New information on how APOE-4 may increase risk of Alzheimer’s disease

Ever since Dr. Allen Roses and his group at Duke reported in the 1990s that people carrying the APOE-4 gene are at greater risk for getting Alzheimer’s, there has been uncertainty about how a gene that codes for a lipid-transport protein might be involved in dementia risk.  It certainly didn’t seem to fit into the dogma of the time that was based on the amyloid hypothesis.  Over the years it has become absolutely clear that carrying the APOE-4 gene is the most important genetic risk factor for late-onset Alzheimer’s. Apolipoprotein E comes in three distinct isoforms differing by just a few amino acids, APOE-2, APOE-3, and APOE-4.  By convention the genes that code for these proteins are written in italics, so the genes, or alleles, are APOE-2, APOE-3, and APOE-4.  APOE-3 is the most common form, as shown in the chart below, and it is considered to confer neutral risk.  Carrying one copy of APOE-4 increases risk of getting Alzheimer’s disease by about 3-fold and carrying two copies increases risk at least 12-fold. APOE-2 is rare, but appears to be protective.  According to one recent study, people with two copies of APOE-2 are 1000 times less likely to get Alzheimer’s than those with two copies of APOE-4.

So what’s the connection between a gene that codes for a lipid-transport protein and Alzheimer’s? In recent years, it has been noted that certain glial cells (including astrocytes) in the brains of people with Alzheimer’s contain numerous lipid droplets. There are several types of glial cells, but in general they are cells that provide both structural and nutritional support to neurons. A very recent and exciting paper shows that human glial cells grown in culture from APOE-4 homozygotes (having two copies of APOE-4) are loaded with lipid droplets, but those from the brains of APOE-3 homozygotes have very few lipid droplets.  The glial cells in APOE-4 carriers have an altered lipid metabolism, and it is possible that this could be a target for intervention in the future.

My thanks to Prof. Art Woods at the University of Montana for calling this paper to my attention.