Evidence-Based Reviews

Lowering risk of Alzheimer’s disease

Current Psychiatry. 2010 June;9(6):23-35

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

References

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Discuss this article

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.

References
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: http://www.genetests.org. 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 trials^d,e and they may have serious adverse effects.

References
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.