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] Additionally, amyloid-directed antibodies (eg, aducanumab, lecanemab) have been approved. [100, 101]
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] :
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Antidepressants
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Anxiolytics
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Antiparkinsonian agents
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Beta-blockers
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Antiepileptic drugs (for their effects on behavior)
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Neuroleptics
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. [102] 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. [103]
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. Additionally, amyloid-directed antibodies (eg, aducanumab, lecanemab) have been approved. [100, 101]
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:
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Donepezil (Aricept, Aricept ODT)
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Rivastigmine (Exelon, Exelon Patch)
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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. [104]
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. [105] 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. [106]
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). [107] 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. [107]
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.
Anti-amyloid beta monoclonal antibodies
As of early 2023, two anti-amyloid beta monoclonal antibodies (ie, aducanumab, lecanemab) are available in the Unites States. [100, 101] Lecanemab has gained full approval from the FDA. Aducanumab is available via accelerated approval and continued approval is contingent upon verification of clinical benefit in a confirmatory trial. Anti-amyloid beta monoclonal antibodies may potentially be the first disease-modifying therapy for AD.
Aducanumab
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.
The approval decision was based on the ability of aducanumab to remove amyloid beta plaques, without any evidence that the amyloid beta clearance is correlated with less cognitive or functional decline. This decision generated considerable debate among clinicians, especially because the results from the two Phase 3 trials, EMERGE and ENGAGE, were divergent and, even after the post hoc analysis, the data were insufficient to prove aducanumab efficacy. [100] 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. [108, 109, 110]
The Phase 4 confirmatory trial (ENVISION) required by the FDA to gain full approval began enrolling patients in May 2022 and anticipates data completion by 2026. [100]
Lecanemab
Lecanemab (Leqembi) is an amyloid beta-directed antibody indicated for Alzheimer disease in patients. Treatment should be initiated in patients with mild cognitive impairment or mild dementia stage of disease, the population in which treatment was studied in clinical trials. Lecanemab targets soluble aggregated amyloid beta species (protofibrils) to disrupt plaque formation. [111]
The multicenter, global CLARITY AD trial enrolled 1795 participants with early stage Alzheimer disease. Patients were randomized 1:1 to receive lecanemab or placebo. Researchers assessed cognition primarily with the Clinical Dementia Rating–Sum of Boxes (CDR-SB), which evaluates a person’s abilities in 6 areas, including memory and problem solving, using an 18-point scale. After 18 months, participants who received lecanemab scored, on average, 0.45 points better on the CDR-SB than those who got a placebo (P < 0.001).
Key secondary end points were the change in amyloid burden on PET, the score on the 14-item cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-cog14; range, 0 to 90; higher scores indicate greater impairment), the Alzheimer's Disease Composite Score (ADCOMS; range, 0 to 1.97; higher scores indicate greater impairment), and the score on the Alzheimer's Disease Cooperative Study-Activities of Daily Living Scale for Mild Cognitive Impairment (ADCS-MCI-ADL; range, 0 to 53; lower scores indicate greater impairment).
In a substudy involving 698 participants, there were greater reductions in brain amyloid burden with lecanemab than with placebo (difference, -59.1 centiloids; 95% CI, -62.6 to -55.6). Other mean differences between the 2 groups in the change from baseline favoring lecanemab as follows: ADAS-cog14 score, -1.44 (P < 0.001); ADCOMS, -0.050 (P < 0.001); and ADCS-MCI-ADL score, 2.0 (P < 0.001). However, lecanemab risks include infusion-related reactions (26.4%) and amyloid-related imaging abnormalities with edema or effusions in 12.6%. [101]
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. [112] Studies suggest that the use of memantine with donepezil affects cognition in moderate to severe AD [113] but not in mild to moderate AD. [114, 115] A once-daily, fixed-dose combination of memantine extended-release (ER) and donepezil (Namzaric) was approved by the FDA in 2014. [116] 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. [117] 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). [118]
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. [119]
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. [120] 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. [121]
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. [122]
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. [123] 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. [124]
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. [125, 126, 127]
Weintraub et al [128] and Petracca et al [129] 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. [130]
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. [131, 132]
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. [133]
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. [134]
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%. [135]
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. [136]
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:
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Vaccination with amyloid species
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Administration of monoclonal antiamyloid antibodies
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Administration of intravenous immune globulin that may contain amyloid-binding antibodies
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Selective amyloid-lowering agents
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Chelating agents to prevent amyloid polymerization
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Brain shunting to improve removal of amyloid
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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. [137]
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. [138] 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. [139, 140]
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. [139, 140]
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. [141]
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. [142]
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. [143]
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. [143]
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. [144, 145] Cognition subjectively or objectively improved in 9 of the 10 patients within 3 to 6 months. [144, 145]
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. [144, 145]
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 Alzheimer disease (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. [146]
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. [147]
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. [148]
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. [149] 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. [150] 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. [151] 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). [152]
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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.
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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.
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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.
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Healthy neurons. Image courtesy of NIH.
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Image courtesy of NIH.
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Preclinical Alzheimer disease. Image courtesy of NIH.
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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.
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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.
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Preclinical Alzheimer disease. Image courtesy of NIH.
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Mild-to-moderate Alzheimer disease. Image courtesy of NIH.
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Severe Alzheimer disease. Image courtesy of NIH.
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Cortical atrophy with hydrocephalus ex vacuo is seen in Alzheimer disease.
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Plaques and tangles in Alzheimer disease.
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Amyloid angiopathy in Alzheimer disease.
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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.
