Multimodal hippocampal and amygdala subfield volumetry in polygenic risk for Alzheimer's disease
Amy N Murray1, Hannah L Chandler1, Thomas M Lancaster2
1Cardiff University Brain Research Imaging Centre (CUBRIC), School of Psychology, Cardiff University, Cardiff, United Kingdom.
Abstract:
Preclinical models of Alzheimer's disease (AD) suggest that volumetric reductions in medial temporal lobe (MTL) structures manifest before clinical onset. AD polygenic risk scores (PRSs) are further linked to reduced MTL volumes (the hippocampus/amygdala); however, the relationship between the PRS and specific subregions remains unclear. We determine the relationship between the AD-PRSs and MTL subregions in a large sample of young participants (N = 730, aged 22-35 years) using a multimodal (T1w/T2w) approach. We first demonstrate that the PRSs for the hippocampus/amygdala predict their respective volumes and specific hippocampal subregions (pFDR < 0.05). We further observe negative relationships between the AD-PRSs and whole hippocampal/amygdala volumes. Critically, we demonstrate novel associations between the AD-PRSs and specific hippocampal subfields such as CA1 (β = -0.096, pFDR = 0.045) and the fissure (β = -0.101, pFDR = 0.041). We provide evidence that the AD-PRS is linked to specific MTL subfields decades before AD onset. This may help inform preclinical models of AD risk, providing additional specificity for intervention and further insight into mechanisms by which common AD variants confer susceptibility.
Insights
Alzheimer's disease polygenic risk scores are linked to reduced medial temporal lobe volumes, including specific hippocampal subfields, years before clinical symptoms appear. This finding may refine early Alzheimer's risk prediction and intervention strategies.
Area of Science:
- Neuroimaging
- Genetics
- Alzheimer's Disease Research
Background:
- Preclinical Alzheimer's disease (AD) models indicate medial temporal lobe (MTL) volume reduction precedes clinical onset.
- Alzheimer's disease polygenic risk scores (PRS) correlate with reduced hippocampus/amygdala volumes, but subregion specificity is unclear.
Purpose of the Study:
- To investigate the relationship between AD polygenic risk scores (PRS) and specific MTL subregions in young adults.
- To identify novel associations between AD-PRS and hippocampal subfields predictive of future AD risk.
Main Methods:
- Utilized a multimodal (T1w/T2w) neuroimaging approach in a large sample (N=730) of young participants (aged 22-35 years).
- Analyzed the predictive power of AD-PRS for MTL volumes and specific hippocampal subregions using statistical modeling.
Main Results:
- AD-PRS significantly predicted hippocampus/amygdala volumes and specific hippocampal subregions (pFDR < 0.05).
- Observed negative associations between AD-PRS and overall hippocampal/amygdala volumes.
- Identified novel links between AD-PRS and specific hippocampal subfields, including CA1 and the fissure (pFDR = 0.045 and 0.041, respectively).
Conclusions:
- AD-PRS is associated with structural differences in specific MTL subfields decades before clinical AD onset.
- These findings enhance understanding of early AD risk mechanisms and may inform targeted preclinical interventions.
- Provides greater specificity for identifying individuals at high risk for Alzheimer's disease based on genetic and neuroimaging markers.
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