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

Ena Xiao, Qiang Chen, Aaron L. Goldman, Hao Tan, Kaitlin Healy, Brad Zoltick, Saumitra Das, Bhaskar Kolachana, Joseph H. Callicott, Dwight Dickinson, Karen F. Berman, Daniel Weinberger, Venkata Mattay

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
JournalBiological Psychiatry: Cognitive Neuroscience and Neuroimaging
DOIs
StateAccepted/In press - 2017

Fingerprint

Alzheimer Disease
Haplotypes
Single Nucleotide Polymorphism
Healthy Volunteers
Episodic Memory
Brain
Cognition
Meta-Analysis
Biomarkers
Magnetic Resonance Imaging
Oxygen

Keywords

  • Alzheimer's disease
  • Episodic memory
  • Genetics
  • Hippocampal function
  • Neuroimaging genetics
  • Polygenic risk profile score
  • RPS

ASJC Scopus subject areas

  • Radiology Nuclear Medicine and imaging
  • Cognitive Neuroscience
  • Clinical Neurology
  • Biological Psychiatry

Cite this

Late-Onset Alzheimer's Disease Polygenic Risk Profile Score Predicts Hippocampal Function. / Xiao, Ena; Chen, Qiang; Goldman, Aaron L.; Tan, Hao; Healy, Kaitlin; Zoltick, Brad; Das, Saumitra; Kolachana, Bhaskar; Callicott, Joseph H.; Dickinson, Dwight; Berman, Karen F.; Weinberger, Daniel; Mattay, Venkata.

In: Biological Psychiatry: Cognitive Neuroscience and Neuroimaging, 2017.

Research output: Contribution to journalArticle

Xiao, Ena ; Chen, Qiang ; Goldman, Aaron L. ; Tan, Hao ; Healy, Kaitlin ; Zoltick, Brad ; Das, Saumitra ; Kolachana, Bhaskar ; Callicott, Joseph H. ; Dickinson, Dwight ; Berman, Karen F. ; Weinberger, Daniel ; Mattay, Venkata. / Late-Onset Alzheimer's Disease Polygenic Risk Profile Score Predicts Hippocampal Function. In: Biological Psychiatry: Cognitive Neuroscience and Neuroimaging. 2017.
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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 = "Alzheimer's disease, Episodic memory, Genetics, Hippocampal function, Neuroimaging genetics, Polygenic risk profile score, RPS",
author = "Ena Xiao and Qiang Chen and Goldman, {Aaron L.} and Hao Tan and Kaitlin Healy and Brad Zoltick and Saumitra Das and Bhaskar Kolachana and Callicott, {Joseph H.} and Dwight Dickinson and Berman, {Karen F.} and Daniel Weinberger and Venkata Mattay",
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T1 - Late-Onset Alzheimer's Disease Polygenic Risk Profile Score Predicts Hippocampal Function

AU - Xiao, Ena

AU - Chen, Qiang

AU - Goldman, Aaron L.

AU - Tan, Hao

AU - Healy, Kaitlin

AU - Zoltick, Brad

AU - Das, Saumitra

AU - Kolachana, Bhaskar

AU - Callicott, Joseph H.

AU - Dickinson, Dwight

AU - Berman, Karen F.

AU - Weinberger, Daniel

AU - Mattay, Venkata

PY - 2017

Y1 - 2017

N2 - 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.

AB - 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.

KW - Alzheimer's disease

KW - Episodic memory

KW - Genetics

KW - Hippocampal function

KW - Neuroimaging genetics

KW - Polygenic risk profile score

KW - RPS

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