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Related Experiment Videos

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

Ena Xiao1, Qiang Chen1, Aaron L Goldman1

  • 1Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, Maryland.

Biological Psychiatry. Cognitive Neuroscience and Neuroimaging
|March 22, 2018
PubMed
Summary

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Genetic risk for late-onset Alzheimer's disease (LOAD) cumulatively impacts hippocampal function in healthy individuals. This effect on synaptic function precedes cognitive and brain structure changes, highlighting early LOAD pathology.

Area of Science:

  • Neuroscience
  • Genetics
  • Alzheimer's Disease Research

Background:

  • Late-onset Alzheimer's disease (LOAD) is influenced by multiple genetic risk factors.
  • Understanding the cumulative genetic burden on brain function is crucial for early detection and intervention.
  • Previous studies have identified several loci associated with increased LOAD risk.

Purpose of the Study:

  • To investigate the cumulative effect of LOAD risk loci on hippocampal function, cognition, and brain morphometry in healthy adults.
  • To determine if a polygenic risk score (RPS) for LOAD is associated with measurable changes in brain function and structure.
  • To explore the relationship between genetic risk and early markers of neurodegeneration.

Main Methods:

  • A polygenic risk profile score (RPS) was developed using LOAD risk loci from a recent meta-analysis.
Keywords:
Alzheimer’s diseaseEpisodic memoryGeneticsHippocampal functionNeuroimaging geneticsPolygenic risk profile scoreRPS

Related Experiment Videos

  • The RPS was applied to a sample of 231 healthy control subjects (19-55 years) to assess hippocampal function during episodic memory tasks using fMRI.
  • Cognitive metrics and brain morphometry (in 280 subjects) were also assessed in relation to the RPS.

    • Main Results:

    • The LOAD-RPS showed a significant negative association with hippocampal function (p < .05, FWE corrected).
    • No significant associations were found between LOAD-RPS and cognitive or morphometric measures.
    • Individual risk variants in CLU, PICALM, BCL3, PVRL2, and RELB showed effects on hippocampal function, though not surviving multiple testing correction.

    Conclusions:

    • A cumulative genetic risk for LOAD negatively impacts hippocampal function in healthy individuals.
    • This effect on synaptic function appears to precede observable changes in cognition and brain morphometry.
    • Findings suggest that genetic predisposition to LOAD can lead to early synaptic dysfunction, aligning with the temporal progression of LOAD biomarkers.