January 21, 2021
Anyone who has a family member with Alzheimer’s disease worries: Does Alzheimer’s run in my family? Will I also go on to develop the disease?
Concerns about Alzheimer’s may become particularly pressing in older people who may be experiencing memory issues of their own. Genetic testing for Alzheimer’s is available through consumer testing companies like 23andMe. For one to two hundred dollars, you can send in a test swab of saliva or a cheek swab or blood specimen and find out if you carry a gene (specific coded information) that increases your risk of developing Alzheimer’s.
But just because you can get tested, doesn’t mean you should get tested. Because while a direct-to-consumer genetic test can inform you on a risk level, it cannot determine for certain whether you will develop Alzheimer’s disease. While some forms of Alzheimer’s are inherited (familial Alzheimer disease, or FAD), particularly early-onset forms of the disease that crop up as early as a person’s 30s or 40s, most cases of Alzheimer’s (also called sporadic cases) arise in older adults and are thought to be influenced not just by a single gene mutation like in FADs, but rather by several genes and also by lifestyle factors like diet and exercise.
One gene in particular has received a lot of attention: the APOE gene, which codes for a protein called apolipoprotein E that affects how cholesterol and other fats are processed in the body. Each of us carries two copies of the APOE gene, one inherited from our mother, and the other from our father.
The APOE gene comes in three main varieties, or alleles, numbered E2, E3 and E4. By far the most common form of APOE, carried by an estimated 78 percent of people worldwide, is the APOE-E3 variety, which has no effect on Alzheimer’s risk. Another 8 percent of people carry the APOE-E2 variety, which actually helps protect against Alzheimer’s and lowers the chances that you will develop the disease.
Most people worry about the third form of APOE, called APOE-E4, which is the strongest known genetic risk factor for late-onset Alzheimer’s. Some 14 percent of people carry one or two copies of this gene variant.
Those who carry one copy of APOE-E4 are at a two-fold to three-fold increased risk of developing Alzheimer’s disease; from 14 to 17 percent of those who carry APOE-E4 will develop dementia during their lifetimes, compared to 5 to 7 percent of those who do not carry any copies of the APOE-E4 variant. Those who carry two copies of APOE-E4 are at an 8-fold to 12-fold risk of developing Alzheimer’s; some 30 to 40 percent who carry two copies will eventually develop dementia.
Those who carry the APOE-E4 variant who do develop Alzheimer’s also tend to develop the disease at a younger age. Carrying one copy of APOE-E4 reduces the age of Alzheimer’s onset by two-and-a-half years; carrying two copies reduces the age at onset by about five years.
While APOE-E4 increases Alzheimer’s risk, scientists still aren’t sure how or why. It may promote deposition of beta-amyloid, the toxic protein that clumps together to form plaques in the brain; it may impede clearance of beta-amyloid from the brain and spinal fluid; or some other mechanism may be at work.
But just because you carry the APOE-E4 allele doesn’t mean you will develop Alzheimer’s disease. Many people who carry APOE-E4 never get Alzheimer’s. And many people who carry other variants of APOE do get Alzheimer’s. Nor does the presence of APOE-E4 predict who will progress from mild cognitive impairment, a brain condition marked by forgetfulness and memory problems, to full-blown Alzheimer’s.
So should you get tested for APOE-E4?
Given the unpredictability of APOE-E4 and its effects on Alzheimer’s risk, most experts do not advise getting tested for its presence. No effective therapies are currently available to modify the course of Alzheimer’s progression, so even if you do carry the APOE-E4 gene and believe that your risk might be higher, there are no drugs you can take to prevent or cure Alzheimer’s. Learning you carry the APOE-E4 gene may only cause undue anxiety if you convinced yourself that you are destined to come down with the disease.
For all these reasons, the National Institute on Aging recommends against routine genetic testing for Alzheimer’s disease except in a research setting, such as a clinical trial. Many experts also recommend that anyone considering getting tested should talk with a genetic counselor first about what the results might mean and how you might react to the result.
Most older people worried about Alzheimer’s can simply be monitored by their doctors and be given period memory tests like the Mini-Mental State Exam. They may not score at optimal levels, but that’s a normal part of aging.
If memory continues to worsen over time, your doctor might order a genetic test, or conduct brain scans to look for signs of beta-amyloid deposits in the brain. But it’s worth noting that more than 70 percent of those over 65 who show signs of beta-amyloid plaques in their brains never develop dementia in their lifetimes.
Brain scans can also help to rule out other, potentially treatable disorders that may be causing memory problems or other symptoms. Increasingly, blood tests that assess beta-amyloid or another protein called tau are showing promise for the diagnosis of Alzheimer’s as well.
Understanding the limits of genetic testing, and the uncertainties of diagnostic tests for Alzheimer’s, can help to put concerns in perspective. Lifestyle measures to help maintain brain skills, such as cognitively stimulating activities, social engagement, regular physical activity, a heart-healthy diet, and quality sleep, should be largely encouraged. At this time, such healthy behaviors will be significantly more useful than genetic testing.
By ALZinfo.org, The Alzheimer’s Information Site. Reviewed by Marc Flajolet, Ph.D., Fisher Center for Alzheimer’s Research Foundation at The Rockefeller University.
Source: Parichita Choudhury, M.D., MSc; Vijay K. Remanan, M.D.; Bradley F. Boeve, M.D.: “APOE E4 Allele Testing and Risk of Alzheimer Disease.” JAMA, January 14, 2021