Most of us, if we’re not research scientists, don’t walk around with the name of a gene variant in our heads. ApoE4 is an exception. Quite a few of us are familiar and typically, it inspires feelings of dread. The story, in brief, is that we all carry the ApoE gene in our genetic make-up. But roughly 20 - 25% of the population has at least one ApoE4 version of the gene which puts them at a 2 -3 times higher risk of developing Alzheimer’s disease over the course of a lifetime, and an earlier average onset. And around 2 -3 % of that group have two copies of the “bad” 4 variant (we inherit two copies of genes, one from each parent) and they, through no fault of their own, are in a tough spot, with an 8-12 times higher lifetime Alzheimer’s risk. 

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So, to say the least, these are sobering stats. And they will weigh on anyone who is considering taking an easy-to-find and relatively inexpensive genetic test, through a commercial company like 23 or Me, or through your own physician. The test will tell you, point-blank, which ApoE group you fall into. Let me say, upfront, I strongly endorse taking that test. But first you need to understand what your ApoE status means and what it doesn’t. 

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It is a marker for Alzheimer’s risk. It is not a crystal ball. Just because your test tells you that you’ve got one of the “4” variants doesn’t mean you’re fated to get AD. What it does tell you is that you’re running a greater-than-average risk and that means you need to be that much more diligent about healthy habits and lifestyle, which is a good idea for everybody, no matter what genes they were dealt. Here’s what else you need to know:

What is APOE exactly? 

It’s a gene that provides the instructions for the body to make a specific protein, also called ApoE, that’s involved in transporting and metabolizing fats or lipids, for instance, cholesterol. It’s especially important inside the brain where it helps maintain brain cells, repair damaged brain damage and clear out metabolic waste. Think of it as a brain handyman. And the gene with the “4” variation just isn’t as good at doing its very complex job. It does substandard work clearing out metabolic waste, especially two of the hallmarks of Alzheimer’s, amyloid plaque and “neurofibrillary” tangles of tau protein which both build up inside the neurons.  It tilts the brain’s immune system, the microglia cells, towards inflammation, contributing to the neuroinflammation that drives AD. It interferes with the ability of the mitochondria inside the neurons to generate the energy that drives the whole show and protects it against metabolic damage. And it comes up short helping cholesterol do what it’s supposed to do, building up the insulation that protects the neurons (“the myelin sheath”) and the membranes that cover the connections between the neurons, the synapses. 

A wake-up call, not a call to surrender. 

OK, that’s quite a laundry list of areas where ApoE4 comes up short. You may be asking yourself at this point, why bother to find out my status if I’m just going to be depressed if the news is bad? Though ApoE4 status means you’ve been dealt a bad card, it’s not proof that you’re going to lose the game. Plenty of people with the gene variant never develop Alzheimer’s. And plenty of people who don’t carry the “4” variant do develop it. It’s all how you play your cards. It’s not rocket science. 

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Given that the “4” variant means your system is less good at handling metabolic waste and more prone to inflammation, do everything in your power to generate less waste and systemic inflammation. There’s even evidence that “4” carriers derive a greater health benefit than the majority of the population not at increased risk. Remember, this is a long game. We know that the pathological brain changes that can ultimately manifest as Alzheimer’s are churning under the surface for some 15-20 years before disease symptoms emerge. The earlier you can get your metabolic house in order, the better. I can tell you that my patients who learn they’re “4” carriers are among the most motivated to make healthy changes and stick to them. They understand they have less margin for error. 

Sleep to the rescue.

As my regular readers should recall, sleep is the body’s best ally when it comes to getting rid of metabolic waste, especially in the brain. Getting 7-9 hours of high-quality restorative sleep activates the brain’s glymphatic system which flushes out amyloid plaque and other wastes. Not getting that good sleep only compounds the problems brought on by ApoE4’s sluggish waste removal capabilities. So, just in case you need one more reason to focus on improving your sleep quality, Apoe4 is a big one.

Movement as self-defense.

When it comes to pushing back against the “4,” embracing movement – be it everyday physical activity or a more structured exercise program – enhances the function of all the systems that don’t work so well if you’ve got the gene variant. Aerobic exercise has been shown to increase brain-derived neurotrophic factor (BDNF), a growth factor that encourages the formation of new brain cells. 

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As well, movement reduces brain inflammation, improves brain blood flow, and juices up those mitochondrial cellular power plants. It really is genetic self-defense one-stop shopping. Remember, intense exercise isn’t called for here (that can be pro-inflammatory), but at least 150 minutes a week of moderate aerobic activity, the government recommendation, is a good benchmark. And throw in two or three weekly sessions of strength training to build up or at least protect your muscles, which is important for metabolic health and is closely associated with brain health. 

Feed your head (well). 

Eating for overall health also means eating for your brain: plenty of nutrient-rich veggies and healthy fats; ditching the sugar and processed foods, and curbing carbs. That will keep insulin resistance in check as well as prediabetes and type 2 diabetes at bay, as an unhealthy metabolism works in league with the “4” variant to age your brain before its time. And a low-carb, high-plant fiber diet also keeps your gut microbiome in balance. There’s evidence that an unhappy microbiome can release amyloid into the bloodstream which could collect in the brain as amyloid plaque. And while I think saturated fats have been unfairly demonized, I do think there’s a strong argument for limiting their consumption here. People with the variant may process it differently, and less effectively, than those without. 

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On the plus side of the ledger, eat plenty of small, oily fish (sardines, mackerel, etc.) and if they’re not to your taste, it’s easy to get plenty of brain-protective omega-3 fatty acids in supplement form. 

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When you eat can also play a major role in metabolic health. I’m a big fan of intermittent fasting (IF) /time-restricted eating (TRE) which helps maintain brain-friendly blood sugar levels. A keto diet is another option (though not for everyone, and check with your doc first) but periodically going into ketosis, that is, producing low-inflammation ketone bodies for energy, is a good thing, if you can manage it. 

The engaged brain is a protected brain.

While we’re at it, let’s not lose sight of what brains are designed to do, thinking, sure, but also engaging with the outside world. The more you keep your brain active – learn a foreign language, practice a musical instrument, read a good book! – the more cognitive reserve you build up. Same goes for maintaining a rewarding circle of friends. All this mental activity may not necessarily slow down the AD changes inside the brain, but it very likely will delay the time, possibly indefinitely, when symptoms show up. Pathology labs have a long record of people whose brains looked severely diseased on autopsy and yet who lived long, fulfilling lives. 

Supplementing the brain.

There’s a medicine cabinet full of supplements for which we have suggestive evidence that they can help protect the brain. I’ve already mentioned omega 3 supplements but I’ll add a few more, still far from an exhaustive list. Curcumin is a good antioxidant supplement and both choline and plasmalogens may have brain-health-specific properties. Other supplements can help enhance energy production in the brain, a vital defense against neurodegeneration: creatine, CoQ10; alpha-lipoic acid, vitamin B12, nicotinamide riboside (part of the B3 family) which converts to NAD+, essential for brain energy. 

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Here’s one I’ve recently written about: low-dose lithium orotate which a number of recent studies suggest may directly inhibit the neurodegenerative process. It’s cheap and at these low doses – 3 to 5 mg – virtually side-effect free. And I’ll toss in two pharma drugs which you may want to explore with your physician: Ezetimibe (Zetia), an anti-cholesterol drug which could help, because APOE4 carriers tend to absorb and retain more cholesterol in the brain and bloodstream, and lowering this absorption may help reduce Alzheimer’s-related risk. Low dose Tadalafil, a PDE-5 inhibitor commonly prescribed (at higher doses) for erectile dysfunction, could potentially improve blood flow to the brain, supporting the nitric oxide signaling pathways that are often impaired in people with the APOE4 gene variant.

Sweating your brain health.

Research out of Finland makes the persuasive case that regular sauna use can protect brain health and lower the risk of dementia. The theory is, the heat promotes the body’s production of heat shock proteins which helps the body properly “fold” proteins, slowing down the accumulation of misfolded brain proteins, like amyloid plaque, which gum up the (brain) works. 

Push back on APOE4 by unwinding often – very often.

While currently there’s no known way to fully “override” the effects of ApoE4, your lifestyle choices can meaningfully shape how that risk plays out over time. Practices like stress reduction, meditation, mindfulness, etc., have been linked to lower inflammation and better vascular health, which are key because chronic stress can elevate blood pressure and strain the brain’s delicate blood vessels. Just as important, simple activities like staying socially connected and spending time in nature appear to support emotional resilience and cognitive health, offering a steady, protective counterweight to the biological vulnerabilities associated with ApoE4.