Apolipoprotein E (APOE) is a well studied gene, given that variants are associated with a greater risk of developing Alzheimer's disease. That said, high blood pressure and high blood cholesterol levels are just as important as risk factors for Alzheimer's disease when compared against all but the worst APOE variant, APOE4. Looking beyond Alzheimer's, in most cases lifestyle choices and their consequences on the operation of metabolism, particularly becoming overweight, have larger effects on risk of age-related disease than genetic variants. The common wisdom of a 75%/25% split between environment and genetics respectively in the matter of age-related disease and mortality may be overestimating the contribution of genetics, per more recent data.
The point of investigating the activities of specific protein variants in which risk or scope of age-related is shifted is this: that the work may lead towards points of effective intervention. Not the gene or protein itself, usually, but something in the mechanisms with which it interacts. The late stages of all age-related conditions are enormously complex, and having the example of differences that affect the progression of the condition can help to pin down which of the many, many possible metabolic processes are most important. That is somewhat in evidence in the research materials here, but of course says nothing about how to effectively target those important mechanisms.
Mention ApoE and Alzheimer's, and the conversation turns to the E4 allele, the strongest susceptibility gene for the disease. But ApoE has another side, in ApoE2. Though this isoform protects against AD, scientists have barely studied it. Now ApoE2 is attracting scrutiny as scientists are asking exactly how some people maintain their mental acuity into old age. A study of ApoE genotypes in 5,000 autopsy-confirmed cases of AD revealed that people with two copies of E2 see their risk of dementia plummet by a stunning 90 percent compared with those with the common E3/E3 genotype. Other work suggested that this could be because ApoE2 reduces amyloid and tau pathology, and boosts gray-matter volume in critical brain regions. E2's benefits seem specific to Alzheimer's, not generic to neurodegeneration.
ApoE is the major cholesterol-carrying protein in the brain. It has been studied since its discovery as an AD risk gene in the early 1990s, but is newly emerging as a hub for glial responses to amyloid and tau aggregate deposition. The gene exists as three polymorphic alleles - E2, E3, and E4 - with a worldwide frequency of 8 percent, 78 percent, and 14 percent, respectively. Several mutated forms are also known. ApoE4 receives by far the most attention from AD researchers, because it boosts the risk of AD up to 15-fold depending on the study population, and occurs in 40 percent of people with AD. E2, the protective allele, has received scant attention, because it is the least common of the three and largely absent from AD samples.
It is suggested that ApoE4 predisposes people to Alzheimer's disease by modulating astrocytes and microglia. Researchers describe transcriptional differences between iPSC-derived human astrocytes and microglia that express ApoE4/4 or ApoE3/3. The ApoE4/4 glia generated more cholesterol than their E3/3 counterparts. They exported and degraded it poorly, causing lipid to build up inside them. The E4/4 glia also pumped out greater amounts of proinflammatory cytokines and extracellular matrix proteins than E3/3s.
Does this have anything to do with Alzheimer's? Lo and behold, in Alzheimer's disease brains, astrocytes and microglia behaved quite similarly to these ApoE4/4 glia. They accumulated lipid and ratcheted up inflammation. Importantly, they did so regardless of their ApoE genotype. The data imply that ApoE4 may nudge microglia and astrocytes toward an Alzheimer's-like state. Perhaps faulty lipid metabolism is one of the earliest changes on the path to Alzheimer's. If so, restoring glial lipid regulation could be a therapeutic approach.