Dementia Prevention Tactics Supported by Science

Given that, knowing your status could meaningfully shape your approach to prevention—which is important because as many as 45% of dementia cases can be prevented or delayed through lifestyle interventions, according to the 2024 Lancet Commission report on dementia prevention.

The latest science on APOE variants

Apolipoprotein E, or APOE, is a gene involved in transporting cholesterol and other fats throughout the body and brain. Everyone inherits two copies—one from each biological parent—and there are three common variants: E2, E3, and E4. The variants you carry have a profound effect on Alzheimer's risk.

• APOE2 is less common and is associated with lower Alzheimer’s risk
• APOE3 is the most common and is present in up to 80% of people, depending on ancestry
• APOE4 is carried by roughly 20-25% of people in many Western countries and is the strongest common genetic risk factor for Alzheimer’s. One copy typically increases an individual’s risk by about two- to threefold, and two copies may increase risk by eight-fold or more.

What this actually means is that while the average person has about a 1 in 10 chance of developing Alzheimer's by age 85, someone with one copy of the APOE4 gene has a 2-3 in 10 chance, and someone with two copies has closer to a 5-6 in 10 chance of developing Alzheimer’s by age 85. Therefore, though having one or more copies of APOE4 raises the odds, it is still not a guarantee.

Importantly, these are risk patterns, not predictions—and using genetics alone to approximate risk can be very imprecise, says top preventive neurologist Dr. Richard Isaacson.

This is where lifestyle modification can significantly bend the curve by lowering the risk and/or delaying the onset of symptoms by a decade of more. In fact, certain interventions (like optimizing your intake of Omega-3 fatty acids) are particularly effective in counteracting APOE4-related risk.

In addition to Omega-3s found in fatty fish, we also know many of the strategies that meaningfully reduce dementia risk—regular exercise, a Mediterranean-style diet, quality sleep, cardiovascular risk factor optimization, and more—may benefit everyone, and E4 carriers even moreso. One 2018 analysis found that such interventions improved cognitive function as much in people with E4 as in those without it.

The “genetics is destiny” viewpoint has also been significantly challenged by the U.S. POINTER and FINGER studies. These trials provide rigorous evidence that lifestyle interventions are not only effective for the general population but may be even more beneficial for APOE4 carriers, who saw a greater cognitive benefit from the lifestyle intervention than non-carriers. In fact, researchers recently found that the benefits of the initial 2-year lifestyle intervention were sustained for over a decade, significantly delaying the onset of cognitive impairment. These results may be due to APOE4 carriers being more “vulnerable” to lifestyle related insults (like high cholesterol or inflammation), and therefore, have the most to gain when those factors are optimized.

[Listen to our fascinating episode of Decoding Women’s Health about this with Dr. Richard Isaacson over here.]

What moves the needle on reducing your risk

The key to prevention is, of course, intervening early. Neurodegenerative disease begins silently decades before the onset of symptoms like memory loss, making midlife prevention a powerful window for protecting long-term brain health.

As the field of dementia prevention matures, with more science emerging all the time, we have collected fresh advice from our experts, including Dr. David Dodick, a top neurologist and the Chief Science & Medical Officer at the Atria Health Institute, and the aforementioned Dr. Isaacson:

• Actively optimize cardiometabolic markers—and don’t settle for “borderline.” For brain health, your blood pressure, cholesterol, and glucose should not just be monitored but also treated, even if they’re so-called borderline.
  • Dr. Isaacson recommends a target blood pressure of less than 120s/70s in most people.
  • Drs. Dodick, Isaacson, and others say we should be treating high LDL cholesterol and apo-B (a protein that carries cholesterol throughout the body) when lifestyle alone isn’t sufficient (ideally using targeted treatments based on a person’s individual biology). For example, research shows statins reduce dementia risk, particularly when used in midlife, contradicting earlier concerns about cognitive harm. While a target LDL goal of less than 100 mg/dl is “normal,” less than 70 mg/dl is closer to “optimal,” and in those with cardiovascular disease, a general goal should be an LDL of less than 55 mg/dl.
  • Dr. Dodick says that blood glucose as measured by HbA1c should be 5.5% or below—stability in this range is particularly important for brain health.
• Treat insulin resistance and visceral fat as brain-aging risk factors. Deep abdominal fat and poor glucose metabolism both accelerate amyloid buildup and brain aging, while building and preserving muscle mass improves metabolic efficiency and cognitive resilience.
• Individual exercise prescriptions can be meaningful tools for body composition. Since visceral fat accelerates brain aging, working toward an optimal mix of muscle, fat, water, and bone is key. Resistance training is one powerful tool—particularly during peri- and postmenopause, when muscle loss accelerates. Resistance training, supported by adequate protein intake and hormonal optimization when needed, is essential for maintaining metabolic and brain health.
• Integrate hormone support into brain-health strategy when clinically appropriate. Declining estrogen during the menopausal transition is linked to accelerated brain aging, while hormone therapy has been associated with healthier brain imaging, aging, and biomarker profiles when started around menopause—and in select cases, later in life.
• Maintaining rigorous sleep hygiene and pursuing formal screening for sleep apnea. These are no longer just “wellness” suggestions, but are essential medical strategies to protect the brain and prevent cognitive aging, dementia, and Alzheimer’s. Poor sleep quality significantly increases Alzheimer’s risk, but this association is intensified in APOE4 carriers. Chronic insomnia (trouble sleeping 3+ days a week for 3 months) is now linked to a 40% higher risk of developing dementia.
  • For APOE4 carriers, this “insomnia effect” leads to even steeper declines in memory and thinking skills. In addition, consistently sleeping less than 6 hours per night in midlife is associated with a 30% increased risk of late-onset dementia. Untreated sleep apnea also accelerates cognitive decline and brain atrophy, and increases the risk of Alzheimer’s disease by 45%.
• Use APOE status to guide precision prevention. Early evidence shows that APOE4 carriers benefit from earlier, more intensive risk modifications, such as: precision nutrition, including intentional omega-3 optimization through diet and supplementation when levels remain low; stricter alcohol limits; and aggressive cardiometabolic control.
• Take heed of all the other modifiable risk factors for dementia. The Lancet Commission’s 2024 report cited 14 lifestyle behaviors that can reduce risk, among them depression, movement, smoking, excessive alcohol consumption, and more.

What’s on the horizon

Over the last five years, Dr. Isaacson’s clinical research team has been working on a new type of APOE blood test.

While most people view APOE as a gene, Dr. Isaacson thinks about it as a kind of protein. People with one or more copies of the APOE4 genetic variant produce varying amounts of APOE4 protein, which can now be measured in the blood. His latest research has shown that using a ratio of APOE4 protein to the total amount of APOE2, APOE3, and APOE4 protein (also referred to as Pan-APOE) may be a more dynamic and accurate predictor of Alzheimer’s risk in real-time when compared to a static genotype alone.

Dr. Isaacson uses the analogy of a car engine when describing this new test. If a person’s DNA is the car engine, the amount of protein expressed (and the ratio) can function like an engine light, helping evaluate how well the body is functioning. For example, if you are doing everything right by putting high quality fuel in the car (eating food that supports brain health), getting regular oil changes (exercising regularly), and changing worn out brakes (managing your stress), the engine can be primed to run with peak performance (give you a more favorable APOE4 protein to Pan-APOE ratio).

Dr. Isaacson’s team hopes to bring this test into use as a lab-developed clinical grade test later this year.

The bottom line

APOE is the strongest common genetic risk factor for Alzheimer's—an unusually influential single gene in what remains a complex disease shaped by many factors. Genetic testing can help you and your care team tailor your prevention approach, but it doesn't determine your fate. The interventions that reduce dementia risk—cardiovascular optimization, resistance training, Mediterranean diet, quality sleep, and the other factors mentioned above—work regardless of genetic status, and emerging research suggests they may offer even greater protection for those at highest risk.

—Written by Dr. David Dodick and Siobhan O’Connor