Alzheimer Disease 

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.^[1]

A speech given by Dr. Alzheimer on November 3, 1906, was the first time the pathology and the clinical symptoms of presenile dementia (later to be renamed Alzheimer disease [AD]) were presented together. Alzheimer published his findings in 1907.^[2]

AD is an acquired cognitive and behavioral impairment of sufficient severity that markedly interferes with social and occupational functioning. It is an incurable disease with a long and progressive course. AD not only has detrimental effects on the patient but tends to take a significant toll on patients’ families and caretakers as well.

The most common form of dementia, AD affects about 4.5 million people in the United States alone, and that number is projected to exceed 13 million by the year 2050.^[3] Economically, it is a major public health problem. In the United States, the cost of caring for patients with dementia was $144 billion per year in 2009. The most recent data available on the cost for healthcare and long-term care services per patient, from 2004, show that the average yearly cost was about $33,007.^[4]

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

Currently, an autopsy or a brain biopsy is the only ways to make a definitive diagnosis of AD, although the diagnosis is usually made clinically from the history and findings on Mental Status Examination (see Workup).

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

For related information, see the Alzheimer’s Disease Slideshow.

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, makes the microtubules stable.

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

AD affects the 3 processes that keep neurons healthy: communication, metabolism, and repair. This disruption causes certain nerve cells in the brain to 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 anatomic pathology of Alzheimer disease includes neurofibrillary tangles (NFTs); senile plaques (SPs; also known as beta-amyloid plaques) at the microscopic level; and cerebrocortical atrophy, which predominantly involves the association regions and particularly the medial aspect of the temporal lobe. NFTs and SPs, which were described by Alois Alzheimer in his original report on the disorder in 1907,^[2] are now universally accepted as a hallmark of the disease.

Considerable attention has been devoted to elucidating the composition of NFTs and SPs 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 starch like (or amyloid) substance, usually in the center of these lesions, which 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.)

Although the amyloid cascade hypothesis has gathered the most research dollars, other interesting hypotheses have been proposed, including the mitochondrial cascade hypothesis.^[5]

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^[5] ; and neuronal loss and synaptic degeneration, which are thought to ultimately mediate the cognitive and behavioral manifestations of the disorder.

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).

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. Whether AB plaques themselves cause AD or whether they are a byproduct 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 patients with AD have them to a much greater extent, especially in certain regions of the brain that are important in memory.

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. 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. 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.

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.^[6] Therefore, even small numbers of NFTs in these areas of the medial temporal lobe may be abnormal.

In contrast, there is consensus that the presence of even low numbers of NFTs in the cerebral neocortex with concomitant SPs is characteristic of AD.

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. The fibrillar form of AB has been shown to be neurotoxic to cultured neurons at high concentrations.

Apoptosis (self-regulated cell destruction) is one possible mechanism of cellular death in AD. Cultured cortical and hippocampal neurons treated with AB protein exhibit changes characteristic of apoptosis, including nuclear chromatin condensation, plasma membrane blebbing, and internucleosomal DNA fragmentation. The fibrillar form of AB has also 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 NPs also incriminate AB in AD. The 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. Having 1 copy of the APOE E4 allele increases the risk of developing AD perhaps 4 times compared with all other alleles, and having 2 copies of the E4 allele increases the risk up to 10 times.

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. Dementia severity correlates better with the number of neocortical NFTs than with NPs. Tau is a protein that stabilizes neuronal microtubules. The APOE E2 allele, the least prevalent of the 3 common APOE alleles, is associated with the lowest risk of developing AD,^[7] with a lower rate of annual hippocampal atrophy and higher CSF β-amyloid and lower phosphotau, suggesting less AD pathology.^[8] 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.

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 functions, and cholinergic deficiency and 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. Such studies have demonstrated that an increase in oxidative damage selectively occurs within the brain regions involved in regulating cognitive performance. Increased levels of oxidative damage occur in patients with mild cognitive impairment (MCI), which is believed to be one of the earliest stages of AD and is a condition that is devoid of dementia or the extensive neurofibrillary pathology and neuritic plaque deposition observed in AD.

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 MCI and AD. Protein synthesis may be one of the earliest cellular processes disrupted by oxidative damage in AD.^[9]

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 its 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 beta amyloid protein with glial cells, which may be one of the first steps in the inflammatory cascade (see Inflammatory reactions below).

Inflammatory reactions

Inflammatory and immune mechanisms may play a role in the degenerative process in AD. Reactive microglia are embedded in neuritic plaques. Increased cytokines are seen in the serum, cortical plaques, and neurons of patients with AD compared with aged-matched control subjects. Interestingly, the anti-inflammatory cytokine transforming growth factor beta 1 (TGF-β1) has recently 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.

One study by Finch et al found an association between AD and the major histocompatibility complex, located on chromosome 6.^[10] The age at onset of AD was significantly lower in patients carrying the A2 allele.

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 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. Senile plaques 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 a recent 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.^[11]

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 of incidence of AD.^[12]

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 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 Golgi complex that are involved in similar functions. Recent evidence supports the role of presenilins in AB metabolism. Mice deficient in the expression of PS1 exhibit dramatic decrease in proteolytic cleavage of the transmembrane domain of APP by secretase.

PS1 is immunoreactive with neuritic plaques (NP). 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

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 and older with a first-degree relative with AD showed that estrogen therapy might actually increase the risk of stroke and dementia.^[13]

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

The following risk factors for Alzheimer-type dementia have been identified^{[14, 15, 16, 17]} :

• Advancing age
• Family history
• Apolipoprotein E epsilon 4 genotype
• Obesity
• Insulin resistance
• Vascular factors
• Dyslipidemia
• Hypertension
• Inflammatory markers
• Down syndrome

In addition, epidemiology studies have suggested some possible risk factors (such as aluminum^{[18, 19]} and previous depression) and some protective factors (education,^{[20, 21]} , anti-inflammatory drugs). Moderate-to-severe head trauma appears to be linked to the development of AD as well as other forms of dementia later in life. A study that followed over 7,000 US veterans from 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 apolipoprotein E gene and sustaining head trauma seemed to act additively to increase the risk of developing AD, although there was no direct correlation.^[22]

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.^[23] The PET scan revealed a qualitatively different activation pattern in patients with prediabetes or type 2 diabetes mellitus during a memory encoding task compared with healthy individuals who were not insulin resistant. Although their results were not statistically significant due to the small number of subjects (n=23) in the study, this certainly warrants further study because it may lead to a noninvasive test that could help to quantify risk for development of AD in presymptomatic patients.

A similar study was performed in a much larger population of 3,139 participants to investigate the association of diabetes mellitus with an increased risk of AD and to assess whether the risk is constant over time.^[24] A different measure of insulin resistance was calculated, using the homeostasis model assessment. They found a similar association between insulin resistance and AD over 3 years, which then disappeared after that time. Disturbances in insulin metabolism may not cause neurological changes but may influence and accelerate these changes, leading to an earlier onset of AD.

Genetic causes

Although most cases of AD are sporadic (ie, not inherited), familial forms of AD do exist; however, they account for less than 7% of all cases.

Mutations in genes coding for 3 proteins unequivocally cause AD. These genes (which code for amyloid precursor protein [APP, on chromosome 21], for PS1 [on chromosome 14], and for PS2 [on chromosome 1]) all 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.

Genetic factors associated or potentially associated with AD are summarized in Tables 1 and 2.

Table 1. Genetic Factors Associated With Alzheimer Disease (Open Table in a new window)

Table 2. Other Locus or Susceptibility Genes Potentially Associated with Alzheimer Disease (Open Table in a new window)

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. Go to Alzheimer Disease in Individuals With Down Syndrome for complete information on this topic.

Subsequently, several missense mutations within the APP gene that resulted in amino acid substitutions in APP were identified in these FAD kindreds. Such mutations appear to alter the previously described proteolytic processing of APP, generating amyloidogenic forms of AB. Skin fibroblasts from subjects 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

In cases of early-onset autosomal-dominant AD cases, 50-70% 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 physiologic role of presenilins and the pathogenic effects of their mutations are not yet well understood. (See Pathophysiology.)

APOE E4 allele

The gene encoding the cholesterol-carrying apolipoprotein E (APOE) on chromosome 19 has been linked to early-onset familial and sporadic AD. The gene is inherited as an autosomal codominant trait with 3 alleles. This article focuses on the allele that may have a direct correlation to AD.

APOE E4 gene “dose” is correlated with increased risk and earlier onset of AD.^[10] Persons with 2 copies of the APOE E4 allele (4/4 genotype) have 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.

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 biological risk factor for the disease, especially in those younger than 70 years.

United States statistics

Using 2000 US Census results, Hebert et al estimated that about 4.5 million people in the United States had AD.^[3] These researchers calculated that by 2030, an estimated 7.7 million Americans aged 65 and older will have AD and that by 2050, that number will rise to more than 13 million.

According to a 2010 report, AD affects approximately 5.3 million people in the United States.^[4] A larger number of individuals have decreased cognitive function (eg, mild cognitive impairment); this condition frequently evolve into a full-blown dementia, thereby increasing the number of affected persons. The statistical projections cited in this report indicate that the number of persons affected by the disorder in the United States could range from 11 to 16 million by the year 2050.^[4]

The lifetime risk of AD is estimated to be 1:4-1:2. More than 14% of individuals older than 65 years have AD, and the prevalence increases to at least 40% in individuals older than 80 years.

International statistics

Prevalence rates of AD similar to those in the United States have been reported in industrialized nations. The prevalence of dementia in subjects 65 years 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^[25] reported that 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 transition in the early 1990s. American and European studies consistently reported AD to be more prevalent than VaD. They found a dementia prevalence rate among Chinese aged 50 years and older on the islet of Kinmen for this age group of 11.2 per 1,000. 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 low. Indian studies were 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 this represents a subgroup of the less than 10% of all familial cases of the disease.

More than 90% of cases of AD are sporadic and occur in individuals older than 60 years. However, of interest, 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 the association between dementia and the pathological features of AD (eg, neuritic plaques, diffuse plaques, tangles) is stronger in younger old persons (ie, age 75 years) than in older old persons (ie, 95 years). 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.

These results demonstrate that the relationship between cerebral atrophy and dementia persist into the oldest ages, but the strength of association between pathological features of AD and clinical dementia diminished. It is important to take age into account when assessing the likely effect of interventions against dementia on the population.^[11]

Sex distribution for Alzheimer disease

AD affects both men and women; however, Plassman et al found the risk of developing AD to be significantly higher in women than in men, primarily due to women’s higher life expectancy.^[26]

Prevalence of Alzheimer disease by race

AD and other dementias are more common in African Americans than in whites. According to the Alzheimer’s Association, in the population aged 71 and older, African Americans are almost 2 times 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.

In individuals age 65 and older, 7.8% of whites, 18.8% of African-Americans, and 20.8% of Hispanics have AD or other dementias, and the prevalence of AD and other dementias is higher in older versus younger age groups.^[4]

AD is initially associated with memory impairment that progressively worsens. Over time, patients with AD can display anxiety, depression, insomnia, agitation, and may become violent and paranoid. Eventually the patient with AD loses all bodily function, including the ability to walk and swallow; feeding is possible only by gastrointestinal tube. Difficulty swallowing may lead to aspiration pneumonia.

The time from diagnosis to death varies from as little as 3 years if the patient is older than 80 years when diagnosed to as long as 10 or more years if the patient is younger. The primary cause of death is intercurrent illness, such as pneumonia.

In the United States, AD is frequently considered a leading cause of death. In 2006, AD was the seventh leading cause of death^[27] ; however, AD as an underlying cause of death is frequently underreported.^[28]

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 him or her, will likely experience reactions of sadness and anger, and that these are normal reactions to such a catastrophic 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.

As the patient continues to decline, family members should be careful to select qualified and trustworthy individuals to be involved in the day-to-day management of the patient. Any suspicions of elder abuse should be immediately addressed.

Throughout the course of the illness, it is important that the family be counseled to continue to treat the patient as a competent adult as much as possible, despite the patient’s decreasing ability to care for himself or herself.

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 resources, see eMedicine’s Dementia Center as well as Alzheimer Disease, Alzheimer Disease in Individuals With Down Syndrome, Dementia Overview, and Dementia Medication Overview.