribution of NFTs in CTE differs markedly from that in normal aging and AD, in which there is early involvement of the entorhinal cortex and hippocampus with later involvement of the neocortex in advanced stages.

The symptoms of CTE may include the following[76] :

  • Recurrent headaches

  • Dizziness

  • Mood disorders

  • Aggression

  • Impaired judgment and impulse control

  • Parkinsonian movement disorders

  • Progressive dementia

For more information, see the Medscape Reference article Repetitive Head Injury Syndrome.

Other disorders

Other disorders to consider in the differential diagnosis of AD include the following:

  • Age-associated memory impairment

  • Alcohol or drug abuse

  • Depression

  • Vitamin B12 deficiency

  • Cerebrovascular disease (and vascular dementia)

  • Hearing or visual impairment

  • Hypernatremia

  • Hypoglycemia

  • Hypothyroidism or hyperthyroidism

  • Lewy body dementia

  • Normal pressure hydrocephalus

  • Parkinson's disease with dementia

  • Polypharmacy

  • Volume depletion

  • Wernicke-Korsakoff Syndrome

Differential Diagnoses

 

Workup

Approach Considerations

Alzheimer disease (AD) is a clinical diagnosis. However, ancillary imaging studies (eg, computed tomography [CT]; magnetic resonance imaging [MRI]; single-photon emission CT [SPECT]; or positron emission tomography [PET]) and laboratory tests may be used. These tests help exclude other possible causes for dementia (eg, cerebrovascular disease, cobalamin [vitamin B12] deficiency, syphilis, thyroid disease).

Diagnostic criteria established by the National Institute on Aging (NIA) and the Alzheimer’s Association are intended principally to facilitate research. However, the NIA-AA also proposed “core clinical criteria” for diagnosis of mild cognitive impairment (MCI) by health care providers without access to cerebrospinal fluid (CSF) testing or advanced imaging.[71] The NIA-AA criteria for diagnosis of dementia due to AD are clinical, with biomarkers in an assisting, nonessential role.[72]

Blood Studies

Laboratory tests can be performed to rule out other conditions that may cause cognitive impairment. Current recommendations from the American Academy of Neurology (AAN) include measurement of the cobalamin (vitamin B12) level and a thyroid function screening test. Additional investigations are left up to the physician, to be tailored to the particular needs of each patient. Initial test results that require further investigation include the following:

  • Abnormalities in complete blood cell count and cobalamin (vitamin B12) levels require further workup to rule out hematologic disease

  • Abnormalities found in screening of liver enzyme levels require further workup to rule out hepatic disease

  • Abnormalities in thyroid-stimulating hormone (TSH) levels require further workup to rule out thyroid disease

  • Abnormalities in rapid plasma reagent (RPR) require further workup to rule out syphilis

  • Abnormalities in HIV serology and/or PCR require further workup to rule out HIV/AIDS

  • Abnormalities in paraneoplastic antibodies require further workup to rule out autoimmune encephalitis

  • Abnormalities in CSF proteins tau, P-tau, and 14-3-3 require further workup to rule out Creutzfeldt-Jakob disease

There is a possible link between vitamin D deficiency and cognitive impairment.[77, 78] However, vitamin D deficiency has not been identified as a reversible cause of dementia.

Brain MRI or CT Scanning

American Academy of Neurology (AAN) recommendations indicate that structural neuroimaging with either a noncontrast computed tomography (CT) scan or magnetic resonance image (MRI) is appropriate in the initial evaluation of patients with dementia, in order to detect lesions that may result in cognitive impairment (eg, stroke, small vessel disease, tumor).

Imaging studies are particularly important for ruling out potentially treatable causes of progressive cognitive decline, such as chronic subdural hematoma or normal-pressure hydrocephalus.[1] In patients with AD, brain MRIs or CT scans can show diffuse cortical and/or cerebral atrophy, but these findings are not diagnostic of AD.

In clinical research studies, atrophy of the hippocampi (structures important in mediating memory processes) on coronal MRI is considered a valid biomarker of AD neuropathology. Nonetheless, measurement of hippocampal volume is not used in routine clinical care in the diagnosis of AD.

A study by Chen et al suggests that resting state functional MRI can help classify patients with AD, patients with amnestic mild cognitive impairment (MCI), and cognitively healthy patients.[79] Default mode network (DMN) imaging appears to distinguish AD, MCI, and controls well, and it may complement positron emission tomography (PET) scanning or prove to be more sensitive.[80]

A study by McMillan et al suggests that MRI may provide a reasonably accurate, noninvasive surrogate for cerebrospinal fluid (CSF) biomarkers, reducing the need for lumbar puncture in discriminating AD from frontotemporal lobar degeneration (FTLD).[81, 82] The investigators derived a structural brain pattern from MRI that predicts the ratio of total tau to β-amyloid in CSF, to discriminate AD from FTLD. In this way, they were able to differentiate between the 2 dementia types 75% of the time.[81, 82]

Other investigators have suggested that MRI plus biomarkers may be key to finding early AD.[83, 84] In a cross-sectional, longitudinal cohort study of 207 older adults with normal cognition, investigators found a correlation between decay in the DMN, as observed on resting-state functional connectivity MRI (rs-fcMRI), and levels of 2 CSF biomarkers of early AD. This suggests that rs-fcMRI may be an effective noninvasive means of detecting early asymptomatic AD.[83, 84]

In the study, Ances and colleagues reported that decreases in DMN integrity had an independent association with reductions in CSF amyloid beta 42 and increases in CSF phosphorylated tau181.[83, 84] Moreover, the posterior cingulate cortex and the medial temporal lobe, 2 regions that are frequently impacted by AD, were found to have the most prominent decreases in functional connectivity.

For more information, see the Medscape Reference article Imaging of Alzheimer Disease.

SPECT or PET scanning

Brain scanning with SPECT or PET (see the image below) is not recommended for the routine workup of patients with typical presentations of AD. These modalities may be useful in atypical cases or when a form of frontotemporal dementia is a more likely diagnosis.[85]

Image courtesy of NIH. Image courtesy of NIH.

The Amyloid Imaging Taskforce (AIT), an assembly of experts from the Alzheimer's Association and the Society of Nuclear Medicine and Molecular Imaging (SNMMI), developed guidelines for the use of amyloid β (Aβ) positron emission tomography (PET) imaging to clarify diagnoses of AD or frontotemporal dementia. The guidelines outline 3 scenarios in which determining amyloid positivity or negativity would increase the level of diagnostic certainty and alter patient management.

According to the guidelines, amyloid imaging is appropriate in patients with persistent or progressive unexplained mild cognitive impairment, in those satisfying core clinical criteria for possible AD because of unclear clinical presentation, and in patients with progressive dementia and atypically early age of onset. The committee recommends against imaging in asymptomatic individuals and patients with a clear AD diagnosis with typical age of onset. Scanning cannot be used to stage dementia or determine its severity, and it should not be used in lieu of genotyping for suspected autosomal mutation carriers.[86]

Florbetapir F 18 (AMYViD) was approved by the FDA in April 2012 as a diagnostic imaging agent. It is indicated for PET brain imaging of beta-amyloid neuritic plagues in adults being evaluated for Alzheimer disease or other cognitive decline.[87, 88, 89]

Approval for florbetapir F 18 was based on 3 clinical studies that examined images from healthy adult patients as well as patients with a range of cognitive disorders, including some terminally ill patients who had agreed to participate in a postmortem brain donation program. Measurements from postmortem cortical amyloid burden correlated with median florbetapir F 18 scores.[90]

In a study by Clark et al, the presence and density of beta amyloid correlated closely in individuals who had florbetapir-PET imaging within 99 days before death and then upon autopsy.[91] Patients with probably Alzheimer disease, mild cognitive impairment, or older healthy controls showed significantly different mean cortical florbetapir uptake value ratios in a study by Fleisher et al.[92]

In October 2013, the FDA approved a second 18F-labeled Pittsburgh compound B (PIB) derivative, flutemetamol F18 injection (Vizamyl), for use with PET brain imaging in adults undergoing evaluation for Alzheimer disease and dementia. Like florbetapir F18, flutemetamol F18 attaches to beta-amyloid in the brain and produces a PET image that can be used to assess its presence. A positive scan indicates there is likely a moderate or greater amount of amyloid in the brain, but it does not establish a diagnosis of Alzheimer disease or other dementia. The effectiveness of flutemetamol F18 was established in 2 clinical studies with 384 participants who had a range of cognitive function.[93]

A third agent, florbetaben F18 (Neuraceq), was approved by the FDA in March 2014. Images may be obtained between 45-130 minutes following the injected dose. FDA approval was based on safety data from 872 patients who participated in global clinical trials as well as 3 studies that examined images from adults with a range of cognitive function, including 205 end-of-life patients who had agreed to participate in a post-mortem brain donation program. Images were analyzed from 82 subjects with post-mortem confirmation of the presence or absence of beta-amyloid neuritic plaques.[94]

A study of 129 cognitively normal adults aged 65-87 years (mean, 73.7 years) indicated that a combination of memory tests and brain imaging may help to identify the earliest stages of AD, before symptoms appear.[95] The investigators found that poor episodic memory in the context of synaptic dysfunction and elevated amyloid identified subjects who were at high risk for progression to AD dementia.

Subjects in this study underwent testing of memory and executive function along with fluorine-18 fluorodeoxyglucose positron emission tomography (FDG-PET) scanning and amyloid deposition with C 11 Pittsburgh Compound B (PiB PET).[95] The researchers found that amyloid burden and lower FDG metabolism (synaptic dysfunction) independently predicted episodic memory performance. Subjects with worse memory performance had higher PiB deposition and lower FDG metabolism in regions of the brain commonly affected in AD.

For more information, see the Medscape Reference article Imaging of Alzheimer Disease.

Electroencephalography

Electroencephalography (EEG) is valuable when Creutzfeldt-Jakob disease or other prion-related disease is a likely diagnosis (see EEG in Dementia and Encephalopathy). Periodic high-amplitude sharp waves can eventually be detected in most cases of Creutzfeldt-Jakob disease.

EEG is also useful if pseudodementia is a realistic consideration when a normal EEG in a patient who appears profoundly demented would support that diagnosis. Multiple unwitnessed seizures rarely can present as dementia, and an EEG would be valuable for evaluating such a possibility.

Lumbar Puncture

Perform lumbar puncture in select cases to rule out conditions such as normal-pressure hydrocephalus or central nervous system infection (eg, neurosyphilis, neuroborreliosis, cryptococcosis).

CSF levels of tau and phosphorylated tau are often elevated in Alzheimer disease (AD), whereas amyloid levels are usually low. The reason for this is not known, but perhaps amyloid levels are low because the amyloid is deposited in the brain rather than the CSF. By measuring both proteins, sensitivity and specificity of at least 80%—and more often 90%—can be achieved.

In May 2022, the FDA approved the first in vitro diagnostic test for early detection of AD. The test measures the ratio of β-amyloid 1-42 and β-amyloid 1-40 concentrations in CSF. A positive test result is consistent with the presence of amyloid plaques, similar to that revealed in a PET scan. A negative result is consistent with a negative amyloid PET scan result.[96]

At present, however, routine measurement of CSF tau and amyloid is not recommended except in research settings. Lumbar puncture for measurement of tau and amyloid may become part of the diagnostic workup when effective therapies that slow the rate of progression of AD are developed, particularly if the therapies are specific for AD and carry significant morbidity.

 

Genotyping

Genotyping for apolipoprotein E (APOE) alleles is a research tool that has been helpful in determining the risk of AD in populations, but until recently it was of little, if any, value in making a clinical diagnosis and developing a management plan in individual patients. Numerous consensus statements have recommended against using APOE genotyping for predicting AD risk.[39]

Investigators from the Copenhagen General Population Study and the Copenhagen City Heart Study have reported that plasma levels of APOE epsilon 4 (APOE ε4) are associated with the risk of dementia, independent of the APOE genotype.[97, 98] The risk of Alzheimer disease increased with decreasing levels of APOE levels, with a highly significant 3-fold increased risk for the lowest tertile of APOE levels relative to the highest tertile—an association that remained even after adjusting for the APOE genotype.[97, 98] The APOE genotypes with highest risks of Alzheimer disease were ε43 and ε44, whereas those with the lowest risks were ε22, ε32, ε42, and ε33.[98]

Concern has previously been expressed that in asymptomatic individuals, genetic testing that identifies increased risk may trigger an untoward psychological response. However, in a trial of the effect of disclosing APOE genotyping results to 162 asymptomatic adults who had a parent with AD, Green et al found that follow-up testing over the course of a year showed no significant differences with disclosure versus nondisclosure on time-averaged measures of anxiety, depression, or test-related distress.[99] Test-related distress was reduced in those who learned that they did not carry the APOE E4) allele. Persons who had high levels of emotional distress before undergoing genetic testing were more likely to have emotional difficulties after disclosure.[99]

Genetic testing for APP and presenilin mutations

According to guidelines from the American College of Medical Genetics and the National Society of Genetic Counselors, testing for the APP and presenilin genes associated with early-onset autosomal dominant AD should be offered in the following situations[39] :

  • In symptomatic patients with early-onset AD who have a family history of dementia or an unknown family history (eg, because of adoption)

  • In persons with a family history of autosomal dominant dementia with one or more cases of early-onset AD

  • In relatives with a mutation consistent with early-onset AD (ie, PS-1, PS-2,APP)

Before undergoing testing, patients should receive appropriate counseling on the predictive value of genetic testing for AD. Afterward, patients should receive counseling on the implications of the results. Recommendations on pre- and post-test counseling are detailed in the guidelines from the American College of Medical Genetics and the National Society of Genetic Counselors.[39]

 

Treatment

Approach Considerations

To date, only symptomatic therapies for Alzheimer disease (AD) are available and thus do not act on the evolution of the disease. All drugs approved by the US Food and Drug Administration (FDA) for the treatment of AD modulate neurotransmitters, either acetylcholine or glutamate. The standard medical treatment for AD includes cholinesterase inhibitors (ChEIs) and a partial N -methyl-D-aspartate (NMDA) antagonist.[3, 4]

Secondary symptoms of AD (eg, depression, agitation, aggression, hallucinations, delusions, sleep disorders) can be problematic. Behavioral symptoms are common and can exacerbate cognitive and functional impairment. The following classes of psychotropic medications have been used to treat these secondary symptoms[5] :

  • Antidepressants

  • Anxiolytics

  • Antiparkinsonian agents

  • Beta-blockers

  • Antiepileptic drugs (for their effects on behavior)

  • Neuroleptics

  • Amyloid-directed antibody

Most studies of psychotropic drugs for AD have demonstrated no or limited efficacy. However, many issues make interpretation of data from these studies difficult.

Current pharmacologic research in AD focuses principally on the development of disease-modifying drugs that can slow or reverse the progression of AD. Targets of these investigational agents have included beta-amyloid production, aggregation, and clearance, as well as tau phosphorylation and assembly. To date, none of these drugs has demonstrated efficacy in phase III trials.[100]  However, a 2018 phase II study showed promising results for an antiamyloid agent in patients with early-stage AD. The study included 856 patients with early AD (mild cognitive impairment due to AD or mild AD dementia) and amyloid pathology confirmed by positron-emission tomography (PET) or cerebral spinal fluid (CSF) tracer. The agent, BAN2401, was found to significantly reduce brain amyloid at high doses. The study also showed a dose-dependent, statistically significant, and clinically meaningful slower decline in cognition and function with the highest dose compared to placebo.[101]

Potential surgical treatments in the future may include the use of devices to infuse neurotrophic factors, such as growth factors, to palliate AD.

Hospitalization should be considered for any unstable medical condition that may complicate the patient’s treatment. If the patient becomes a danger to him/herself or others, short-term hospitalization may be indicated to facilitate ruling out infectious and metabolic processes and adjusting psychotropic medications. The most common reason for admission to a long-term care facility is the need for 24-hour supervision that cannot be given at home and/or caregiver stress/burnout.

Treatment of Mild to Moderate Disease

Early diagnosis and treatment allows AD patients to maintain the highest levels of cognitive and functional ability possible. Cholinesterase inhibitors (ChEIs) and mental exercises are used in an attempt to prevent or delay the deterioration of cognition in patients with AD.

Cholinesterase inhibition

Numerous lines of evidence suggest that cholinergic systems that modulate information processing in the hippocampus and neocortex are impaired early in the course of AD. These observations have suggested that some of the clinical manifestations of AD are due to loss of cholinergic innervation to the cerebral cortex.

Centrally acting ChEIs prevent the breakdown of acetylcholine. Three such agents have been approved by the FDA for the treatment of AD, as follows:

  • Donepezil (Aricept, Aricept ODT)

  • Rivastigmine (Exelon, Exelon Patch)

  • Galantamine (Razadyne, Razadyne ER)

All ChEIs have shown modest benefit on measures of cognitive function and activities of daily living. Patients on ChEIs have shown slower declines on cognitive and functional measures than patients on placebo. However, ChEIs do not address the underlying cause of the degeneration of cholinergic neurons, which continues during the disease. The ChEIs may also alleviate the noncognitive manifestations of AD, such as agitation, wandering, and socially inappropriate behavior.[102]

Although the usefulness of ChEIs was originally expected to be limited to the early and intermediate stages of AD (because the cholinergic deficit becomes more severe later in disease and because fewer intact cholinergic synapses are present), they are also helpful in advanced disease.[103] ChEIs are also helpful in patients with AD with concomitant infarcts and in patients with dementia with Lewy bodies. Frequently, AD and dementia with Lewy bodies occur in the same patient; this is sometimes called the Lewy body variant of AD.

The ChEIs share a common profile of adverse effects, the most frequent of which are nausea, vomiting, diarrhea, and dizziness. These are typically dose related and can be mitigated with slow up-titration to the desired maintenance dose. In addition, gastrointestinal side effects may be reduced by using the transdermal patch rather than the oral form of the drug. As antimuscarinic drugs are used for the treatment of incontinence, logically, ChEIs might exacerbate incontinence. One brief report has supported this hypothesis.[104]

ChEIs prescribed to treat dementia can provoke symptomatic bradycardia and syncope and precipitate fall-related injuries, including hip fracture. In a study of older adults with dementia who were taking cholinesterase inhibitors, hospital visits for syncope were found to be more frequent in patients receiving ChEIs than in control patients (31.5 vs 18.6 events per 1000 person-years).[105] Other syncope-related events, including hospital visits for bradycardia, permanent pacemaker insertion, and hip fracture, were also found to be more common in patients receiving cholinesterase inhibitors. ChEI use in older adults with dementia is associated with increased risk of syncope-related events; these risks must be weighed against the benefits of taking ChEIs.[105]

Anecdotal reports exist of acute cognitive and behavioral decline associated with the abrupt termination of ChEIs. In several of these cases, restarting the ChEI did not lead to substantial improvement. These reports have implications concerning the best practice when switching a patient from one ChEI to another in this class. Reasons for switching might include undesirable side effects or an apparent lack of efficacy. Nonetheless, no published data are available to help clinicians know when it would be helpful to switch to another ChEI.

The common practice of tapering a patient off one CNS-active medication before starting a new one should not be followed when changing ChEIs. For example, a patient who was taking 10 mg of donepezil should be started the next day on galantamine at a dose of at least 8 mg/day and possibly 16 mg/day. No current evidence supports the use of more than 1 ChEI at a time. Centrally acting anticholinergic medications should be avoided.

It is not uncommon for patients to receive both ChEIs and anticholinergic agents, which counteract each other. Medications with anticholinergic effects, such as diphenhydramine, tricyclic antidepressants (eg, amitriptyline, nortriptyline), and oxybutynin (commonly used for bladder spasticity), can cause cognitive dysfunction. Therefore, a careful listing of the patient’s medications is important so that the physician can reduce the doses of, or ideally eliminate, all centrally acting anticholinergic agents.

Mental activity to support cognition

Many patients with normal cognition or those with mild impairment are concerned that they may develop AD. Many experts believe that mentally challenging activities, such as doing crossword puzzles and brainteasers, may reduce the risk in such patients. Whether such activities might slow the rate of disease progression in patients who already have AD is not known. Clinical trials are under way to determine the effect these cognitive activities have on AD progression.

Mental activities should be kept within a reasonable level of difficulty. Activities should preferably be interactive, and they should be designed to allow the patient to recognize and correct mistakes. Most important, these activities should be administered in a manner that does not cause excessive frustration and that ideally motivates the patient to engage in them frequently. Unfortunately, little standardization or rigorous testing has been done to validate this treatment modality.

Some investigators have attempted various forms of cognitive retraining, also known as cognitive rehabilitation. The results of this approach remain controversial, and a broad experimental study needs to be performed to determine whether it is useful in AD.

Treatment of Moderate to Severe Disease

The partial N-methyl-D-aspartate (NMDA) antagonist memantine (Namenda, Namenda XR) is believed to work by improving the signal-to-noise ratio of glutamatergic transmission at the NMDA receptor. Blockade of NMDA receptors by memantine is thought to slow the intracellular calcium accumulation and thereby help prevent further nerve damage. This agent is approved by the FDA for treating moderate and severe AD.

Several studies have demonstrated that memantine can be safely used in combination with ChEIs. The combination of memantine with a ChEI has been shown to significantly delay institutionalization in AD patients.[106] Studies suggest that the use of memantine with donepezil affects cognition in moderate to severe AD[107] but not in mild to moderate AD.[108, 109]  A once-daily, fixed-dose combination of memantine extended-release (ER) and donepezil (Namzaric) was approved by the FDA in 2014.[110] Dizziness, headache, and confusion are some of the most common side effects of memantine.

In June 2013, the FDA approved rivastigmine transdermal for severe AD.[111] Approval was based on the ACTION (ACTivities of Daily Living and CognitION in Patients with Severe Dementia of the Alzheimer's Type) study, in which a higher dose of the drug (13.3 mg/24 hr) demonstrated statistically significant improvement in overall cognition and function compared with a lower dose (4.6 mg/24 hr).[112]

Treatment of Secondary Symptoms

A variety of behavioral and pharmacologic interventions can alleviate clinical manifestations of AD, such as anxiety, agitation, depression, psychotic behavior, and sleep problems. The effectiveness of such interventions ranges from modest and temporary to excellent and prolonged. No specific agent or dose of individual agents is unanimously accepted for the wide array of clinical manifestations. At present, the FDA has not approved any psychotropic agent for the treatment of AD.

Behavioral interventions

Behavioral interventions range from patient-centered approaches to caregiver training to help manage cognitive and behavioral manifestations of AD. These interventions are often combined with the more widely used pharmacologic interventions, such as anxiolytics for anxiety and agitation, neuroleptics for delusions or hallucinations, and antidepressants or mood stabilizers for mood disorders and specific manifestations (eg, episodes of anger or rage).

A French study found that a psychoeducational program for AD patients’ primary caregivers provided the caregivers with more effective understanding of the disease and better coping ability. However, the program had no effect on patients' activities of daily living.[113]

Neuroleptic agents

In 2005, the FDA added a black-box warning on the use of atypical neuroleptics in the treatment of secondary symptoms of AD such as agitation.[114] Analyses suggested that patients on atypical neuroleptics had increased risk of death or stroke compared with patients on placebo. In 2008, a black-box warning was included on haloperidol, prochlorperazine, thioridazine, and chlorpromazine for the same reason.

A pilot study in AD patients with psychosis or agitation that responded to haloperidol treatment found that discontinuation of the drug after 6 months was associated with a higher risk of relapse. The researchers advised that in patients who respond to this antipsychotic medication, the increased risk of relapse after discontinuation needs to be weighed against the side effects associated with continuing the medication.[115]

Another concern is the risk that these agents may contribute to cognitive decline. The Clinical Antipsychotic Trials of Intervention Effectiveness-Alzheimer's Disease study (CATIE-AD) found that the atypical antipsychotics olanzapine, quetiapine, and risperidone were associated with worsening cognitive function at a magnitude consistent with 1 year's deterioration.[116]

The general recommendation is to use such agents as infrequently as possible and at the lowest doses possible to minimize adverse effects, particularly in frail, elderly patients. Particular concern has been raised about the potential for dopamine-depleting agents to aggravate the motor manifestations of dementia with Lewy bodies (DLB), because patients with DLB may be extremely sensitive to these agents.

Antidepressants and mood modulators

Antidepressants have an important role in the treatment of mood disorders in patients with AD. Depression is observed in more than 30% of patients with AD, and it frequently begins before AD is clinically diagnosed. Therefore, palliation of this frequent comorbid condition may improve cognitive and noncognitive performance.

Nyth found citalopram to be beneficial in mood and other neuropsychiatric symptoms in patients in the moderate stage of AD.[117] Because citalopram can cause dose-dependent increases in the QT interval, the FDA recommends using a maximum of 40 mg a day and considering 20 mg a day in the elderly.[118]

In a randomized, placebo-controlled study in 186 patients with probable AD and clinically significant agitation, treatment with 30 mg of citalopram daily reduced agitation and caregiver distress. However, citalopram also increased the risk of adverse cardiac events and slightly reduced cognition, which the study authors note may limit its practical application. In addition, while the study was being conducted the FDA issued an advisory warning that citalopram can prolong the QT interval and older patients should not use doses greater than 20 mg.[119, 120, 121]

Weintraub et al[122] and Petracca et al[123] found sertraline and fluoxetine to have no short- or long-term benefit in mood over placebo. Similarly, Banerjee et al found that treatment of depression with sertraline or mirtazapine provided no benefit compared with placebo and increased the risk of adverse events.[124]

In a randomized, placebo-controlled study of 30 AD patients with sleep disturbances, patients treated with trazodone (50 mg) slept an average of 42.5 minutes more per night compared with those treated with placebo, an increase of 8.5%. Daytime sleepiness or naps and cognition or functionality were not affected by either trazodone treatment or placebo.[125, 126]

Other mood modulators, such as valproic acid, can be helpful for the treatment of disruptive behaviors and outbursts of anger, which patients with moderately advanced or advanced stages of AD may have.

Results of several studies indicate that anticonvulsants (eg, gabapentin, valproic acid) may have a role in the treatment of behavioral problems in patients with Alzheimer disease. However, a trial of 313 patients with moderate AD found that 24 months of treatment with valproate did not delay emergence of agitation or psychosis, did not slow cognitive or functional decline, and was associated with significant toxic effects.[127]

Other agents

A 2016 meta-analysis of seven studies demonstrated prolonged total sleep time at night with melatonin, however, without improvement in cognitive abilities assessed by the mini-mental state examination and the Alzheimer's Disease Assessment Cognitive Subscale.[128]  

Research on the effects of prescribing hypnotics such as zolpidem, zopiclon, or zaleplon to treat sleep problems in dementia patients found that these so-called Z drugs significantly increase fracture risk. In the study, at two-year follow-up, overall fracture risk increased by 40% and the risk for hip fracture by 59%.[129]

Suppression of Brain Inflammation

Many studies have suggested that intense inflammation occurs in the brains of patients with AD. Epidemiologic studies suggest that some patients on long-term anti-inflammatory therapy have a decreased risk of developing AD. Nonetheless, no randomized clinical trial longer than 6 months has demonstrated efficacy of anti-inflammatory drugs in slowing the rate of progression of AD.

Although previous reports reflect delayed onset of AD in individuals who used nonsteroidal anti-inflammatory drugs (NSAIDs), a study by Breitner et al showed that NSAIDs do not protect against AD, at least in very old people. Relying on computerized pharmacy dispensing records and biennial dementia screening, these investigators found that AD incidence was increased in heavy NSAID users. These findings may represent deferral of AD symptoms from earlier to later old age.[130]

Experimental Therapies

A variety of experimental therapies have been proposed for AD. These include antiamyloid therapy, reversal of excess tau phosphorylation, estrogen therapy, vitamin E therapy, and free-radical scavenger therapy. Studies of these therapies have yielded mostly disappointing results.

In the past 10 years, numerous antiamyloid therapy studies have been conducted to decrease toxic amyloid fragments in the brain, including studies of the following:

  • Vaccination with amyloid species

  • Administration of monoclonal antiamyloid antibodies

  • Administration of intravenous immune globulin that may contain amyloid-binding antibodies

  • Selective amyloid-lowering agents

  • Chelating agents to prevent amyloid polymerization

  • Brain shunting to improve removal of amyloid

  • Beta-secretase inhibitors to prevent generation of the A-beta amyloid fragment

To date, no phase III study of antiamyloid therapies has shown a combination of acceptable efficacy and side effects.

Growing awareness that tau is a central player in AD pathogenesis has suggested that this protein may offer an avenue for therapeutic intervention. Studies are ongoing with agents that may prevent or reverse excess tau phosphorylation and thereby diminish formation of neurofibrillary tangles.[131]

Free-radical scavenger therapy has also attracted attention, because excess levels of free radicals in the brain are neurotoxic. Nonetheless, no study has demonstrated efficacy of free-radical scavengers in the treatment of the cognitive symptoms of AD.

Various studies indicate that oxidative stress may be a part of the pathogenesis of AD. In the Alzheimer’s Disease Cooperative Study, high-dose vitamin E (2000 units per day of alpha-tocopherol) for 2 years slowed the progression of disease in patients with moderate AD.[132] This benefit presumably resulted from the antioxidant effects of vitamin E.

Similarly, a trial in 613 patients with mild to moderate AD found that a daily 2000 IU dose of vitamin E slowed functional decline. In the study, patients were randomly assigned to treatment with vitamin E alone, a combination of vitamin E and memantine, or placebo. Over the mean followup of 2.27 years, patients treated with vitamin E alone demonstrated a delay in clinical progression of 19% per year compared with placebo.[133, 134]

In addition, increases in caregiver time, as measured on the Caregiver Activity Scale, were lowest in the vitamin E group compared with the other groups. No benefit was observed for memantine or combined treatment with memantine and vitamin E.[133, 134]

Other studies, however, have suggested that vitamin E supplementation may increase risk of adverse cardiovascular outcomes. Therefore, use of vitamin E is not currently recommended.

Despite in vitro evidence of a protective effect of estrogen, no data show that women with AD who are placed on estrogen therapy (ET) have fewer symptoms or progress more slowly than women treated with placebo. Furthermore, a randomized clinical trial of estrogen in cognitively normal women aged 65 years and older with a first-degree relative with AD showed that ET might actually increase the risk of stroke and dementia.[26] Whether ET might decrease risk if started well before age 65 years is not known.

Elevated cholesterol levels are a risk factor for AD, and epidemiologic data suggest that the use of statins may reduce this risk. However, a trial of simvastatin in patients with mild to moderate AD and normal lipid levels found that although statin treatment significantly lowered cholesterol levels, it did not slow the progression of symptoms.[135]

Transcranial magnetic stimulation (TMS) has been used to identify therapeutic targets in AD and to monitor the effects of pharmacologic agents, and both TMS and transcranial direct current stimulation are being explored for a possible therapeutic role in AD. However, evidence of therapeutic benefit from these modalities is highly preliminary.[136]

Aducanumab (Aduhelm) is the first amyloid-directed antibody to be granted accelerated FDA approval for the treatment of Alzheimer disease in patients with mild cognitive impairment (MCI) or mild dementia stage of disease.

Approval was based on three separate double-blind, randomized, placebo-controlled, dose-ranging studies in patients with Alzheimer disease. One of the endpoints was the reduction of amyloid beta plaque in the brain. Amyloid beta plaque was quantified using PET imaging to estimate the brain levels of amyloid beta plaque in a composite of brain regions expected to be widely affected by Alzheimer disease pathology. Treated patients had significant dose- and time-dependent reduction of amyloid beta plaque, while patients in the control arm of the studies had no reduction of amyloid beta plaque. Continued approval is contingent upon verification of clinical benefit in confirmatory trial(s). By granting market authorization, the FDA diverged from the recommendation against approval by its own Peripheral and Central Nervous System Drugs Advisory Committee. Debate continues around the approval, post-marketing studies beyond biomarkers to clinical effectiveness, and targeted patient population for treatment.[137, 138, 139]

Presymptomatic disease-modifying therapy

Disease-modifying therapies would delay the onset of AD and/or slow the rate of progression. Since brain changes associated with AD probably start decades before dementia becomes clinically apparent, many investigators believe that disease-modifying therapies are much more likely to be effective if they are started in a presymptomatic stage.

Neuropsychological, neuroimaging, and genetic methods are identifying patients at increased risk. Although phase III trials for several potential disease-modifying therapies have been completed, none of these agents have shown clear efficacy and therefore have not yet been approved by the FDA.

Dietary Measures

There are no special dietary considerations for Alzheimer disease. However, caprylidene (Axona) is a prescription medical food that is metabolized into ketone bodies, and the brain can use these ketone bodies for energy when its ability to process glucose is impaired. Brain-imaging scans of older adults and persons with AD reveal dramatically decreased uptake of glucose. A study of 152 patients with mild to moderate AD found that at day 45, Alzheimer’s Disease Assessment Scale–cognitive subscale (ADAS-Cog) scores stabilized in the caprylidene group but declined in the placebo group.[140]

The ADAS-Cog change from baseline score was also analyzed for apolipoprotein E (APOE) E4 genotype. The APOE E4-negative patients receiving caprylidene showed improved cognitive function when compared with APOE E4-negative patients receiving placebo. In APOE E4-positive patients, the mean change in ADAS-Cog total scores for the 2 groups was essentially identical at all time points, with more patients showing decline rather than improvement at days 45 and 90.[140]

A novel lifestyle intervention may reverse cognitive decline in AD patients. In a study of 10 patients with memory loss associated with either AD, mild cognitive impairment, or subjective cognitive impairment, researchers found that a personalized comprehensive lifestyle intervention tailored to address metabolic deficits identified on laboratory testing as affecting the plasticity of the patient's brain improved memory loss.[141, 142] Cognition subjectively or objectively improved in 9 of the 10 patients within 3 to 6 months.[141, 142]

Although interventions were tailored to each patient, they all included elimination of simple carbohydrates from the diet, increased consumption of fruit, vegetables, and non-farmed fish, and adherence to a strict meal pattern with timed periods of fasting. All interventions also included an exercise program, counseling on stress reduction techniques, and use of a variety of daily supplements, including vitamin D3, fish oil, coenzyme Q10, melatonin, and methylcobalamin. Female patients were advised to resume previously discontinued hormone replacement therapy when appropriate.[141, 142]

Physical Activity

Routine physical activity and exercise may have an impact on AD progression and may perhaps have a protective effect on brain health.[6] Increased cardiorespiratory fitness levels are associated with higher hippocampal volumes in patients with mild AD, suggesting that cardiorespiratory fitness may modify AD-related brain atrophy.[7]

The activity of each patient should be individualized. The patient’s surroundings should be safe and familiar. Too much activity can cause agitation, but too little can cause the patient to withdraw and perhaps become depressed. Maintaining structured routines may be helpful to decrease patient stress in regard to meals, medication, and other therapeutic activities aimed at maintaining cognitive functioning.

The patient needs contact with the outside environment. The physician should encourage participation in activities that interest the patient and result in cognitive stimulation but do not stress the patient. The range of possibilities is wide and may include visits to museums, parks, or restaurants.

Prevention of Alzheimer Disease

There are no proven modalities for preventing AD.[3] Evidence, largely epidemiologic, suggests that healthy lifestyles can reduce the risk of AD. Physical activity, exercise, and cardiorespiratory fitness may be protective.[6, 7]

In a 44-year longitudinal population study of Swedish women, researchers found that a high cardiovascular fitness in midlife was associated with a decreased risk of subsequent dementia. Data show women with high fitness levels had an 88% lower risk of developing dementia compared with women who were moderately fit in midlife. Additionally, when the highly fit women did develop dementia, they developed the disease an average of 11 years later than women who were moderately fit.[143]

A French study of 8,085 nondemented participants aged 65 years and older found that frequent consumption of fruits and vegetables, fish, and omega-3 rich oils may decrease the risk of dementia and AD, especially in APOE E4 noncarriers.[144]

Although no definitive dietary recommendations can be made, in general, nutritional patterns that appear beneficial for AD prevention fit the Mediterranean diet. Following this type of diet, along with recommendations for physical activity, has the added benefit of lowering the risk of cardiovascular and metabolic disorders.[145]

Animal studies suggest that diets low in calories benefit cognitive function in old age. A German study of 50 healthy, normal-weight to overweight elderly patients found that 3 months of calorie restriction (30% reduction) resulted in a significant increase in verbal memory scores, which was correlated with decreases in fasting plasma levels of insulin and high sensitive C-reactive protein.[146] The effect of calorie reduction on memory was most pronounced in patients with best adherence to the diet.

Light to moderate alcohol consumption has been linked to reduced risk of development of AD.[147] In contrast, a Finnish study found that abstainers, heavy drinkers, and binge drinkers had an increased risk of cognitive impairment when compared to light to moderate drinkers.[148] Among abstainers, however, increased risk was limited to subjects who did not carry the APOE E4 allele.

Heavy drinking is the strongest potentially modifiable risk factor for dementia, according to a retrospective analysis involving 30 million people in France. Data from the study show that those with a history of alcohol use disorders had a threefold increased risk for dementia and that over half those with early-onset dementia had a history of alcohol problems. Of 57,000 patients who had developed dementia under the age of 65 years, 57% had a history of alcohol use disorders (66% of men and 37% of women).[149]

 

Guidelines

Guidelines Summary

Alzheimer's Association

In 2018, the Alzheimer's Association released the first clinical practice guidelines for the evaluation of cognitive impairment suspected to be a result of Alzheimer's disease and related dementias in both primary care and specialty care settings. The guidelines contain 20 recommendations, 16 of which are classified as "A" recommendations. The primary recommendation is that all middle-aged or older individuals who self-report or for whom their care partner reports cognitive, behavioral, or functional changes undergo a timely multitiered evaluation. Other recommendations emphasize the importance of obtaining a history from the patient and someone who knows the patient well to establish the presence and characteristics of any substantial changes to categorize the cognitive behavioral syndrome, investigate possible causes and contributing factors to arrive at a diagnosis/diagnoses, and appropriately educate, communicate findings and diagnosis, and ensure ongoing management, care, and support.[150]  

 

Medication

Medication Summary

The mainstay of therapy for patients with Alzheimer disease (AD) is the use of centrally acting cholinesterase inhibitors to attempt to compensate for the depletion of acetylcholine (ACh) in the cerebral cortex and hippocampus. A partial N-methyl-D-aspartate (NMDA) antagonist is approved for treatment of moderate and severe AD. Various medications are used for treatment of secondary symptoms of AD, including antidepressants, anti-anxiety agents, and antipsychotic agents.

Cholinesterase Inhibitors

Class Summary

Cholinesterase inhibitors (ChEIs) are used to palliate cholinergic deficiency. All 4 currently approved ChEIs (ie, donepezil, rivastigmine, galantamine) inhibit acetylcholinesterase (AChE) at the synapse (specific cholinesterase).

Rivastigmine also inhibits butyrylcholinesterase (BuChE). Although BuChE levels may be increased in AD, it is not clear that rivastigmine has greater clinical efficacy than donepezil and galantamine.

Galantamine has a different second mechanism of action; it is also a presynaptic nicotinic modulator. No data exist to indicate that this second mechanism is of clinical importance.

Donepezil (Aricept, Aricept ODT)

Donepezil is indicated for the treatment of dementia of the Alzheimer type. Donepezil has shown efficacy in patients with mild to moderate AD, as well as moderate to severe AD. It selectively inhibits acetylcholinesterase, the enzyme responsible for the destruction of acetylcholine, and improves the availability of acetylcholine. Donepezil's long half-life provides a long duration of drug availability for binding at the receptor sites. There is no evidence to suggest that the underlying disease process of dementia is affected by administration of donepezil.

Dosing recommendations for mild to moderate AD are 5-10 mg given once daily. Patients with moderate to severe AD can be given 10 or 23 mg once daily.

Rivastigmine (Exelon, Exelon Patch)

Rivastigmine PO is indicated for the treatment of mild to moderate dementia of the Alzheimer type. Initial dosing recommendations are 1.5 mg PO BID, with a maximum dose of 12 mg/day PO. Rivastigmine is a potent, selective inhibitor of brain AChE and BChE. Rivastigmine is considered a pseudo-irreversible inhibitor of AChE.

While the precise mechanism of rivastigmine's action is unknown, it is postulated to exert its therapeutic effect by enhancing cholinergic function. This is accomplished by increasing the concentration of acetylcholine through reversible inhibition of its hydrolysis by cholinesterase.

The transdermal patch 13.3 mg/24 h is approved for all stages of Alzheimer disease, including severe. Dose titration is needed when initiating.

Galantamine (Razadyne, Razadyne ER)

Galantamine is indicated for the treatment of mild to moderate dementia of the Alzheimer type. It enhances central cholinergic function and likely inhibits AChE. There is no evidence that galantamine alters the course of the underlying dementing process. The dosing recommendation for the immediate-release formulation is 4 mg twice daily. The extended-release formulation is given at a dose of 8 mg once daily. The maintenance dose after dose titration is 16-24 mg/day.

Donepezil transdermal (Adlarity)

Donepezil transdermal is a reversible acetylcholinesterase inhibitor. It is the first patch to continuously deliver consistent doses of donepezil through the skin. The FDA approved the transdermal system for the treatment of mild, moderate, or severe Alzheimer dementia.

N-Methyl-D-Aspartate Antagonists

Class Summary

The only drug in the N -methyl-D-aspartate (NMDA) antagonist class that is approved by the US Food and Drug Administration is memantine. This agent may be used alone or in combination with AChE inhibitors.

Memantine (Namenda, Namenda XR)

Namenda is approved for the treatment of moderate to severe dementia in patients with AD. The initial dose for the immediate-release formulation is 5 mg once daily, and it can be titrated to a maximum dose of 20 mg/day. The initial dose for the extended-release formulation is 7 mg once daily, and it can be titrated to a maximum dose of 28 mg/day.

Combination Drugs

Class Summary

Combination products may aid in ease of administration (decreased pill burden) and enhance compliance.

Memantine/donepezil (Namzaric)

Fixed dose combination capsule containing memantine extended-release and donepezil for patients with moderate-to-severe Alzheimer disease currently stabilized on donepezil 10 mg once daily. Administer once daily in the evening. Memantine is a NMDA receptor antagonist and donepezil is an acetylcholinesterase inhibitor.

Monoclonal Antibodies, Anti-amyloid Beta

Class Summary

Monoclonal antibodies are being developed that targets beta amyloid and binds to aggregated forms of beta-amyloid to reduce plaques associated with Alzheimer disease.

Aducanumab (Aduhelm)

Aducanumab is a high affinity, fully human IgG1 monoclonal antibody that targets beta amyloid and binds to aggregated forms of beta-amyloid; preferentially binds to parenchymal over vascular amyloid. The FDA granted accelerated approval for aducanumab based on reduction in amyloid beta plaques observed in patients treated for Alzheimer disease. The prescribing information specifies approval for patients with mild cognitive impairment or a mild dementia stage of disease, the population studied in the clinical trials. 

Nutritional Supplement

Class Summary

Medical foods are dietary supplements intended to compensate specific nutritional problems caused by a disease or condition. Caprylidene is a prescription medical food that is metabolized into ketone bodies. The brain can use these ketone bodies for energy when its ability to process glucose is impaired, which brain-imaging scans suggest is the case in AD.

Caprylidene (Axona)

Caprylidene is indicated for clinical dietary management of metabolic processes associated with mild to moderate AD. General dosing recommendations include administering 40 g/day (1 packet of caprylidene powder, containing 20 g of medium-chain triglycerides) during breakfast.

Diagnostic Imaging Agents

Class Summary

Imaging agents that bind to beta amyloid plaque may be useful in the diagnosis of early onset dementia.

Florbetapir F 18 (AMYViD)

Radioactive diagnostic agent for use with PET brain imaging. Binds to beta-amyloid neuritic plaques and the F 18 isotope produces a positron signal that is detected by a PET scanner.

Flutemetamol F 18 (Vizamyl)

Flutemetamol F18 is a radioactive diagnostic agent for use with PET brain imaging. It binds to beta-amyloid neuritic plaques, and the F18 isotope produces a positron signal that is detected by a PET scanner.

Florbetaben F 18 (Neuraceq)

Flutemetamol F18 is a radioactive diagnostic agent for use with PET brain imaging. It binds to beta-amyloid neuritic plaques, and the F18 isotope produces a positron signal that is detected by a PET scanner.

 

Questions & Answers

Overview

What is Alzheimer disease (AD)?

What physical and mental status test findings suggest Alzheimer disease (AD)?

What are signs of mild Alzheimer disease (AD)?

What are the signs and symptoms of moderate Alzheimer disease (AD)?

What are the symptoms of severe Alzheimer disease (AD)?

What are the signs of end-stage Alzheimer disease (AD)?

How is Alzheimer disease (AD) diagnosed?

What is the standard treatment for Alzheimer disease (AD)?

Which psychotropic medications are used to treat secondary symptoms of Alzheimer disease (AD)?

Can Alzheimer disease (AD) be prevented?

What is the prevalence of Alzheimer disease (AD)?

How is Alzheimer disease (AD) diagnosed?

What are the treatment options for Alzheimer disease (AD)?

How was Alzheimer disease (AD) first identified?

What is the role of genetics in the pathogenesis of Alzheimer disease (AD)?

What is the neuroanatomy of Alzheimer disease (AD)?

What is the role of neurofibrillary tangles (NFTs) and senile plaques (SPs) in the pathology of Alzheimer disease (AD)?

How does the pathophysiology of Alzheimer disease (AD) differ from that of normal aging?

How does destruction of nerve cells affect healthy neuron processes in patients with Alzheimer disease (AD)?

Which neuropathological event precedes the clinical onset of Alzheimer disease (AD)?

What is the composition of neurofibrillary tangles (NFTs) in Alzheimer disease (AD)?

What is the composition of senile plaques (SPs) in Alzheimer disease (AD)?

Which brain lesions are associated with Alzheimer disease (AD)?

What is the composition of plaques in Alzheimer disease (AD)?

How do plaques develop in Alzheimer disease (AD)?

How do tangles develop in Alzheimer disease (AD)?

Where do neurofibrillary tangles (NFTs) accumulate in the brain of a patient with Alzheimer disease (AD)?

Where do senile plaques (SPs) accumulate in the brain of a patient with Alzheimer disease (AD)?

When is the presence of neurofibrillary tangles (NFTs) and senile plaques (SPs) suggestive of Alzheimer disease (AD)?

Is low density neurofibrillary tangles (NFTs) suggestive of Alzheimer disease (AD)?

What is the relationship between amyloid deposition and neurofibrillary tangles (NFTs) in the pathogenesis of Alzheimer disease (AD)?

What is the role of beta-amyloid in the pathogenesis of Alzheimer disease (AD)?

Has the amyloid hypothesis for the pathogenesis of Alzheimer disease (AD) been proven?

Which factor may be predictive of Alzheimer disease (AD) severity?

What is the role of granulovacuolar degeneration in the pathogenesis of Alzheimer disease (AD)?

What is the role of the cholinergic system in the pathogenesis of Alzheimer disease (AD)?

What is the role of oxidative damage in the pathogenesis of Alzheimer disease (AD)?

What is the role of oxidative stress in in the pathogenesis of Alzheimer disease (AD)?

What is the role of reactive oxygen species (ROS) in the pathogenesis of Alzheimer disease (AD)?

What is the role of intracellular calcium in the pathogenesis of Alzheimer disease (AD)?

Does blocking the increase in free intracellular calcium decrease neuron injury in Alzheimer disease (AD)?

What is the role of the receptor for advanced glycation end products (RAGE) in the pathogenesis of Alzheimer disease (AD)?

How is receptor for advanced glycation end products (RAGE) expressed in patients with Alzheimer disease (AD)?

What is the role of inflammation and immune processes in the degenerative process in Alzheimer disease (AD)?

Do NSAIDs prevent senile plaque formation in patients with Alzheimer disease (AD)?

What is the role of unrelated class A scavenger receptors (class A SR) in the pathogenesis of Alzheimer disease (AD)?

What is the role of clusterin in the pathogenesis of Alzheimer disease (AD)?

What is the role of presenilin 1 (PS1) and presenilin 2 (PS2) in the neurogenetics of Alzheimer disease (AD)?

How are presenilin 1 (PS1) and presenilin 2 (PS2) detected in patients with Alzheimer disease (AD)?

What properties of presenilin 1 (PS1) may present future treatment options for Alzheimer disease (AD)?

What role does estrogen loss have in the pathogenesis of Alzheimer disease (AD)?

What is the etiology of Alzheimer disease (AD)?

What are the risk factors for Alzheimer disease (AD)?

What is a risk factor for developing Alzheimer disease (AD) in late-life?

What is the role of genetics in the etiology of Alzheimer disease (AD)?

Which genetic mutations cause early-onset autosomal dominant Alzheimer disease (AD)?

Which genes may be etiologic factors for late-onset Alzheimer disease (AD)?

Are patients with Down syndrome at increased risk for Alzheimer disease (AD)?

What is the role of skin fibroblasts in the pathogenesis of Alzheimer disease (AD)?

Does presenilin 1 (PS1) cause early-onset autosomal-dominant Alzheimer disease (AD)?

Do apolipoprotein E (APOE) E2 and E3 alleles increase the risk for Alzheimer disease (AD)?

What is the relationship between hypertension (high blood pressure), apolipoprotein E epsilon 4 (APOE E4) and Alzheimer disease (AD)?

What is the risk of developing Alzheimer disease (AD) in individuals with the apolipoprotein E epsilon 4 (APOE E4) allele?

Does exposure to fine particulate matter (PM) increase the risk for Alzheimer disease (AD)?

What is the role of insulin resistance in the pathogenesis of Alzheimer disease (AD)?

Which infectious agents may increase the risk for Alzheimer disease (AD)?

What is the role of depression in the etiology of Alzheimer disease (AD)?

What is the role of head trauma in the etiology of Alzheimer disease (AD)?

Do epigenetic factors have a role in the etiology of Alzheimer disease (AD)?

Does lead exposure have a role in the etiology of Alzheimer disease (AD)?

Is oxidative stress a possible cause of sporadic Alzheimer disease (AD)?

Do antioxidant supplements prevent Alzheimer disease (AD)?

Is vitamin E effective in the prevention of Alzheimer disease (AD)?

What is the prevalence of Alzheimer disease (AD) in the US?

How does the risk for Alzheimer disease (AD) vary between males and females?

What are the mortality rates of Alzheimer disease (AD) in the US?

What is the prevalence of Alzheimer disease (AD) in industrialized nations?

According to the WHO, how does the prevalence of Alzheimer disease increase after age 60?

What is the global prevalence of Alzheimer disease (AD)?

What is the age distribution for Alzheimer disease (AD)?

What is the relationship between dementia and Alzheimer disease (AD) in individuals older than 95 years?

Are males or females at greater risk for Alzheimer disease (AD)?

Does Alzheimer disease (AD) have a racial predilection?

What is the prognosis for Alzheimer disease (AD)?

What should be the emphasis when counseling patients and their families following a diagnosis of Alzheimer disease (AD)?

What should be discussed with patients as symptoms become more pronounced in Alzheimer disease (AD)?

What should be considered in day-to-day management decisions for patients with Alzheimer disease (AD)?

What resources may be helpful for patients and their families regarding Alzheimer disease (AD)?

Presentation

What is the presentation of Alzheimer disease (AD)?

Who should provide the history for a patient with suspected Alzheimer disease (AD) and what should be noted?

What should be considered when taking the history of a patient with suspected Alzheimer disease (AD)?

What should be included in the initial mental status testing for Alzheimer disease (AD)?

What are the cognitive symptoms of early Alzheimer disease (AD)?

What are standardized mental assessments for Alzheimer disease (AD)?

When is a complete neurologic exam performed in the diagnosis of Alzheimer disease (AD)?

What are the stages of Alzheimer disease (AD)?

What is mild cognitive impairment (MCI) in patients with Alzheimer disease (AD)?

What is the presentation of preclinical Alzheimer disease (AD)?

What are signs and symptoms of mild Alzheimer disease (AD)?

How does mild Alzheimer disease (AD) progress?

What is the expected reaction of patients and families to the initial diagnosis of Alzheimer disease (AD)?

What is the presentation of moderate Alzheimer disease (AD)?

What are the symptoms of moderate Alzheimer disease (AD)?

How does moderate Alzheimer disease (AD) affect behavior?

What may provide a sense of security to patients with Alzheimer disease (AD)?

How are judgement and impulse control affected by moderate Alzheimer disease (AD)?

What is the presentation of severe Alzheimer disease (AD)?

What are secondary symptoms of severe Alzheimer disease (AD)?

What are the signs of end-stage Alzheimer disease (AD)?

What is the official term for dementia in Alzheimer disease (AD) in the DSM-5?

Which organizations have released clinical guidelines for the diagnosis of Alzheimer disease (AD)?

What are the NIH-Alzheimer’s Disease and Related Disorders Association (NIH-ADRDA) criteria for the diagnosis of Alzheimer disease (AD)?

What are the 2011 National Institute on Aging/Alzheimer’s Association (NIA-AA) criteria for the diagnosis of Alzheimer disease (AD)?

What are the DSM-5 criteria for the diagnosis of Alzheimer disease (AD)?

DDX

How is depression diagnosed in patients with Alzheimer disease (AD)?

Which instruments are used for assessing depression in patients with Alzheimer disease (AD)?

How is chronic traumatic encephalopathy (CTE) differentiated from Alzheimer disease (AD)?

How does the distribution of neurofibrillary tangles (NFTs) in CTE differ from that in normal aging and Alzheimer disease (AD)?

What are the symptoms of chronic traumatic encephalopathy (CTE)?

Which disorders should be considered in the differential diagnoses of Alzheimer disease (AD)?

What are the differential diagnoses for Alzheimer Disease?

Workup

What is the role of imaging studies in the diagnosis of Alzheimer disease (AD)?

How are the National Institute on Aging/Alzheimer’s Association (NIA-AA) diagnostic criteria for Alzheimer disease (AD) used?

What are AAN recommendations for lab tests in the evaluation of Alzheimer disease (AD)?

Is vitamin D deficiency a reversible cause of Alzheimer disease (AD)?

What are the AAN recommendations for neuroimaging in the initial evaluation of patients with dementia?

Which biomarker has validity for Alzheimer disease (AD) neuropathology?

What is the role of MRI and default mode network (DMN) imaging in the evaluation of Alzheimer disease (AD)?

What is the efficacy of MRI in the diagnosis of Alzheimer disease (AD)?

What is the efficacy of MRI plus CSF biomarkers for the diagnosis of early Alzheimer disease (AD)?

What default mode network (DMN) imaging findings suggest Alzheimer disease (AD)?

What are the roles of SPECT scanning and PET scanning in the diagnosis of Alzheimer disease (AD)?

What are the Amyloid Imaging Taskforce (AIT) guidelines for the use of amyloid beta PET imaging in the diagnosis of Alzheimer disease (AD)?

What is the role of florbetapir F 18 in the diagnosis of Alzheimer disease (AD)?

What is the efficacy of florbetapir-PET imaging for the diagnosis of Alzheimer disease (AD)?

What is the role of flutemetamol F18 (Vizamyl) in the diagnosis of Alzheimer disease (AD)?

Is florbetaben F18 (Neuraceq) effective for the diagnosis of Alzheimer disease (AD)?

Which tests are effective in identifying Alzheimer disease (AD) before symptoms appear?

What is the role of EEG in the diagnosis of Alzheimer disease?

What is the role of lumbar puncture in the diagnosis of Alzheimer disease (AD)?

What is the role of cerebrospinal fluid (CSF) analysis in the diagnosis of Alzheimer disease (AD)?

What is the role of genetic testing in the diagnosis of Alzheimer disease (AD)?

What is the role of apolipoprotein E (APOE) genotyping in the evaluation of Alzheimer disease (AD)?

What are the concerns regarding genotyping for Alzheimer disease (AD) risk assessment in asymptomatic individuals?

What are the ACMG and the NSGC testing guidelines for genes associated with early onset Alzheimer disease (AD)?

Treatment

What are the treatment options for Alzheimer disease (AD)?

Which medications have been used to treat the secondary symptoms of Alzheimer disease (AD)?

What is the efficacy of psychotropic drugs for Alzheimer disease (AD)?

What pharmacologic research is being conducted for the treatment of Alzheimer disease (AD)?

When is hospitalization indicated in patients with Alzheimer disease (AD)?

What are the benefits of early diagnosis and treatment of Alzheimer disease (AD)?

What is impaired early in the course of Alzheimer disease (AD)?

Which agents have been approved by the FDA for the treatment of Alzheimer disease (AD)?

What is the efficacy of cholinesterase inhibitors (ChEIs) for the treatment of Alzheimer disease (AD)?

What are adverse effects of cholinesterase inhibitors (ChEIs) for the treatment of Alzheimer disease (AD)?

What are the possible adverse effects of abrupt termination of cholinesterase inhibitors (ChEIs) in patients with Alzheimer disease (AD)?

How should changing cholinesterase inhibitors (ChEIs) be handled in patients with Alzheimer disease (AD)?

Should patients with Alzheimer disease (AD) be treated with cholinesterase inhibitors (ChEIs) and anticholinergic agents simultaneously?

Which mental activities may reduce the risk of Alzheimer disease (AD)?

How should mental activities be selected in the treatment of mild Alzheimer disease (AD)?

Is cognitive rehabilitation effective in the treatment for Alzheimer disease (AD)?

How does memantine (Namenda, Namenda XR) work to treat moderate to severe Alzheimer disease (AD)?

Is memantine (Namenda, Namenda XR) effective for the treatment of Alzheimer disease (AD)?

Is rivastigmine transdermal effective in the treatment of severe Alzheimer disease (AD)?

Are psychotropic medications approved by the FDA for the treatment of Alzheimer disease (AD)?

Which behavioral interventions are used in the treatment of Alzheimer disease (AD)?

What are the FDA black-box warnings for the use of atypical neuroleptics in the treatment of secondary symptoms of Alzheimer disease (AD)?

What are the concerns regarding the use of neuroleptic agents for the treatment of secondary symptoms of Alzheimer disease (AD)?

What is the role of neuroleptic agents for the treatment of secondary symptoms of Alzheimer disease (AD)?

What is the role of antidepressants in the treatment of secondary symptoms of Alzheimer disease (AD)?

What is the role of citalopram in the treatment of secondary symptoms of Alzheimer disease (AD)?

Are SSRIs effective in the treatment of secondary symptoms of Alzheimer disease (AD)?

Is trazodone effective for the treatment of sleep disturbances in patients with Alzheimer disease (AD)?

Which agents are used for the treatment of disruptive behaviors in patients with advanced Alzheimer disease (AD)?

What is the role of anticonvulsants in the treatment of Alzheimer disease (AD)?

What other agents have demonstrated prolonged total sleep time at night in patients with Alzheimer disease (AD)?

What is the role of anti-inflammatory drugs in the treatment of Alzheimer disease (AD)?

Which experimental therapies have been proposed for Alzheimer disease (AD)?

Which antiamyloid therapy studies have been conducted for the treatment of Alzheimer disease (AD)?

Are there any therapeutic agents that reverse excess tau phosphorylation in patients with Alzheimer disease (AD)?

Is free-radical scavenger therapy effective therapy for Alzheimer disease (AD)?

What has been found to slow the progression of disease in patients with moderate Alzheimer disease (AD)?

What is the role of estrogen therapy in the treatment of Alzheimer disease (AD)?

What is the role of statins in the treatment of Alzheimer disease (AD)?

What is the role of transcranial magnetic stimulation (TMS) in the treatment of Alzheimer disease (AD)?

What is the theory behind disease-modifying therapies for delaying the onset of Alzheimer disease (AD)?

What is the role of neuropsychological, neuroimaging, and genetic testing in the treatment of Alzheimer disease (AD)?

What is the role of caprylidene (Axona) in the treatment of Alzheimer disease (AD)?

Which lifestyle changes may reverse cognitive decline in patients with Alzheimer disease (AD)?

What is the effect of cardiorespiratory fitness on Alzheimer disease (AD) progression and brain health?

Which activities should be encouraged in patients with Alzheimer disease (AD)?

Which factors may reduce the risk of Alzheimer disease (AD)?

Does cardiovascular fitness prevent Alzheimer disease (AD)?

Which dietary changes may be beneficial for Alzheimer disease (AD) prevention?

Does calorie reduction increase cognitive function?

Does alcohol consumption increase the risk of Alzheimer disease (AD)?

Medications

What is the mainstay of therapy for patients with Alzheimer disease (AD)?

Which medications in the drug class Cholinesterase Inhibitors are used in the treatment of Alzheimer Disease?

Which medications in the drug class N-Methyl-D-Aspartate Antagonists are used in the treatment of Alzheimer Disease?

Which medications in the drug class Combination Drugs are used in the treatment of Alzheimer Disease?

Which medications in the drug class Monoclonal Antibodies, Anti-amyloid Beta are used in the treatment of Alzheimer Disease?

Which medications in the drug class Nutritional Supplement are used in the treatment of Alzheimer Disease?