The Genetics of Alzheimer’s and Dementia
Keywords: APOE gene, Alzheimer’s disease, late onset of dementia, longevity, Pre-alzheimer’s APOE genetic test.
Anil Kumar, PhD | Last updated: 22 Jun 2020
Living up to the age of 80 or even 90 years is fairly common today.
This wasn’t the case hundred years ago, or even few decades ago.
Today, a woman in Hong Kong is expected to live an average age of 88 years. Japan, Switzerland and Norway have similar life-spans for women and men.
Most of this is due to advances in treatment of diseases. And huge expenditure in public health as well as management of chronic conditions. What used to kill people regularly–heart attack, diabetes, bacterial and viral infections–can be managed today. That has helped in extending our longevity.
History of longevity
The first argument about aging in modern times was made in 1889, by Alfred Russel Wallace—a colleague of Darwin—who argued that when human beings “have provided a sufficient number of successors,” there are no reason to live long and consume the scarce resources.
Another contemporary, August Weismann, proposed a different theory. Natural selection works to prioritize survival of the whole species—not an individual. Therefore, a person’s lifespan can be longer as long as they can adapt to the environment. His argument suggested genetics should play a considerable role in this adaptation.
Because people didn’t live long enough until recently, there wasn’t a way to prove how genes affect longevity and aging.
The genetics of aging
Strong evidence is now accumulating in support of this theory. Siblings of centenarians have four-times higher chance of living up to their nineties. Studies of twins show reasonable evidence that long life span can be passed on to children. Detailed genetic analysis suggests a handful of genes play major role in inheriting long life spans.
As life spans increased in past few decades, Weismann’s idea of adaptation to the environment is clearly at play.
It hasn’t been all that rosy though. With this increased life span, a new challenge of cognitive decline has emerged.
Health conditions of the mind, such as Alzheimer’s Disease and dementia are emerging during these late years. Very little knowledge is available today in the understanding of these conditions—let alone any cure—but efforts are growing.
Many experts and public health researchers believe Alzheimer’s might be the next diabetes. By affecting a large population and draining valuable resources in coming decades.
Fortunately, the recent research in genetics suggests it’s not all bad news. A steady pace of understanding has evolved to demystify a close correlation between certain genes and cognitive decline.
We have a long way to go see the full picture. However, evidence that certain genes might increase the risk of Alzheimer’s Disease and early onset of dementia is emergin.
Genetic risk of Alzheimer’s risk
Once such gene is called APOE or apo-lipo-protein E.
Normally, this gene is responsible for making proteins that maintain the cholesterol levels in our blood. It isn’t surprising that APOE plays important role in inheriting the risk of cardiovascular disease.
More importantly though, research has shown that it also helps clear the amyloid plaques in the brain. Gradual accumulation of such plaques results in damage to neurons and a slow progressive decline in brain activity.
There are three versions of the APOE gene: E2, E3, and E4. Since we get one gene from each parent, the APOE genes appear in pairs. Several in depth studies have shown that E4/E4 pair has the highest impact on mental decline with age.
The amyloid plaques are the hallmark of Alzheimer’s disease. That’s because E4 gene aren’t as effective as others in clearing them.
E3 is the most common gene: 3 out of every 4 people carry them. However, E2 version is more beneficial. It helps clear the amyloid plaque and reduces risk of Alzheimer’s disease as well as early-onset of dementia.
APOE4 gene and cognitive decline
Data from recent genetic studies have found those carrying E4/E4 pair show unexpectedly higher rates of Alzheimer’s Disease at 91%—a fifteen-fold increase compared to general population. The condition might start late sixties, which is earlier than usual.
Among those carrying only one of the E4 genes, this rate is 47% and age of onset around 75 years. In contrast, those carry E2/E2 pairs have barely 20% chance of Alzheimer’s. And a very late age of about 84 years to see the signs.
One analysis demonstrates APOE4 enhances damage to the blood-brain barrier leading to Alzheimer’s disease.
The tangled web of APOE gene
Some progress in uncovering the roles of other factors has highlighted a much more complicated picture. For example, some genes might negate the E4/E4 curse. This might help explain why not all societies see this universal decline. And previously unknown yet unrelated effects are being reported.
A 2020 study from Stanford University suggests the presence of single gene of KLOTHO in E4/E4 group might help in better clearance of amyloid plaques and reduced risk of Alzheimer’s disease. This longevity gene has links to memory and learning enhancement.
APOE4 has also played an important role during the COVID-19 pandemic. Multiple studies show higher risk and severity of disease in presence of APOE4. Analysis of UK Biobank genetic data concludes E4/E4 pair increases risk of severe infection by two-and-half times.
There is no cure for Alzheimer’s yet. But knowing the risk can motivate people in making changes to their life style. Those are still a much more significant risk factors in comparison to the genetic risks we inherit.
Source: APOE e4 Genotype Predicts Severe COVID-19 in the UK Biobank Community Cohort by Kuo et. al. in The Journals of Gerontology: Series A, 26 May 2020.
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