Genetic Risk for Alzheimer’s Disease: Hope for APOE4 Homozygotes
Last May, my inbox was flooded with articles about a recent scientific paper published in Nature Medicine. These articles suggested that people with two copies of the APOE4 allele, known as APOE4 homozygotes, have a genetic form of Alzheimer’s and are destined to develop the disease.
To make matters worse, according to these articles, on average cognitive and memory issues began around 65, about a decade earlier than for non-APOE4 carriers. Alzheimer’s signs are likely already in the brain at the tender age of 55!
The thought that Alzheimer’s might be my destiny was terrifying. The realization that I may only have a few remaining years without cognitive impairment was paralyzing. I felt like a decade of my future life may have instantaneously vaporized – and there aren’t many decades left!
I questioned my healthy initiatives and fretted about genetic testing.
My reaction motivated me to learn about APOE4 risk, and I am passing along some of what I learned to you.
What is APOE4?
The APOE gene is a gene that codes a protein named apolipoprotein E, which carries fats and cholesterol in your body.
We inherit one APOE variant from each parent. The three common variants of APOE, or alleles, are creatively named 2, 3, and 4. Each variant influences Alzheimer’s risk – APOE4 carries increased risk. APOE 3 carries a neutral risk. APOE2 is neuroprotective.
Since you have 2 variants, from 2 different people, there are a few possible combinations. The APOE4/APOE4 variation is the rarest affecting only about 2% of the world’s population. People with 2 APOE4 variations are commonly referred to as APOE4 homozygotes. Up to 20% of people have one APOE4 variant.
So, if you are an APOE4 homozygote, CONGRATULATIONS! You finally made it into the top 2% of something, although I am sure you would prefer to be in the top 2% of almost anything else.
Why Alzheimer’s is not Destiny for APOE4 Homozygotes (links to sources below).
Not all APOE4 homozygotes develop Alzheimer’s.
Even with some of the brain changes characteristic of the disease, some APOE4 homozygotes never develop dementia.
Environmental and lifestyle factors can reduce Alzheimer’s risk.
Certain protective genes may help to counterbalance the increased risk from APOE4.
APOE4 risk differs by ethnic and racial ancestry, but most study data came from white participants. More research is needed.
Many Alzheimer’s drugs are in development offering hope for treatment and possibly prevention.
There is also interesting ongoing research about the role of “epigenetics”, the study of changes in gene activity without alterations to the underlying DNA that influence whether and how APOE4 is “turned on” or “turned off”.
From the standpoint of a layperson, I am not sure how much we learned from the various newspaper articles describing the Nature Medicine paper – I learned that an article about Alzheimer’s can push me into a tailspin and a state of anguish for the better part of a week, but I didn’t learn anything that changed the advice of my medical doctor.
I think people with a familiar connection to Alzheimer’s suspect there may be a genetic component to Alzheimer’s. We knew from prior studies and guides that Alzheimer’s risk increases with one or two APOE4 alleles. We now know that there are steps we can take – lifestyle changes – that will reduce the risk of Alzheimer’s, whether you are an APOE4 carrier or not. For me, these articles solidified my commitment to a healthier lifestyle, which ultimately is a positive outcome.
In the section below, I have cited (1) support for the bulleted points above and (2) additional resources and guides explaining APOE4 and its effects. Happy reading!
I am not a doctor or medial professional. The purpose of this blog is to share my personal thoughts and encourage discussion. Please consult your doctor for medical advice, before making any dietary or health-related changes or with questions about any medical concerns or conditions.
SUPPORT:
Do Two APOE4 Alleles Always Mean Alzheimer's? | ALZFORUM. (“The genotype is not an absolute dementia predictor because a proportion of APOE4/4 carriers do live into old age without symptoms.”)
Alzheimer’s study suggests genetic cause of specific form of disease— Harvard Gazette (“But there is a variability in the range of when people develop symptoms. And that suggests that there might be environmental or lifestyle factors that can make people’s brains more resilient, or conversely, more vulnerable. This research really supports both ideas that genetics is a major driver in Alzheimer’s disease, but you can modulate your risk of showing symptoms.”)
Commentary from medical professionals about the study - APOE4 homozygozity represents a distinct genetic form of Alzheimer's disease. | ALZFORUM
Medications in development - A Holy Grail for ApoE4? - Apollo Health (regarding a possible drug candidate for APOE4 homozygotes); ALZ-801 Alzheimer's Treatment - Alzheon | Preserving Future Memories.
Dementia prevention, intervention, and care 2024 (“Overall, around 45% of cases of dementia are potentially preventable by addressing 14 modifiable risk factors at different stages during the life course.”)
Microglial Epigenetics Hints at How ApoE Toggles Alzheimer’s Risk | ALZFORUM (“… noted that the convergence between ApoE4 genotype and expression of other AD risk genes argues against the recently proposed idea that ApoE4 homozygosity is a distinct form of AD …”)
ADDITIONAL RESOURCES:
The APOE4 Forum - Welcome – ApoE4.Info This is a well-organized, entire community of E4/E4s with contributing scientists and questions and answers from all over the world. A lovely medical doctor has created a comprehensive primer on APOE4 and possible prevention strategies in plain English. Genetics are not destiny.
There is a Brain Mind free master class on Alzheimer’s Prevention by Dr. Richard Isaacson. Alzheimers — BrainMind – 20 videos each of 10 minutes or less. Video 4 specifically addresses APOE4 and Alzheimer’s Risk. Dax Shepherd interviewed Dr. Isaacson on his Armchair Expert with Dax Shepard podcast, which you can find on Spotify. Excellent & Informative.
Dr. Dale Bredesen and Apollo Health, The Most Effective Alzheimer's Recovery Protocol - Apollo Health. Here is a link to his blog article False Hopelessness Yet Again? - Apollo Health about the research paper. Dr. Bredesen, who has been at the forefront of Alzheimer’s prevention for over three decades, is the creator of the Bredesen Protocol, which is a comprehensive approach to prevent and reverse cognitive decline. He has also written several books about Alzheimer’s prevention.
Dr. Heather Sandison is the founder of Solvere Health Clinic in San Diego and Marama, the first residential memory-care facility with the goal of returning cognitively declined residents to independent living. Dr Heather Sandison I am currently mid-way through her new book, Reversing Alzheimer’s, The New Toolkit to Improve Cognition and Protect Brain Health.