What is APOE4 — the gene most strongly associated with Late Onset Alzheimer's Disease?

When it comes to late onset Alzheimer’s Disease (LOAD), there is one gene that specifically stands out from the crowd. It’s called Apolipoprotein Epsilon 4 (APOE4), and it is the single largest genetic risk factor for LOAD diagnosis.

There are three Apolipoprotein E genes that code for the production of APOE in both the liver and brain. They are APOE2, APOE3, and APOE4. These genes are found on chromosome 19, and happen to be dictated by a single nucleotide polymorphism. Single nucleotide polymorphisms are genetic mutations that are simply one nucleotide, or in other words, these are extremely small mutations.

APOE4 is expressed in roughly 14% of the globe’s population. The frequency of expression increases in those stemming from the descendants of hunter-gatherer societies, those whose ancestors lived in regions with a high parasitic burden, or among those who have heritage that can be traced to extremely food-scarce/ light-scarce regions, such as the arctic circle.

Consequently, individuals hailing from areas like Norway, which has been historically food scarce, had a high parasitic burden, and has an extremely cold climate, express APOE4 at a higher frequency than average. For some reason not yet known to science, APOE4, is found very infrequently among populations that were historically agrarian.

APOE4 may confer benefits to carriers while they are young, but at the cost of contributing to functional impairments with age. Image produced and created by author.

The base pair mutations of the ammino acid cysteine to arginine on sections 112 and 158 of mature APOE characterize the APOE4 mutation. APOE2, an APOE variant associated with prolonged life span, is noted by the base sequence cysteines on positions 112 and 158 of the protein. APOE3, which is defined as the intermediate between APOE2 and APOE4, has arginine in position 158 of the mature lipoprotein and cysteine in position 112.

The protein has critical importance in the vascular and nervous systems, as its expression is crucial for the proper regulation of some of the body’s most significant functions. For example, APOE plays a role in the clearance of bad cholesterol, regulating the brain’s immune system, controlling inflammation, regulating neuron plasticity, cell reproduction, regulating cerebral blood flow, and in the formation of new blood vessels.

APOE4 is a single nucleotide polymorphism that has been correlated with an increased frequency in the diagnosis of Late Onset Alzheimer’s Disease. Image by Anirudh on Unsplash

When APOE4 is expressed, some of the functional aspects of the protein become altered in a way that causes distinct vascular changes. A fantastic study from the Elahi lab at UCSF’s Memory and Aging Center found, for the first time, that carriers of APOE4 experience altered vascular density in vivo with the help of retinal scanners. These findings shed some light on the role that APOE4 likely plays in exacerbating a VCID-like phenotype of A.D by reducing capillary density and increasing the risk of atherosclerosis in carriers.

APOE4 does not just alter the vascular density of carriers. Indeed, it also dysregulates key cellular processes, such as cellular endocytic recycling. Researchers from the University of Texas Southwest found that the isoelectric point of APOE4, or the pH at which the protein functions how it needs to, is around a pH of 6.4. This consequently interferes with the recycling of content inside of cells. This novel finding may explain one aspect about APOE4 that contributes to the pathogenesis of A.D, as the researchers concluded:

Our results now show that pharmacological as well as genetic inhibition of NHE activity in the early endosome is sufficient to completely resolve the ApoE4 induced endosomal recycling block and restore the normal cell surface recycling rate of the synaptic ApoE receptor Apoer2 and the excitatory AMPA- and NMDA-type glutamate receptors that are regulated by Apoer2 and that traffic together with Apoer2 through the endosomal recycling compartments

In summation, APOE4 is the most strongly correlated genetic risk factor for LOAD. However, having a copy (or two) of the gene far from guarantees diagnosis of A.D. If you remain worried about the risk of developing Alzheimer’s or Dementia, the best form of action is to enact preventative measures. Regular exercise, alongside a lower glycemic index diet seem to be two particularly effective means of action that can significantly reduce the likelihood of LOAD.