If you carried a gene that doubled your likelihood of getting Alzheimer's disease, would you want to know? What if there was a simple lifestyle change that virtually abolished that elevated risk? People with a gene known as APOE e4 have a higher risk of cognitive impairment and dementia in old age. Even before behavioral symptoms appear, their brains show reduced metabolism, altered activity and more deterioration than those without the high-risk gene. Yet accumulating research is showing that carrying this gene is not necessarily a sentence for memory loss and confusion—if you know how to work it to your advantage with exercise.
Scientists have long known that exercise can help stave off cognitive decline. Over the past decade evidence has mounted suggesting that this benefit is even greater for those at higher genetic risk for Alzheimer's. For example, two studies by a team in Finland and Sweden found that exercising at least twice a week in midlife lowers one's chance of getting dementia more than 20 years later, and this protective effect is stronger in people with the APOE e4 gene. Several others reported that frequent exercise—at least three times a week in some studies; up to more than an hour a day in others—can slow cognitive decline only in those carrying the high-risk gene. Furthermore, for those who carry the gene, being sedentary is associated with increased brain accumulation of the toxic protein beta-amyloid, a hallmark of Alzheimer's.
More recent studies, including a 2012 paper published in Alzheimer's & Dementia and a 2011 paper in NeuroImage, found that high-risk individuals who exercise have greater brain activity and glucose uptake during a memory task compared with their less active counterparts or with those at low genetic risk.
This link to metabolism may help explain why exercise protects APOE e4 carriers. According to a theory proposed in May by anthropologist David Raichlen and psychologist Gene Alexander, both at the University of Arizona, the answer lies in our evolutionary past. Two million years ago, when our ancestors were much more physically active—for example, perhaps running long distances to hunt prey—only the high-risk gene variant existed, they argue. The gene allowed for better metabolism during intense activity, and its downside, faster cognitive decline, was counteracted by our ancestors' active way of life. As humans adopted more sedentary habits, other variants of the gene appeared, and in modern times we are now seeing the negative effect of the high-risk gene more often than its benefit.
Although these studies suggest that exercise is exceptionally protective for those at highest risk, some findings buck the trend. One large-scale study reported that high levels of leisure-time activity reduced risk of dementia five years later but only in those who did not carry the high-risk APOE e4 gene. These inconsistencies suggest the interaction may be complex, although most of the evidence still indicates that an active lifestyle has great value.
Exercise is important for healthy aging, regardless of genetics, but Raichlen emphasizes that “for individuals that are APOE e4 carriers, studies certainly underline the importance of maintaining physical activity across the life span.” And with further research, he suggests, “a better understanding of the evolutionary origins of genotype-lifestyle interactions will help identify populations that may particularly benefit from behavioral changes.”