The 2020 Lancet Commission on Dementia Prevention, Intervention and Care reported that fully addressing 12 lifestyle risk factors can prevent or delay up to 40% of dementia cases [1]. These risk factors include less education, hearing impairment, smoking, depression, physical inactivity, traumatic brain injury, high blood pressure, social isolation, air pollution, diabetes, obesity, and excessive alcohol consumption.
What if you have a genetic risk factor? Apolipoprotein E, commonly known as APOE, is a gene associated with varying risk of developing Alzheimer's disease, depending on which variant you have. There are three different variants—APOE2, APOE3, and APOE4—and you have two copies, one each from your mother and father. The APOE2 variant is the rarest form of APOE and is associated with a reduced risk for Alzheimer's. The APOE3 variant is the most common and has an average risk for Alzheimer's. The APOE4 variant, present in up to 15% of people, increases the risk for Alzheimer's disease. It is important to note that having one or even two copies of the APOE4 variant does not mean the individual will definitely develop Alzheimer’s disease. Similarly, not having the APOE4 variant does not mean the individual will never get Alzheimer’s.
We previously discussed that the effectiveness of Alzheimer’s prevention strategies may vary depending on which APOE variants you have. For example, a group of lifestyle interventions improved cognitive function and memory in people with APOE4, but benefits were smaller in those who did not have the APOE4 variant [2]. Here, we review the latest findings regarding dementia prevention strategies as they relate to APOE genetics.
The Mediterranean diet is inspired by the dietary habits of Greece, Southern Italy, and Spain, and is high in fresh fruits, vegetables, fish, olive oil, and nuts. A systematic review of studies examining the relationship between this diet and cognitive health concluded that higher adherence to the Mediterranean diet is associated with up to a 33% lower risk of developing mild cognitive impairment and Alzheimer's disease [3]. Everyone benefits from the Mediterranean diet, but some studies suggest that benefits may be greater in people without the APOE4 variant [4].
APOE4 is associated with insulin resistance in the brain. In a comprehensive review of dementia prevention strategies, a low-carbohydrate diet or a low-glycemic index diet is recommended for people with the APOE4 variant [5].
Omega-3 fatty acids such as docosahexaenoic acid (DHA), rich in salmon, mackerel, and other fatty fish, are building blocks of the brain. Getting sufficient levels of DHA is thought to be an important consideration for preventing Alzheimer's disease. People with APOE4 may have a reduced capacity to deliver DHA into the brain [6], and therefore, consuming 2-4 servings of fatty fish per week is recommended for these people [5].
Studies assessing the relationship between alcohol consumption and brain health have shown conflicting results, with some studies suggesting light-to-moderate drinking benefits brain health, while other studies reporting harm with even the lowest amounts. In people who carry the APOE4 variant, however, any amount or type of alcohol appears to increase the risk of Alzheimer’s disease [7]. Therefore, limiting alcohol consumption is recommended for people with the APOE4 variant [5].
Observational studies have found that exercise is associated with a significantly lower risk of Alzheimer's disease [8]. Several studies have demonstrated that people with APOE4 respond more positively to exercise than people without APOE4. In people with APOE4, higher physical activity was associated with greater cognitive functions [9] and lower levels of beta-amyloid, a biological marker of Alzheimer's disease [10], while these benefits were smaller in magnitude in people without APOE4. Thus, increasing physical activity, while important for everyone, may have more pronounced benefits in people with APOE4 [11]. With regards to types of exercise, high-intensity exercise may be the most effective in protecting against cognitive decline for people with APOE4 [5; 12]. Increasing the overall amount and intensity of exercise is recommended for people with APOE4.
High blood pressure (i.e., hypertension) during midlife is associated with an increased risk for Alzheimer's disease. In an observational study, people with APOE4 who had hypertension were 13 times more likely to have poor cognitive function compared to those without APOE4 with normal blood pressure [13]. However, treatment of hypertension significantly reduced the risk of cognitive decline from 13-fold to only 2-fold. Therefore, managing high blood pressure may be particularly important for people with APOE4 [11]. Findings from the Systolic Blood Pressure Intervention Trial - Memory and Cognition in Decreased Hypertension (SPRINT-MIND) study suggests that aggressive systolic blood pressure lowering at or below 120 mmHg is optimal for reducing risk of cognitive decline [14]. Diastolic blood pressure should also be targeted at or below 70 mmHg.
Higher LDL-cholesterol, or ‘bad cholesterol’, particularly in mid-life, is associated with higher dementia risk [15]. APOE plays a role in the transport, metabolism, and distribution of lipids in the brain. APOE4 is associated with higher LDL-cholesterol levels, and therefore higher cardiovascular risk [16]. APOE2, on the other hand, is associated with a significantly lower LDL-cholesterol. One observational study reported that cholesterol-lowering statins may provide greater benefits with regards to cognitive function and dementia risk in people who have two copies of the APOE4 variant compared to people with zero or one copy of APOE4 [17].
Lifelong learning is associated with good cognitive health, and higher levels of cognitive activity at mid- or late-life are linked to higher levels of cognitive functions and lower risk of Alzheimer’s disease [18; 19]. Everyone benefits from greater cognitive engagement; it is not clear whether it has greater benefits for those with the APOE4 variant versus those without [11]. Some examples of cognitive engagement include reading, writing, learning a new language, and learning how to play a musical instrument.
Evidence from observational studies have reported that lack of sleep is associated with cognitive decline and higher risk of dementia. In a longitudinal study of about 8,000 participants, getting six hours or less of sleep per night at ages 50 and 60 was associated with 24-37% higher risk of dementia compared to those who got seven hours of sleep [20]. These associations were not affected by APOE variants, suggesting that getting 7-8 hours of sleep per night is optimal regardless of whether you have the APOE4 variant or not. Some tips for getting adequate amounts of sleep include maintaining a regular sleep schedule/routine, creating a comfortable sleep environment, avoiding caffeine after ~1pm, limiting the use of electronics before bedtime, and abstaining from food and alcohol before bedtime. If you suspect you have insomnia or sleep apnea, talk to your healthcare provider about treatment options.
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As outlined above, there are concrete steps you can take to reduce the risk of Alzheimer’s disease or delay its onset, regardless of genetic risk factors. Personalized prevention strategies based on APOE genetics is an exciting and evolving area of research. Stay tuned for more updates as we learn more.
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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