Is risk of Alzheimer disease a reason to use dietary supplements?

We need a better understanding of what genetic susceptibility tests for Alzheimer disease (AD) mean and how disclosure of test results affects behavior. Vernarelli et al's (1) article in this issue of the Journal addresses these concerns. About half of the neurodegenerative dementias in late life are due to late-onset AD, its most common form, and another sixth of dementias are due to disseminated cerebrovascular disease. Cerebrovascular and cardiovascular disease and risk factors for them increase the likelihood of developing AD as well as vascular and mixed dementias (2).

AD has many forms that are linked to genes, including the autosomal dominant early-onset forms of AD that appear in midlife, with defects on chromosomes 21, 14, or 1. Except for families of patients with early-onset AD, testing in asymptomatic individuals is not usually recommended (3). APOE*4 genotype testing is used as a diagnostic adjunct for those with dementia (4). The APOE*4 allele (ϵ4+) on chromosome 19 is a susceptibility gene that directs formation of apolipoprotein E, a protein responsible for cholesterol transport. When the ϵ4+ genetic variant is present on the allele, the prevalence of atherosclerosis is pronounced, and the prevalence of late-onset AD is increased. When type 2 diabetes is also present, risks of AD and vascular and mixed dementias increase further (5).

Vernarelli et al (1) found that ≈40% of middle-aged people who had a first-degree relative with AD had the ϵ4+ allele, and 60% had the ϵ4− allele. Thus, ϵ4+ is a measure of predisposition or susceptibility, not certainty. Although ϵ4+ increases risk in some individuals, biology, education, experience, and the social environment may function either as an accelerator or a brake on AD expression, which complicates risk assessment.

The authors found no significant differences between ϵ4+ and ϵ4− individuals with respect to overall diet, exercise, or medications. Diet and sedentary lifestyle are also risk factors for both cardiovascular disease and type 2 diabetes, and ϵ4+ strengthens the associations. However, many of those who knew they had the ϵ4+ allele turned to dietary supplements, perhaps thinking they might improve health and decrease AD risk.

There is little evidence that dietary supplements can prevent or treat AD. Multivitamins do not reduce the risk of dementia (6). Large doses of vitamin E have little effect in slowing progression to AD among those with mild cognitive impairment (7). Combinations of vitamin B-12 and folic acid in very large doses reduce homocysteine concentrations (a risk factor for cerebrovascular disease) but fail to improve cognitive function in elderly persons with no or moderate cognitive impairment (8), nor do they slow cognitive decline in those with mild to moderate AD (9). Vitamin B-6, vitamin B-12, and folic acid either alone or in various combinations do not improve cognitive function or dementia (10), with the possible exception of folic acid alone or with vitamin B-12 among those with high homocysteine concentrations (11). There is inadequate evidence that fish oils or omega-3 fatty acids protect against decreases in cognitive functions and the incidence or clinical progression of dementias (12). Riboflavin, vitamin B-6, vitamin C, blueberry extract, α-lipoic acid, and the adrenal hormone dehydroepiandrosterone (DHEA) lack evidence of efficacy in humans.

Ginkgo biloba has been studied extensively for its effects on memory. It lacks predictable, clinically significant benefits in persons with acquired cognitive impairments, including dementia of any degree of severity (13). The Ginkgo Evaluation of Memory Study (GEMS), a randomized controlled trial of G. biloba in elderly persons aged >75 y, found no effects on all-cause dementia, on AD, or on the rate of progression to dementia in elderly persons with mild cognitive impairment (14). Polypharmacy was common in GEMS; nearly 75% of participants used at least one prescription medication and one dietary supplement, and a third used ≥3 dietary supplements plus ≥3 prescription medications, posing risks of adverse drug interactions (15). For example, G. biloba increases the risk of bleeding when taken with aspirin. Another possible effect of polypharmacy on health behaviors is that use of multiple supplements may decrease adherence to prescription medications.

Health behaviors that might be more beneficial are worth considering. For example, ϵ4+ increases risks of high serum cholesterol, and ϵ4+ and high serum cholesterol each increase risk of AD. The statins lower blood cholesterol, delay the onset of dementia, and may decrease the risk of AD (16). Diet, exercise, and pharmacologic measures that reduce serum cholesterol concentrations or other risk factors and improve cardiovascular health possibly also have beneficial effects on the risk of AD, vascular diseases, and dementia. If ϵ4+ participants in this study had made beneficial changes in diet and physical activity, these may have been more useful than supplements in optimizing health. We still do not know whether the genetic testing–stimulated behavior changes that occur after disclosure of ϵ4+ status lead to healthier behaviors and better health in other populations. But we do know that patients who are able to ask questions and discuss answers with a real person may be able to do a better job in planning preventive strategies than those who only receive printed materials.

Each genetic test for AD has very different meanings. A positive result may either confirm the diagnosis of an autosomal dominant form of AD or indicate the presence of one indicator of disease susceptibility (ϵ4+). Individuals who have the ϵ4+ allele do not necessarily develop AD, and those who have the ϵ4− allele are not necessarily exempt. Those who have the ϵ4− allele but who have other risk factors such as family history of AD in ≥2 first-degree relatives, in ≥2 generations, and AD that appears at <65 y of age are at considerably increased AD risk, and they also need counseling.

In summary, the evidence suggests that dietary supplement use is unlikely to prevent cognitive impairment or AD, nor is ϵ4+ status an indication for their use. Behaviors that reduce cardiovascular disease risk are more promising. Clinical nutrition scientists share responsibility with others on the medical team for communicating genetic information and helping patients to enhance their health-related behaviors. This means becoming fluent in speaking this new genetic language with both our colleagues and our patients.