Late-Onset Alzheimer's Disease Polygenic Risk Profile Score Predicts Hippocampal Function

Background We explored the cumulative effect of several late-onset Alzheimer's disease (LOAD) risk loci using a polygenic risk profile score (RPS) approach on measures of hippocampal function, cognition, and brain morphometry. Methods In a sample of 231 healthy control subjects (19–55 years of age), we used an RPS to study the effect of several LOAD risk loci reported in a recent meta-analysis on hippocampal function (determined by its engagement with blood oxygen level–dependent functional magnetic resonance imaging during episodic memory) and several cognitive metrics. We also studied effects on brain morphometry in an overlapping sample of 280 subjects. Results There was almost no significant association of LOAD-RPS with cognitive or morphometric measures. However, there was a significant negative relationship between LOAD-RPS and hippocampal function (familywise error [small volume correction-hippocampal region of interest] p <.05). There were also similar associations for risk score based on APOE haplotype, and for a combined LOAD-RPS + APOE haplotype risk profile score (p <.05 familywise error [small volume correction-hippocampal region of interest]). Of the 29 individual single nucleotide polymorphisms used in calculating LOAD-RPS, variants in CLU, PICALM, BCL3, PVRL2, and RELB showed strong effects (p <.05 familywise error [small volume correction-hippocampal region of interest]) on hippocampal function, though none survived further correction for the number of single nucleotide polymorphisms tested. Conclusions There is a cumulative deleterious effect of LOAD risk genes on hippocampal function even in healthy volunteers. The effect of LOAD-RPS on hippocampal function in the relative absence of any effect on cognitive and morphometric measures is consistent with the reported temporal characteristics of LOAD biomarkers with the earlier manifestation of synaptic dysfunction before morphometric and cognitive changes.