Dataset Information

Multimodal hippocampal and amygdala subfield volumetry in polygenic risk for Alzheimer's disease.

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 (? = -0.096, pFDR = 0.045) and the fissure (? = -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.

SUBMITTER: Murray AN

PROVIDER: S-EPMC7886309 | biostudies-literature | 2021 Feb

REPOSITORIES: biostudies-literature

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Multimodal hippocampal and amygdala subfield volumetry in polygenic risk for Alzheimer's disease.

Murray Amy N AN Chandler Hannah L HL Lancaster Thomas M TM

Neurobiology of aging 20201102

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 ...[more]

PMID: 33227567

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Project description:Hippocampal subfields exhibit differential vulnerabilities to Alzheimer's disease-associated pathology including abnormal accumulation of amyloid-β deposition and neurofibrillary tangles. These pathological processes extensively impact on the structural and functional interconnectivities of the subfields and may explain the association between hippocampal dysfunction and cognitive deficits. In this study, we investigated the degree of alterations in the microstructure of hippocampal subfields across the clinical continuum of Alzheimer's disease. We applied a grey matter-specific multi-compartment diffusion model (Cortical-Neurite orientation dispersion and density imaging) to understand the differential effects of Alzheimer's disease pathology on the hippocampal subfield microstructure. A total of 119 participants were included in this cross-sectional study. Participants were stratified into three categories, cognitively normal (n = 47), mild cognitive impairment (n = 52), and Alzheimer's disease (n = 19). Diffusion MRI, plasma biomarkers and neuropsychological test scores were used to determine the association between the microstructural integrity and Alzheimer's disease-associated molecular indicators and cognition. For Alzheimer's disease-related plasma biomarkers, we studied amyloid-β, total tau and neurofilament light; for Alzheimer's disease-related neuropsychological tests, we included the Trail Making Test, Rey Auditory Verbal Learning Test, Digit Span and Montreal Cognitive Assessment. Comparisons between cognitively normal subjects and those with mild cognitive impairment showed significant microstructural alterations in the hippocampal cornu ammonis (CA) 4 and dentate gyrus region, whereas CA 1-3 was the most sensitive region for the later stages in the Alzheimer's disease clinical continuum. Among imaging metrics for microstructures, the volume fraction of isotropic diffusion for interstitial free water demonstrated the largest effect size in between-group comparisons. Regarding the plasma biomarkers, neurofilament light appeared to be the most sensitive biomarker for associations with microstructural imaging findings in CA4-dentate gyrus. CA 1-3 was the subfield which had stronger correlations between cognitive performance and microstructural metrics. Particularly, poor performance on the Rey Auditory Verbal Learning Test and Montreal Cognitive Assessment was associated with decreased intracellular volume fraction. Overall, our findings support the value of tissue-specific microstructural imaging for providing pathologically relevant information manifesting in the plasma biomarkers and neuropsychological outcomes across various stages of Alzheimer's disease.

Dataset Information

Multimodal hippocampal and amygdala subfield volumetry in polygenic risk for Alzheimer's disease.

Publications

Multimodal hippocampal and amygdala subfield volumetry in polygenic risk for Alzheimer's disease.

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