My Alzheimer's Journey

Part 56 - Genetic Variant APOE4

After sleeping about four hours (that is my best guess because I am uncertain when I actually went to sleep), I woke up at 1:30 in the morning. It is December 22. I have two cats beside me. The apartment is quiet. Except for the white noise in my ears, I feel good.

Being a creature of habit, I got a bottle of water, I checked the flight app (I told you a few days ago it has become an obsession), and I checked Reddit.

There is a very interesting post in r/Alzheimers. The OP (original poster) is a “middle-aged person” with an elderly father suffering with Alzheimer’s disease. OP asked their father’s neurologist if they should have their APOE genes tested to determine their Alzheimer’s risk factor. The neurologist cautioned against the test because OP would not want to have the results on their medical records “for life insurance purposes”. OP said the neurologist mentioned there were other reasons not to have the test - although those reasons were not stated by the neurologist.

My first reaction to OP’s neurologist response was sadness and anger that we have to worry that potential negative information could impact our ability to secure life insurance. Or, impact the cost of life insurance.

I decided to spend my early morning researching the APOE gene.

The APOE gene is involved in making a protein called apolipoprotein E. In layman’s terms, apolipoprotein E combines with fats (lipids) in the body to form molecules called lipoproteins. Lipoproteins are responsible for packaging cholesterol and other fats and carrying them through the bloodstream. That is a very simplistic description for this very important gene. To learn more about the functions of the APOE gene, I suggest you read research article PO6249 on UniProt.

There are four variants of the APOE gene.

APOE1 is extremely rare. A 2006 study titled, The fourth apolipoprotein E haplotype found in the Yoruba of Ibadan, reports there are only four people with the APOE1 gene.

APOE2 is often referred to as the protective version of the APOE gene. It is also associated with longevity. This is a relatively rare gene. “Worldwide, its frequency is approximately seven percent, but its distribution is uneven. Whereas it is fairly common in Southeast Asia, Australia, and some African populations (up to 19 percent), it is absent from most indigenous American groups” (Singh et al., 2006; Abondio et al., 2019).

APOE3 is involved in regulating lipid transport among cells and tissues. It is considered neutral in that it does not increase or decrease Alzheimer’s risk. APOE3 is the most common APOE variant.

APOE4 is the bad boy variant. With about one-fifth of the world’s population carrying APOE4, this variant is known to substantially increase the risk of Alzheimer’s disease.

During my first appointment at Duke Neurology in June 2025, my APOE genotyping revealed both APOE 3 and APOE 4. These results (among other things) made the decision that I needed a PET scan.

Interestingly, a Duke neuroscientist first recognized that APOE4 increased Alzheimer’s risk. When Dr. Allen Roses and his team identified APOE4 as a risk factor for Alzheimer’s disease, they were met with skepticism. (I believe the discovery was announced in 1991; although, there are some reports stating the date as the late 1980’s). At that time, most people (researchers, neurologists, and pharmaceutical company executives) believed that Alzheimer’s disease was caused by amyloid protein fragments building up in the brain, resulting in memory loss.

Dr. Roses argued that amyloid plaques were the result of the disease - not the cause.

As an aside, Dr. Roses was an amazing human being. Sadly, he died in 2016 from a heart attack. He was 73 years old. Everything I read about Dr. Roses shows that he was not just a brilliant doctor, but an amazing father, husband, and friend to many. He never missed a Duke basketball game in 40 years. Look for a future blog post about Dr. Roses.

While the connection between APOE4 and Alzheimer’s disease is written in stone today, it isn’t clear why APOE variants differentially affect Alzheimer’s risk. In fact, it’s not even clear what the gene’s protein product (designated “ApoE”) does in the first place.

Scientists agree that APOE4 is the bad boy variant in the sense of increasing people’s risk for cognitive decline later in life. It seems that the big question everyone is trying to answer is whether the protein ApoE is the problem or if APOE4 is the connection to Alzheimer’s disease.

The answer to that question is likely the key that unlocks a cure for Alzheimer’s.

Thinking about OP’s question about getting tested for the APOE4 gene, if I were in my 30s or 40s, I sure as hell would get tested. We should all live healthier, regardless of any disease risk factors we have. Yet, it isn’t that easy. I zoomed through life with an adventurous and entrepreneurial spirit. Sometimes, I ate a healthy diet - not always. A juicy steak tastes damn good, and it was often a reward for accomplishing something in my life. My life was high stress, but I loved it. As an entrepreneur, some of my business adventures were highly successful and some were not. I enjoyed immediate gratification from the successes. That gratification was not always healthy.

If someone told me forty years ago that I was at high risk of having the Alzheimer’s disease in my late sixty’s, I would have eaten more salmon and less steak, I would have saved more money, and I would have had a PET scan every five years.

I didn’t know, though. So, what is the point of looking back.