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Does APOE4 Impact the Effectiveness of Alzheimer’s Prevention Strategies?

Does APOE4 Impact the Effectiveness of Alzheimer’s Prevention Strategies?

Apolipoprotein E, commonly known as APOE, is a gene associated with varying risk of developing Alzheimer's, depending on which type (i.e., allele) you have. There are three different alleles—APOE2, APOE3, and APOE4—and everyone has two alleles (APOE2/APOE2, APOE2/APOE3, APOE2/APOE4, APOE3/APOE3, APOE3/APOE4, or APOE4/APOE4). The APOE2 allele is the rarest form of APOE and is associated with a reduced risk for Alzheimer's. The APOE3 allele is the most common and has average risk for Alzheimer's. The APOE4 allele, present in up to 15% of people, increases the risk for Alzheimer's disease. A recent review published in the Journal of Prevention of Alzheimer's Disease critically evaluates the impact of APOE4 on the effectiveness of various Alzheimer's prevention strategies, including diet, physical activity, cognitive engagement, supplements, and medications [1].

Lifestyle Interventions

Researchers have found that a group of lifestyle changes improved cognitive function and memory in older people with APOE4 [2]. The lifestyle changes included nutritional guidance, physical exercise, cognitive training, and management of metabolic and vascular risk factors. For people who do not have the APOE4 allele (i.e., non-carriers), these lifestyle changes appeared to improve cognitive functions too, but the effect was not statistically different when compared to people in the control group that received only general health advice. Future data from the extended 7-year follow up of this clinical trial will provide additional information on whether lifestyle changes are effective in preventing dementia, and whether benefits are more pronounced in APOE4 carriers compared to non-carriers.

Physical Activity

Observational studies have found that exercise is associated with a 45% decreased risk of Alzheimer's [3]. Several studies have demonstrated that APOE4 carriers respond more positively to exercise than non-carriers. In APOE4 carriers, higher physical activity was associated with greater cognitive functions [4] and lower levels of beta-amyloid, a biological marker of Alzheimer's disease [5], while these benefits were less pronounced in non-carriers. Thus, increasing physically activity, while important for everyone, may have more pronounced benefits in APOE4 carriers compared to non-carriers [1].


The Mediterranean diet is the diet most extensively studied for brain health with the greatest amount of data on cognitive functions. The Mediterranean diet is inspired by the dietary habits of Greece, Southern Italy, and Spain, and is high in olive oil, omega-3 fatty acids in fish and nuts, and fresh fruits and vegetables. A systematic review of all studies examining the relationship between this diet and cognitive health concluded that a higher adherence to the Mediterranean diet is associated with up to a 33% reduced risk of developing mild cognitive impairment and Alzheimer's [6]. Although both APOE4 carriers and non-carriers benefit from the Mediterranean diet, some studies suggest that benefits may be greater in non-carriers [7]. Additional research is needed to explore the benefits of Mediterranean diet in both APOE4 carriers and non-carriers.

Omega-3 Polyunsaturated Fatty Acids

Omega-3 polyunsaturated fatty acids (PUFAs) such as docosahexaenoic acid (DHA) are building blocks of the brain involved with numerous cellular pathways. Getting sufficient levels of DHA is thought to be an important consideration for Alzheimer's prevention. There have been three randomized controlled trials that support the use of DHA supplementation in APOE4 carriers who are cognitively healthy [8][9][10]. These studies reported that benefits were greater in APOE4 carriers than non-carriers. Also, studies suggest that omega-3 PUFAs may have less of a benefit after appearance of cognitive symptoms [1].

Another important consideration is the effect of omega-3 PUFAs on blood cholesterol levels. Two small clinical studies have suggested that very high doses of DHA may elevate total or LDL ("bad") cholesterol in APOE4 carriers but not in non-carriers [11][12]. Further research is needed to determine the optimal dose for Alzheimer's prevention in APOE4 carriers and non-carriers.

Vitamin D

Vitamin D, which can come from food or produced by the skin with sun exposure, is important for brain health. Studies have suggested that both low and high vitamin D levels are associated with lower cognitive functions [13][14]. But the results were different depending on which APOE alleles people had. In non-carriers or those with just one copy of the APOE4 allele, higher vitamin D levels were associated with lower cognitive functions [15]. In contrast, in people who had two copies of the APOE4 allele, higher vitamin D levels were associated with better cognitive functions. Therefore, the ideal level of vitamin D may depend on the number of copies of APOE4 one carries. Additional research is required to determine the optimal range of vitamin D for cognitive functioning in both APOE4 carriers and non-carriers.

Alcohol Consumption

The evidence is mixed with regards to alcohol. Some studies suggest that light-to-moderate alcohol—one drink a day for women, two for men—might be beneficial for brain health. However, a more recent study suggested that even light drinking may be associated with cognitive decline. The relationship between alcohol consumption and brain health appears to be different depending on whether or not you carry the APOE4 allele. Consumption of any amount of alcohol may increase the risk of Alzheimer's for APOE4 carriers, while light (1-6 drinks per week) and moderate (7-14 drinks per week) alcohol consumption was associated with better cognitive functions in non-carriers [16][17]. Based on the available evidence to date, light-to-moderate alcohol consumption may be beneficial for Alzheimer's prevention in non-carriers, but decreasing alcohol intake or abstaining from alcohol may be beneficial for APOE4 carriers [1].

Cognitive Engagement

Staying cognitively active such as taking a class may protect against cognitive decline. Some studies suggested that engaging in cognitive activities were associated with reduced risk of cognitive decline, and benefits were more pronounced for APOE4 carriers [18]. Other studies have suggested that non-carriers benefit more from cognitive engagement than APOE4 carriers [19]. Overall, greater cognitive engagement may decrease the risk of Alzheimer's, but it is not clear whether it has greater benefits for APOE4 carriers or non-carriers [1].

Blood Pressure Medications

High blood pressure (i.e., hypertension) during midlife is associated with an increased risk for Alzheimer's disease, as well as vascular dementia, another form of dementia. In an observational study, APOE4 carriers with hypertension were 13 times more likely to have poor cognitive function compared to non-carriers with normal blood pressure [20]. However, treatment of hypertension significantly reduced the risk of cognitive decline for APOE4 carriers from 13-fold to only 2-fold compared to non-carriers with normal blood pressure. Therefore, managing high blood pressure may be particularly important for APOE4 carriers [1]. More research is underway to determine the optimal blood pressure ranges for Alzheimer's prevention for APOE4 carriers.

Cholesterol Medications

High cholesterol in midlife has been associated with increased risk for Alzheimer's disease and vascular dementia [21]. However, the impact of high cholesterol on Alzheimer's risk may not be the same for APOE4 carriers and non-carriers. One study reported that high cholesterol doubled the risk of dementia in non-carriers but was not associated with an increased risk in APOE4 carriers [22]. But people taking statins (i.e., cholesterol-lowering medications) who were able to bring their cholesterol down to normal levels had significantly decreased risk of dementia, regardless of APOE4 carrier status. Thus, managing hyperlipidemia is important for everyone, but benefits may be especially pronounced for non-carriers with regards to Alzheimer's prevention.

With greater incorporation of APOE genetic data into clinical studies, future study results will inform us of more specialized and effective prevention strategies for APOE4 carriers and non-carriers.


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Yuko Hara, PhD, is Director of Aging and Alzheimer's Prevention at the Alzheimer's Drug Discovery Foundation. Dr. Hara was previously an Assistant Professor in Neuroscience at the Icahn School of Medicine at Mount Sinai, where she remains an adjunct faculty member. Her research focused on brain aging, specifically how estrogens and reproductive aging influence the aging brain's synapses and mitochondria. She earned a doctorate in neurology and neuroscience at Weill Graduate School of Medical Sciences of Cornell University and a bachelor's degree in biology from Cornell University, with additional study at Keio University in Japan. Dr. Hara has authored numerous peer-reviewed publications, including articles in PNAS and Journal of Neuroscience.

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