APOE ε4 Allele-associated Alzheimer's disease risk is consistent with increased lifetime exposure to a neurotoxic process

Abstract

In the adult human brain, approximately one trillion synapses are constructed and deconstructed daily as part of normal learning and memory. A growing body of evidence suggests that Alzheimer’s disease (AD) is characterized by dysregulated neuroplasticity processes that initially shift the balance toward synaptic loss causing poor episodic memory, while later changes induce synaptic slaughter causing dementia. Inheritance of a single copy of the apolipoprotein E (APOE) ε4 allele has been shown to increase the risk of AD by 3-4-fold, with homozygosity associated with a 12-16-fold increase in risk. Further, there is a decrease of risk associated with the APOE ε2 allele. The pathological consequence of APOE genotype, accounting for the vast majority of AD risk, has led to intense efforts to understand the mechanistic basis of the interplay between APOE status and loss of synapses. Studies conducted across the age spectrum from infancy through senescence have demonstrated that APOE ε4-positive status is associated with increased brain activity and macromolecule turnover in young healthy individuals, with the reverse extant in elderly subjects. The recent demonstration that the brains of APOE ε4-positive healthy young adults utilize approximately 16% more of the lipid membrane constituent docosahexaenoic acid (DHA) opens the possibility that part of the increased long-term neurotoxicity might be explained by pharmacokinetics. For example, if the hippocampal neurons of two individuals possess the same susceptibility to either an endogenous or exogenous stress factor, the neurons with the highest turnover of proteins, lipids, and other macromolecules would experience a larger integrated dose of detriment. Small differences in pharmacokinetic effects might be amplified by the extremely long prodromal phase of AD, i.e., average age of presentation for a homozygous ε4 is about 68 years of age. Introduction