Can we stave off APOE4 effects on brain health? Dr. Domenico Pratico', MD, FCPP

Alzheimer's disease is a neurodegenerative disorder characterized by the accumulation of amyloid plaques and tau tangles in the brain.  The condition, which accounts for approximately 60-65% of all dementia cases, primarily affects memory, thinking, and behavior, gradually impairing an individual's ability to perform daily activities.

Having one or two copies of APOE 4 increases the risk to develop Alzheimer's. However, a healthy lifestyle can signficantly reduce it.

In its most common form, the late onset, not a single cause has been identified so far. However, recent studies have shown that multiple factors can influence the risk for Alzheimer's disease. Importantly, a risk factor should not be considered as a cause of the disease but simply a modulator of the disease onset.

Age is probably the best-known risk factor, since with increasing age, the risk of developing Alzheimer's increases significantly. Besides age, another strong risk factor is a gene (a piece of DNA which we inherit from our parents) called apolipoprotein E (APOE).   

While there is only one APOE form in most animal species, humans are the only species known to produce multiple APOE variants (aka isoforms). The most common are APOE2, APOE3, and APOE4; the fourth one, APOE1, is extremely rare.

Which of these APOE versions we are carrying makes a big difference in our Alzheimer’s disease risk. In fact, of the three variants, only APOE4 increases the risk of Alzheimer’s significantly. As for each gene, we have always 2 copies of them. Studies have shown that having one copy of APOE4 allele accelerates AD onset by 2–5 years, while two copies accelerate onset by 5–10 years. By contrast, the APOE2 allele is generally regarded as neuroprotective.

There are 3 major variants of the APOE: APOE2, APOE3, and APOE4. Each has a different effect on nerve cells.

How does APOE4 influence AD risk?

APOE4 influences brain health negatively through various mechanisms:

• Induces damage by disrupting the normal processes used by the cells to remove waste material. Thus, it facilitates the accumulation of toxic proteins which with time overwhelm the normal intracellular clean-up process. This built up throughout the years damages first the function of the cells then it triggers its death.

• Is a trigger for inflammation within the brain. It activates immune cells that produce chemicals with potent inflammatory action (i.e., chemokine cytokines) and attack nerve cells. This reaction can also impair the function of an important brain structure such as the blood brain barrier, which becomes leaky and loses its integrity.

• Interferes with the ability of the nerve cells to produce energy by damaging or reducing the efficiency of the mitochondria, little organelles inside the cell that oversee the production ATP, the cell fuel. This fact results in progressive stress and starvation of the nerve cells which ultimately die (i.e., degeneration).

Why does APOE4 matter?

Approximately 25% of all people worldwide carry at least one copy of the APOE4, whereas it is estimated that about 3-4% carry two. However, it is important to stress again the concept that having one or two APOE4 copies does not automatically mean you will develop Alzheimer's disease.

Importantly, there is some good news on this front. Having APOE4 gene means you need to be more aggressive about prevention. To this end, science advises healthy lifestyle interventions, which if put in place significantly reduce the risk of Alzheimer’s disease even in carrier of the APOE4 gene.

These results can be easily achieved by following the “4 Cardinal Points of Healthy Behavior” which provides a framework for everyone who wants to achieve heathy aging and preserve brain health.

NORTH is for Nutrition and healthy diet (vegetables, fruits, olive oil, grains)

EAST is for Exercise daily (walk, bike, jog, etc.)

SOUTH is for Socialization and cognitive activities (book club, gardening club, etc.)

WEST is for Wellness monitoring (prevention and cure)

The four cardinal points of behavioral health.

Is there a medical treatment for individuals with APOE4?

Researchers are now testing APOE2 gene therapy replacement in humans. Some early results of these studies are encouraging since they show that APOE2 can reduce amyloid plaque buildup and inflammation in the brain, and even slow cognitive decline.

Should you get genetic testing for APOE4?

I would recommend this test only if one is ready to use the results to change behavior by following the 4 Cardinal points described above. We must always remember that while the “genetic code” is a primary factor for a healthy long life, environmental influences are potentially even more important. In this sense genetic should not lead us into the “give up” but into the “act on” state of mind.

Can we stave off APOE4 effects on brain helth? Yes, we can!

And as I always say, keep in mind that it is never too early and never too late to follow the 4 Cardinal points of healthy behavior.

If you are interested in reading more of my blogs:

Check out my recent blog: The 4 Cardinal Points of Behavior Domenico Pratico', MD, FCPP

Dr. Domenico Pratico' , MD, FCPP

Domenico Praticò, MD, holds the Scott Richards North Star Charitable Foundation Chair for Alzheimer’s Research and serves as a Professor at the Alzheimer’s Center at Temple, as well as a Professor of Neural Sciences at Lewis Katz School of Medicine at Temple University.

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