Chapter 98
Neurodegeneration — 4
APOE4 hurts the brain in various ways, but an important one is the way it causes faulty cholesterol metabolism, which in turn increases cholesterol buildup in cells, impairs myelination (the critical insulation around nerve fibers), and renders the blood-brain barrier dysfunctional.
From a study of over five hundred people with two copies of APOE4, we saw almost all of them manifest Alzheimer’s pathology. Also, the onset of symptoms and biomarker changes, earlier than in individuals with other APOE genotypes, was more predictable. However, many individuals are resilient and do not develop symptoms or cognitive decline. Nonetheless, the findings were considered to redefine having two copies of the APOE4 gene as a distinct genetic form of Alzheimer’s disease. Also, apart from other APOE genotypes, single-cell sequencing of brain microglia in patients who died with Alzheimer’s disease with two copies of APOE4 revealed liquid droplets that were neurotoxic, promoting Tau pathology.
So it is good news that removal of APOE4 in the experimental model protects against the loss of myelination, inflammation, and impact of Tau. That’s also the target and goal of our current amyloid antibody therapies. Gene therapy in patients directed at removing APOE4 is already being tested in patients.
Further good news is that about 30 percent of people with heavy amyloid and Tau deposits in their brain do not ever manifest Alzheimer’s disease clinically. That’s not just because they don’t live long enough; it may be attributable, at least in part, to biologic modifying factors. While we cannot predict that favorable outcome yet, we are learning more about genes that protect and promote brain resilience to these protein deposits, besides APOE2, such as MEF2, APOE Christchurch, Klotho, fibronectin 1, Reelin-COLBOS, and APOE-R136S. For example, a gene variant that promotes amyloid accumulation around brain blood vessels but not Alzheimer’s disease pathology has been identified. Add to that epigenetic changes, as tracked by DNA methylation, that foster resilience. Ironically, there may also be some cognitive benefits of the APOE4 allele with respect to boosting short-term memory.