Hippocampal subfield atrophy in high genetic risk for AD:Unraveling sex- and AD stage-specific rates
Poster No:
852
Submission Type:
Abstract Submission
Authors:
Tavia Evans1, Natalia Vilor-Tejedor2, Albert Rodrigo2, Patricia Genius2, Blanca Rodríguez-Fernández2, Federica Anastasi2, Arcadi Navarro2, Juan Domingo Gispert2, Hieab Adams3
Institutions:
1Erasmus mc, Rotterdam, Zuid Holland, 2Barcelonaβeta Brain Research Center, Barcelona, Catalonia, 3Department of Genetics, Radboud University, Nijmegen, Gelderland
First Author:
Co-Author(s):
Introduction:
Neuropathological studies have shown that hippocampal atrophy is affected in cognitive aging and Alzheimer's disease (AD) (Brickman, 2011; Evans, 2018). Moreover, current evidence suggests that hippocampal subfields have partially different genetic architecture and may improve the sensitivity of the detection of AD (Liu, 2015). In this study, we aimed at evaluating whether hippocampal subfield trajectories exhibit variations across different stages of AD, as well as to evaluate whether there is a sex-related impact on the rate of hippocampal volume decline. Additionally, we investigated whether genetic predisposition to AD contributes to the accelerated rate of hippocampal volume atrophy across AD stages and sex, and how this contribution is specifically driven by variants located in the APOE gene.
Methods:
The study comprised 562 participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI-1) cohort (75.2 yo; 42.3% women), with complete demographic, genetic, and 1.5T magnetic resonance imaging scans at baseline and every 6 months for a total of 96 months (Controls (amyloid negative), CUN= 161; mild cognitive impairment, MCIN = 260, AD patients, ADN = 141). Hippocampal subfields were extracted using the longitudinal processing method within FreeSurfer (version 6.0). Genetic predisposition to AD was assessed through polygenic scoring using PRSice version 2, with and without considering the APOE region (chr19:45,409,011-45,412,650; GRCh37/hg19). Linear mixed-effect models with random- time slope and intercept for individuals were used to investigate the association between genetic predisposition to AD and hippocampal subfields volumetric trajectories over time. Models were adjusted by age, sex, AD disease status (CU, MCI, AD), years of education and total hippocampal volume. Disease and sex status-specific trajectories dependent on genetic predisposition to AD were assessed by including an interaction term.
Results:
We observed significant reduction in hippocampal subfields volumes over time, showing more pronounced atrophy among participants with MCI and AD compared to CN [Figure 1A]. In addition, high genetic predisposition to AD was associated with accelerated atrophy rates in the CA1, hippocampal tail, molecular layer, presubiculum, subiculum, as well as the overall hippocampal region [Figure 1B]. Disease-dependent models showed that MCI participants at high genetic predisposition to AD exhibited a more severe atrophy rate in the hippocampal tail, molecular layer, presubiculum, subiculum, and the overall hippocampus compared to those with a lower genetic predisposition [Figure 2A]. Sex-related differences were also observed, with women at high genetic predisposition showing more pronounced atrophy in the fimbria and hippocampal fissure regions [Figure 2B]. All effects ceased to be significant when the variants in the APOE gene region were not considered. Additional analyses evaluating the effect of functional genetic variants of the APOE gene revealed that the effects were mainly driven by brain hippocampal eQTLs of the APOE gene (e.g. rs75627662).
·Figure 1. A) Smoothed Mean Hippocampal Subfields Trajectories by Diagnostic Group. B) Association between genetic predisposition to Alzheimer’s disease and hippocampal subfields trajectories.
·Figure 2. Influences of genetic predisposition to Alzheimer’s disease on hippocampal subfields volumetric changes over time. A) By diagnostic group (AD, MCI, CN). B) By sex (Female, Male).
Conclusions:
Our findings emphasized the importance of considering both hippocampal subfields and genetic predisposition to AD, specifically APOE variants, and their interactions in understanding AD progression and sex-specific trajectories. Moreover, our results suggested different patterns of atrophy between CN (amyloid negative individuals) and MCI and AD patients (amyloid positive individuals), suggesting differences related to aging versus AD pathophysiology in hippocampal subfields trajectories. The findings provide valuable insights for refining early detection strategies and targeted intervention approaches for more effective AD management.
Disorders of the Nervous System:
Neurodegenerative/ Late Life (eg. Parkinson’s, Alzheimer’s) 2
Genetics:
Genetic Association Studies 1
Lifespan Development:
Aging
Neuroanatomy, Physiology, Metabolism and Neurotransmission:
Cortical Anatomy and Brain Mapping
Novel Imaging Acquisition Methods:
Anatomical MRI
Keywords:
Aging
MRI
STRUCTURAL MRI
Sub-Cortical
Other - Genetics
1|2Indicates the priority used for review
Provide references using author date format
Evans TE (2018), Subregional volumes of the hippocampus in relation to cognitive function and risk of dementia. Neuroimage. 1;178:129-35.
Liu, Y (2015). APOE genotype and neuroimaging markers of Alzheimer's disease: systematic review and meta-analysis. Journal of Neurology, Neurosurgery & Psychiatry, 86(2), 127-134.