Patients who find out they carry the ε4 allele of the apolipoprotein E gene may come to your office downright terrified, and possibly with good reason. Carrying one or two copies of the apolipoprotein E-ε4 gene (ApoE4 for short) is the strongest known genetic risk factor for late-onset Alzheimer’s disease (AD). The effect is dose-dependent, with homozygous individuals being at greater risk than those who are heterozygous, but even one copy of APOE4 confers increased risk compared to a non-ApoE4 carrier. Mutations in other genes, such as presenilin 1 and 2, and the amyloid precursor protein, increase risk for early-onset Alzheimer’s but early-onset accounts for less than 10% of AD cases. The vast majority are late-onset, and as much as 40-60% of AD patients carry at least one E4 allele. If you do the math, however, this means as much as 60% do not carry this genetic risk, so it’s clear that this gene is not required to develop AD. Let’s take a closer look at this genotype and see why it’s associated with increased risk for AD.

First, what is an apolipoprotein? The authors of a paper exploring the link between ApoE4 and AD explain it this way: “Apolipoproteins stabilize the surface of lipoproteins, serve as cofactors for enzymatic reactions, and serve as ligands for lipoprotein receptors.” In plain English, apolipoproteins are like docking equipment for lipoproteins, helping them to bind to their target tissues and deliver their precious cargo of cholesterol, fatty acids and fat-soluble nutrients.

Regarding ApoE, specifically, “ApoE is a major apolipoprotein in the brain, mediating the transport, delivery, and clearance of cholesterol and phospholipids. These processes regulate the cholesterol and PUFA content of synaptic membranes and are dependent on the expression and isoform of apoE.” Being that as much as 25% of the body’s cholesterol is found in the brain, and that neurons are highly dependent on polyunsaturated fatty acids (PUFAs) for proper cell membrane structure and function, different ApoE isoforms may have profoundly different effects in the brain.

There are three ApoE isoforms in the human family: E2, E3 and E4. The apoE protein is just 299 amino acids long and these isoforms differ at just two amino acid positions. However, these small changes result in substantial differences in the actions of these molecules, affecting their affinities for cell surface receptors as well as lipoprotein subtypes and their overall stability. Regarding the frequency of the three isoforms in the general population, ApoE2, E3 and E4 occur at frequencies of 7-8%, 77-78% and 14-15%, respectively. Research indicates the E2 allele is protective against AD, E3 is neutral, and E4 confers significantly increased risk. 

However, increased risk is not a death sentence. ApoE4 is neither necessary nor sufficient to cause AD—meaning that individuals may develop AD with no ApoE4 alleles, and even being homozygous for ApoE4 is not a guarantee that someone will develop AD. The National Institutes of Health’s National Institute on Aging said it well:

“APOE ε4 is called a risk-factor gene because it increases a person’s risk of developing the disease. However, inheriting an APOE ε4 allele does not mean that a person will definitely develop Alzheimer's. Some people with an APOE ε4 allele never get the disease, and others who develop Alzheimer's do not have any APOE ε4 alleles.”

So ApoE4 doesn’t cause AD, but there’s no doubt it’s a powerful risk factor. The question is why?

Research indicates the E4 allele was selected against in human populations with a long historical exposure to agriculture, especially grain-based agriculture. For example, populations with the lowest E4 frequency include long-time agriculturalists such as Greeks (6.8%), Mayans (8.9%), and Arabs in northern Israel (4%), while long-time hunter-gatherers have a much higher E4 frequency: 40% among African Pygmies, 37% among both the Khoi San and Papuans, and 21% among the Inuit. So it appears that people who carry the E4 gene may not be evolutionarily well-suited to a high-carbohydrate diet. Researchers note:

“The APOE ε4 allele may not be inherently damaging but only in combination with a high-carbohydrate diet, which is damaging in itself and is likely to be a major contributor to the high risk of CAD [coronary artery disease], and possibly AD, in modern populations with or without the APOE ε4 allele.”

Other Alzheimer’s experts concur, noting that “E4 is not an inherently damaging allele, it is only deleterious in combination with a HC [high-carb] diet (which is deleterious on its own.)” Indeed, high-carb diets have been identified as potentially contributing to increased risk for AD. Perhaps it’s not surprising then, that researchers now regularly refer to AD as “type 3 diabetes” or “brain insulin resistance.” In fact, the pathological similarities between metabolic syndrome, AD and general cognitive decline are so strong that a new phrase has been coined: “metabolic-cognitive syndrome.”

Metabolic syndrome is driven by chronically elevated insulin. The enzyme that degrades insulin—called, simply enough, insulin degrading enzyme (IDE)—has multiple other substrates it degrades, one of which is the beta-amyloid (Aβ) proteins associated with AD. IDE has a higher affinity for insulin than for Aβ, so when insulin levels are elevated, IDE may favor degrading insulin, thus leaving the Aβ to accumulate and form into the infamous amyloid plaques. Indeed, it’s been shown that under hyperinsulinemic conditions, insulin does compete with Aβ for IDE, resulting in the buildup of Aβ and formation of the plaques.

Interestingly, homozygous carriers of ApoE4 produce 50% less hippocampal IDE compared to non-E4 carriers, which may point back to the identification of E4 as an “ancestral allele” that may have been forged among populations who had less exposure to higher carbohydrate intakes and presumably would have had lower insulin levels and less of a need to degrade insulin. (Of course, insulin has many roles far beyond blood glucose regulation, but this is still a major task for insulin.) The accumulation of Aβ in the brain is greatest among E4 carriers, less among those with E3 and the least among those with E2.

With this in mind, ketogenic and low-carbohydrate diets along with other lifestyle interventions are currently being explored with promising results for improving cognitive function among individuals with ApoE4 and mild AD. One such case report showed a patient going from 21/30 to 28/30 on the MoCA test (mild AD to normal). Another case study of an E4+ subject with “early stage memory problems” showed improvement from 22/30 to 30/30 with similar interventions (ketogenic diet plus exercise), and another demonstrated improvement from 22/30 to 30/30 (mild cognitive impairment to normal), although the patient’s genotype was not specified.

Research linking the E4 genotype to increased risk of AD combined with the strong associations between AD and metabolic syndrome presents exciting new avenues to explore for therapeutic strategies to fight this devastating and as of yet incurable illness.