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Of the many forms of dementia, Alzheimer’s disease has received the most research attention. People are often worried they will inevitably contract Alzheimer’s disease if a parent did. But increasingly, scientists have found this is not necessarily the case.
Some People Have a “Risk Allele”
Processes in our bodies are regulated by genes, but not everyone has exactly the same version of each gene. These different versions are called alleles. Different alleles carry different risks for physical conditions in the body, including Alzheimer’s disease and other dementias.
One of the most strongly replicated findings for genetic risk of Alzheimer’s disease in late life involves the APOE gene, and the ε4 allele. You have two alleles for every gene. For the APOE gene, you may have the ε2, ε3, or ε4 alleles. The ε2 allele appears to be protective; people who carry it are less likely to develop Alzheimer’s disease. Having one allele with ε4 increases your risk, however, and having both alleles with ε4 raises it even more.
Distributions of ε4 differ based on ancestry groups, but in general, it is much less common than ε3 (the most common). Moreover, the APOE alleles are only risk and protection factors; they do not determine whether you get the disease. Even people with the highest risk—double ε4—only develop Alzheimer’s disease about 40% to 60% of the time by age 80. This chart presents a simplified example of the distribution of the alleles and the likelihood of developing Alzheimer’s disease by age 80. This chart is based on multiple studies; actual rates differ by age, sex, ancestry, and other factors.
Early Onset vs. Late Life Alzheimer’s Disease
A disclaimer: Early-onset Alzheimer’s disease—which manifests before age 60—has a strong genetic influence. The early form is relatively rare. For example, fewer than 1 in 100,000 adults in their 40s have Alzheimer’s disease.
This genetic influence is evident in the extended Paisa family in Colombia, with 6,000 related individuals. They have a very high rate of early-onset Alzheimer’s disease, starting in their 40s. The disease is tied to a mutation in the PSEN1 gene (E280A); sometimes called the Paisa mutation. Individuals with this mutation will almost certainly develop early-onset Alzheimer’s disease. Nevertheless, scientists recently discovered one of the Paisa family members who had the mutation but did not have Alzheimer’s disease at age 60, lending additional support for the possibility of protective non-genetic factors.
Is It Really This Simple? … No
You may be thinking, “Wow. That seems so easy. All they have to do is fix one allele on one gene.” Turns out APOE isn’t the full story. Yes, scientists have found the increased risk with E4. But scholars are also working on GWAS (Genome-Wide Association Study) models to understand genetic risk factors for many forms of dementia.
GWAS models analyze multiple genes across large groups of people. These analyses are showing that dementia is highly polygenic. That means that multiple-gene constellations are involved, well beyond APOE alleles. Each gene alone may add only a small amount of risk, but collectively a set of genes may contribute to a measurable increase in risk. GWAS shows that dementia risk is usually due to combinations of many genes, each with a small effect, rather than a single gene acting alone. Together, these genes can increase risk, much like multiple ingredients coming together to make a cake, where no single ingredient explains the final result by itself.
Some of these genes are associated with inflammation, and how the brain handles fats that play a key role in the maintenance of neurons (brain cells). Other genes are involved in endosomal/lysosomal function, how the brain keeps abnormal proteins from building up.
Although many genes are involved in setting risk for Alzheimer’s disease, the vast research on the APOE ε4 allele lays the groundwork for understanding the functions of genes in the risk of dementias.
Lifestyle and Genetic Risk
Genetic risk is just that, risk. Lifestyle and genes interact in a process called epigenetics. Epigenetics is how your body uses your genes—like turning a dimmer switch up or down—without changing the gene itself. That process is called gene expression. When people experience stress or eat highly processed foods or are sedentary, epigenetic changes can take place that affect how genes are used.
If someone carries APOE ε4 or other dementia-risk genes, those genes don’t act in isolation. Being sedentary, eating highly processed foods, chronic stress, poor sleep, and metabolic problems can influence epigenetic changes—chemical tags (called DNA methylation or histone changes to be fancy) that turn certain genes up or down without changing the DNA itself. When these changes lead to overactivation or poor regulation of genes involved in inflammation or cellular repair, the risk of dementia may increase.
The good news is that the opposite—exercising, keeping stress down, eating a well-balanced diet—can help lower risk, even in people who have alleles that create high risk. In fact, some studies suggest that people who carry the APOE ε4 allele benefit more than other people from interventions that target prevention of Alzheimer’s disease. Of course, this may partially reflect measurement issues; it is more difficult to show that an intervention was effective when someone was unlikely to develop the disease to begin with.
The upshot is that for many people, lifestyle may matter more than whether a mother, sister, or father had Alzheimer’s disease. You still have the ability to influence your lifestyle, and lifestyle continues to play a fundamental role in the development of dementia—particularly for those at greatest risk.
