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Evidence-Based Reviews

Lowering risk of Alzheimer’s disease

Medical, dietary, and lifestyle choices may promote healthy brain aging

Vol. 9, No. 6 / June 2010
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Pharmacologic treatments for Alzheimer’s disease (AD) may improve symptoms but have not been shown to prevent AD onset. Primary prevention therefore remains the goal. Although preventing AD by managing risk factors such as age or genetics is beyond our control (Box 1), we can do something about other factors.

This article summarizes the findings of many studies that address AD prevention and includes an online-only bibliography for readers seeking an in-depth review. The evidence does not support a firm recommendation for any specific form of primary prevention and has revealed hazards associated with estrogen therapy and nonsteroidal anti-inflammatory drugs (Box 2). Most important, it suggests that you could reduce your patients’ risk of developing AD by routinely supporting their mental, physical, and social health.

The potential benefits of modifying an individual’s AD risk factors likely will depend on his or her genetic makeup, environment, and lifestyle. Even so, counseling patients to exercise more and improve their diets—such as by eating more fish, fruits, and vegetables and less saturated fat—might help protect the brain. Your ongoing efforts to manage hypertension, hypercholesterolemia, and diabetes also may reduce their AD risk.

Box 1

Nonmodifiable risk factors for Alzheimer’s disease

Age remains the strongest risk factor for dementia, particularly for Alzheimer’s disease (AD).a The risk of developing AD doubles every 5 years after age 65 and approaches 50% after age 85.b

Family history is a risk factor for AD, although true familial AD accounts for <5% of cases.c When diseases show a familial pattern, either genetics, environmental factors, or both may play a role. Patients with a first-degree relative with dementia have a 10% to 30% increased risk of developing the disorder.d

Genetic factors play a role in both early-onset and late-onset AD. Early-onset AD (before age 65) accounts for 6% to 7% of cases.e From this small pool of patients, only 13% exhibit clear autosomal dominant transmission over >1 generation.f Three gene mutations have been associated with early-onset AD:

  • 30% to 70% are in the presenilin-1 gene
  • 10% to 15% are in the amyloid precursor protein gene
  • <5% are in the presenilin-2 gene.g,h

For late-onset AD (after age 65), the strongest evidence for a genetic risk factor exists for the epsilon 4 allele of the apolipoprotein E gene (APOE e4).i This genotype has been linked to the development of AD and possibly to vascular dementia.j,k In contrast, the epsilon 2 allele of APOE may exert a protective effect in AD.l APOE e3, the most common allele, appears to play a neutral role in the development of AD.

a. Evans DA. The epidemiology of dementia and Alzheimer’s disease: an evolving field. J Am Geriatr Soc. 1996;44:1482-1483.
b. Jorm AF, Jolley D. The incidence of dementia: a meta-analysis. Neurology. 1998;51:728-733.
c. van Duijn CM, Clayton D, Chandra V, et al. Familial aggregation of Alzheimer’s disease and related disorders: a collaborative re-analysis of case-control studies. EURODEM Risk Factors Research Group. Int J Epidemiol. 1991;20(suppl 2):S13-S20.
d. Chang JB, Wang PN, Chen WT, et al. ApoE epsilon4 allele is associated with incidental hallucinations and delusions in patients with AD. Neurology. 2004;63:1105-1107.
e. Sleegers K, Roks G, Theuns J, et al. Familial clustering and genetic risk for dementia in a genetically isolated Dutch population. Brain. 2004;127:1641-1649.
f. Schoenberg BS, Anderson DW, Haerer AF. Severe dementia. Prevalence and clinical features in a biracial US population. Arch Neurol. 1985;42:740-743.
g. Hsiung GY, Sadovnick AD. Genetics and dementia: risk factors, diagnosis and management. Alzheimers Dement. 2007;3:418-427.
h. GeneTests database. Available at: Accessed March 19, 2010.
i. Li H, Wetten S, Li L, et al. Candidate single-nucleotide polymorphisms from a genomewide association study of Alzheimer disease. Arch Neurol. 2008;65:45-53.
j. Graff-Radford NR, Green RC, Go RC, et al. Association between apolipoprotein E genotype and Alzheimer disease in African American subjects. Arch Neurol. 2002;59:594-600.
k. Slooter AJ, Cruts M, Hofman A, et al. The impact of APOE on myocardial infarction, stroke, and dementia: the Rotterdam Study. Neurology. 2004;62:1196-1198.
l. Tiraboschi P, Hansen LA, Masliah E, et al. Impact of APOE genotype on neuropathologic and neurochemical markers of Alzheimer disease. Neurology. 2004;62:1977-1983.

Box 2

Estrogen and NSAIDs: Not recommended for AD protection

Estrogen. Before the Women’s Health Initiative (WHI) study, various trials of the effects of estrogen therapy on the development of Alzheimer’s disease (AD) in women age ≥65 showed inconsistent results. In the randomized, placebo-controlled WHI Memory Study, conjugated equine estrogen, 0.625 mg/d, plus medroxyprogesterone acetate, 2.5 mg/d, did not prevent mild cognitive impairment or improve global cognitive function and was associated with an increased risk for probable dementia.a Based on this evidence, conjugated equine estrogen with or without medroxyprogesterone is not recommended as therapy to protect cognitive function in older women.

NSAID therapy. Cytokine-mediated inflammation may play a role in neurodegenerative disorders and cognitive impairment in the elderly. Nonsteroidal anti-inflammatory drugs (NSAIDs), including cyclooxygenase-2 (COX-2) inhibitors, have been studied for a possible protective effect against AD and cognitive decline,b possibly by lowering amyloidogenic proteins.c A 1-year randomized controlled trial by the Alzheimer’s Disease Cooperative Consortium found no significant differences in cognition scores of patients treated with once-daily rofecoxib, 25 mg, or twice-daily naproxen sodium, 220 mg, when compared with placebo.d Similarly, naproxen and celecoxib did not prevent AD in the randomized, controlled Alzheimer’s Disease Anti-inflammatory Prevention Trial (ADAPT).e Rofecoxib has been withdrawn from the market, and celecoxib labeling carries a warning of potential for increased risk of cardiovascular events and life-threatening gastrointestinal bleeding associated with its use.

NSAIDs and COX-2 inhibitors are not recommended for the treatment or prevention of dementia or cognitive impairment. Their use for AD prevention is not supported by randomized clinical trialsd,e and they may have serious adverse effects.

a. Shumaker SA, Legault C, Kuller L, et al. Conjugated equine estrogens and incidence of probable dementia and mild cognitive impairment in postmenopausal women: Women’s Health Initiative Memory Study. JAMA. 2004;291:2947-2958.
b. Szekely CA, Breitner JC, Fitzpatrick AL, et al. NSAID use and dementia risk in the Cardiovascular Health Study: role of APOE and NSAID type. Neurology. 2008;70:17-24.
c. Weggen S, Eriksen JL, Das P, et al. A subset of NSAIDs lower amyloidogenic Abeta42 independently of cyclooxygenase activity. Nature. 2001;414:212-216.
d. Aisen PS, Schafer KA, Grundman M, et al. Effects of rofecoxib or naproxen vs placebo on Alzheimer disease progression: a randomized controlled trial. JAMA. 2003;289(21):2819-2826.
e. ADAPT Research Group, Martin BK, Szekely C, Brandt J, et al. Cognitive function over time in the Alzheimer’s Disease Anti-inflammatory Prevention Trial (ADAPT): results of a randomized, controlled trial of naproxen and celecoxib. Arch Neurol. 2008;65(7):896-905.

Cardiovascular risk factors

The risk of developing AD or vascular dementia appears to be increased by conditions that damage the heart or blood vessels. Recent evidence suggests that successfully managing cardiovascular risk factors may decrease the likelihood of dementia in later life.

Hypertension is associated with a higher risk of AD and all-cause dementia. Curiously, some studies have shown that low blood pressure also increases dementia risk, suggesting a U-shaped relationship between blood pressure and cognitive decline. Systolic hypertension in midlife may be associated with dementia 20 years later.

One might assume that antihypertensive therapy would help prevent dementia, but the data are conflicting. The Systolic Hypertension in Europe (SYST-EUR) study1 showed a 53% reduction in vascular dementia or mixed dementia among patients receiving antihypertensive medication and a 60% reduction in AD. Similarly, the PROGRESS2 clinical trial of prevention of recurrent stroke by antihypertensive treatment reported a 34% reduction in a composite measure of cognitive impairment and dementia. On the other hand, cognitive function neither improved nor worsened in the Hypertension in the Very Elderly Trial (HYVET-COG),3 whether patients received blood pressure treatment or placebo.

Hyperlipidemia. Lipid metabolism likely is an important pathway in amyloid beta-protein deposition, tau phosphorylation, and disruption of synaptic plasticity and neurodegenerative endpoints. Cognitive decline and incident dementia have been associated with higher dietary intake of saturated fats, partially hydrogenated unsaturated fatty acids (trans fats), and cholesterol. Not all studies have found this association, however. This could be because serum cholesterol levels may decrease in early dementia, limiting the ability to detect an effect of hypercholesterolemia on dementia risk when measurements are made later in life.

Using statins (3-hydroxy-3-methylglutaryl–coenzyme A reductase inhibitors) to treat hypercholesterolemia has been hypothesized to impede large vessel atherosclerosis and its consequences and to trigger metabolic effects in the brain related to AD pathogenesis. Mechanisms by which statins might help prevent dementia include:

  • a direct association between amyloid processing and cholesterol in the brain
  • an indirect effect by decreasing the risk of stroke, as even small cerebral infarcts worsen AD severity.

Nonrandomized epidemiologic studies such as the Cardiovascular Health Study4 and MRC/BHF Heart Protection Study5 suggested that statin treatment might reduce the incidence of dementia, the degree of age-related cognitive decline, and AD’s neuropathologic burden. Large, randomized, controlled trials have not supported these observations, however. Statins failed to reduce the incidence of dementia in:

  • the Heart Protection Study, testing simvastatin for 5 years in 20,536 subjects age 40 to 805
  • the 3-year Preventive Study of Pravastatin in the Elderly at Risk (PROSPER) of 5,800 subjects.6

Similarly, patients receiving adjunctive atorvastatin or placebo showed no significant differences in cognition assessments after 72 weeks in the Lipitor’s Effect in Alzheimer’s Dementia (LEADe) study. This trial enrolled 640 subjects age 50 to 90 with mild-to-moderate dementia who were treated with donepezil.7 A recent Cochrane review concluded that high serum cholesterol may contribute to the development of AD and vascular dementia, but lowering cholesterol levels with statins does not prevent these problems.8

Diabetes mellitus. Diabetes and cognitive decline are closely associated. Diabetes is associated with a 50% to 100% increase in risk of AD and dementia overall and a 100% to 150% increased risk of vascular dementia. The mechanism by which diabetes increases dementia risk is uncertain but does not appear to be mediated entirely through vascular disease. High and low insulin levels may increase the risk of dementia, independent of diabetes and blood glucose. Increased peripheral insulin levels are associated with reduced brain atrophy and cognitive impairment in patients with early AD, suggesting a role for insulin signaling in AD pathophysiology. A possible relationship between insulin and beta amyloid metabolism is being studied.

Elevated postprandial plasma glucose has been associated with accelerated declines in cognitive performance.9 An inverse correlation has been noted between some cognitive measures and hemoglobin A1C levels.10 It is not clear that treating diabetes reduces the risk of dementia. In addition, in the prospective, population-based Rotterdam study, elderly patients with type 2 diabetes treated with insulin had the highest incidence of dementia.11

Tobacco smoke directly affects neuronal function, integrity, and survival. Chronic smoking has been linked to decreased global cerebral blood flow, accelerated cerebral atrophy, and ventricular enlargement.

Some studies suggest an increased risk of dementia in middle-aged and elderly smokers, possibly through a cerebrovascular mechanism such as stroke. Other studies found no association between smoking and dementia risk, and 1 suggested that nicotine may protect against AD by reducing senile plaque formation. Any protective effect of smoking would be offset by increased risks of lung cancer, chronic obstructive pulmonary disease, and vascular dementia.

The apolipoprotein E epsilon 4 (APOE e4) gene may explain, at least in part, the conflicting results of these studies. In 2 population-based cohorts,12,13 smoking was associated with memory decline in patients without, but not with, the APOE e4 genotype.

Dietary factors

Antioxidants. The brains of patients with AD contain elevated levels of endogenous antioxidants. In vitro studies show exogenous antioxidants can reduce the toxicity of beta-amyloid in brain tissue of persons with AD. These findings have led to interest in assessing the role of dietary antioxidants such as vitamins E and C for AD prevention.

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