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Alzheimer’s Genetics 101: For You and Those You Love

The human brain

Statistically speaking, one in five women and one in ten men will get Alzheimer’s in their lifetime; however, certain individuals have a higher genetic risk. Your lifetime risk for Alzheimer’s disease can be as low as 5%, but as high as 70%, depending on your APOE genotype.
Common variations in a gene called apolipoprotein E, or APOE, are highly correlated to risk of Alzheimer’s disease. People with the highest risk for the disease begin to accumulate brain changes as early as their 20s. Knowing you carry the lowest genetic risk can be very reassuring, especially if you have other risk factors for Alzheimer’s disease. Knowing you have a higher genetic risk can motivate you to engage at the earliest possible time in treatments and behaviors that decrease your risk for the onset of Alzheimer’s disease.

There are other gene mutations that outright cause Alzheimer’s disease in multiple family members across multiple generations.  Because those causal variations are rare, they will not be discussed further in this blog.  My comments will focus on common genetic risk variants in the APOE gene.

Throughout my years in medicine, many of my patients have shared common concerns regarding their brain health, especially regarding their genetic risk. I have outlined below several questions which are frequently brought up during brain health assessments at the Center for Brain Health, which I’d like to share with you:

What role does genetics play in developing Alzheimer’s?

Fifteen percent of persons carry at least one copy of the APOE e4 variant (allele), and 2% of people carry two copies. Their risk increases 4-fold or 15-fold respectively. People who carry one copy of the APOE e4 allele have a 25% (men) or 30% (women) likelihood of Alzheimer’s in their lifetime; while people who carry two copies of the APOE e4 allele have a 50% (men) or 70% (women) likelihood of Alzheimer’s in their lifetime. Certain variants cause people to develop symptoms up to two decades earlier than others, leading to an onset as early as in their 40s.  Depending on your APOE genotype, there are very significant differences in your risk for Alzheimer’s and in your age at onset. People deserve the opportunity to know if they carry these genotypes, especially if they have other Alzheimer’s-related risks or concerns about their brain health, because the sooner they know, the sooner they can be motivated to act. We can reduce the risk, delay the onset, and, as research continues to indicate, potentially prevent Alzheimer’s disease!

How do I know if I have an increased genetic risk?

Make an appointment for an assessment with a qualified brain health professional, and get tested. It is a simple blood test. I cannot emphasize enough – the earlier this assessment is conducted, the better the long-term outcomes.

Can anything be done for people who carry the APOE gene risk variant? I mean, what is the use of getting tested for diseases like Alzheimer’s that have no cures at this point?

The biggest threat to the cure of Alzheimer’s today, is a defeatist attitude and a lack of commitment to primary prevention strategies. If I were otherwise at risk for Alzheimer’s (e.g., family history of Alzheimer’s, early menopause, history of concussion, etc.), I would find it reassuring or motivating to have a genetic test that stratified my genetic risk as being lower or higher. It is a fallacy that “Alzheimer’s can’t be cured, so what’s the use.” Observational studies and clinical trials are consistently demonstrating that interventions such as vigorous daily aerobic exercise, strict adherence to a Mediterranean diet, nutraceuticals, cognitive exercises, and medical management of up to 20 modifiable risk factors, can reduce your risk for Alzheimer’s disease by 60%.

Further, imaging and biomarker research shows that in a genotype and gender-dependent fashion, the brain changes that lead to Alzheimer’s are present in our 30’s and even in our 20’s. So the earlier we define our risk factors for Alzheimer’s, particularly our genetic risk, and the earlier we can intervene, and the greater the opportunity and likelihood that we can successfully reduce risk of disease onset.

Those at greatest risk (e4/e4 genotype) can be engaged in a brain health program, including risk assessments and surveillance and targeted interventions (personalized medicine). There is also the opportunity to participate in clinical trials that employ drugs that target the amyloid or tau protein cascades (or both) that underlie brain degeneration in Alzheimer’s, as primary prevention. However, the problem with most clinical trials in Alzheimer’s is timing. Consider the following analogy: In Chicago, Mrs. O’Leary and her cow that kicked over the lantern and caused the Chicago fire are legendary. Imagine the difference it would have made had Mrs. O’Leary doused the lantern with her bucket of hard-earned milk immediately when the fire was small; versus the comedy had she doused the city with the bucket of milk hours later when the city was ablaze. The reason most drug trials for Alzheimer’s fail is because the well-reasoned treatments are applied too late, like a bucket of milk on a city-wide fire. If those treatments were applied pre-symptomatically, when just a spark, and especially targeting those with the most to gain (the APOE e4 allele carriers, and certainly persons carrying two e4 alleles, the “homozygotes”), their effects with respect to prevention could be profound.

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