Abstract
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.
Keywords
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Article info
Publication history
Published online: August 24, 2017
Accepted:
August 5,
2017
Received in revised form:
August 4,
2017
Received:
June 23,
2017
Identification
Copyright
© 2017 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.
