Abstract
Genome-wide association studies have identified multiple Alzheimer’s Disease risk loci with small effect sizes. Polygenic risk scores, which aggregate these variants, are associated with grey matter structural changes. However, genome-wide scores do not allow mechanistic interpretations. The present study explored associations between disease pathway specific scores and grey matter structure in younger and older adults.
Data from two separate population cohorts were used: the Avon Longitudinal Study of Parents and Children, mean age 19.8; and UK Biobank, mean age 64.4 (combined n = 18,689). Alzheimer’s polygenic risk scores were computed using the largest genome-wide association study of clinically assessed Alzheimer’s to date. Relationships between subcortical volumes and cortical thickness, pathway specific scores and genome-wide scores were examined.
Increased pathway specific scores were associated with reduced cortical thickness in both the younger and older cohorts. For example, the reverse cholesterol transport pathway score showed evidence of association with lower left middle temporal cortex thickness in the younger Avon participants (p = 0.034; Beta = -0.013; CI -0.025, -0.001) and in the older UK Biobank participants (p = 0.019; Beta = -0.003; CI -0.005, -4.56 x 10-4).
Pathway scores were associated with smaller subcortical volumes, such as smaller hippocampal volume, in UK Biobank older adults. There was also evidence of positive association between subcortical volumes in Avon younger adults. For example, the tau protein binding pathway score was negatively associated with left hippocampal volume in UK Biobank (p = 8.35 x 10-05; Beta = -11.392; CI -17.066, -5.718) and positively associated with hippocampal volume in the Avon study (p = 0.040; Beta = 51.952; CI 2.445, 101.460).
The immune response score had a distinct pattern of association, being only associated with reduced thickness in the right posterior cingulate in older and younger adults, (p = 0.011; Beta = -0.003, CI -0.005, -0.001 in UK Biobank; p = 0.034; Beta = -0.016, CI -0.031, -0.001 in the Avon study). The immune response score was associated with smaller subcortical volumes in the older adults, but not younger adults.
The disease pathway scores showed greater evidence of association with imaging phenotypes than the genome-wide score. This suggests that pathway specific polygenic methods may allow progress towards a mechanistic understanding of structural changes linked to polygenic risk in pre-clinical Alzheimer’s. Pathway specific profiling could further define pathophysiology in individuals, moving towards precision medicine in Alzheimer’s disease.
Data from two separate population cohorts were used: the Avon Longitudinal Study of Parents and Children, mean age 19.8; and UK Biobank, mean age 64.4 (combined n = 18,689). Alzheimer’s polygenic risk scores were computed using the largest genome-wide association study of clinically assessed Alzheimer’s to date. Relationships between subcortical volumes and cortical thickness, pathway specific scores and genome-wide scores were examined.
Increased pathway specific scores were associated with reduced cortical thickness in both the younger and older cohorts. For example, the reverse cholesterol transport pathway score showed evidence of association with lower left middle temporal cortex thickness in the younger Avon participants (p = 0.034; Beta = -0.013; CI -0.025, -0.001) and in the older UK Biobank participants (p = 0.019; Beta = -0.003; CI -0.005, -4.56 x 10-4).
Pathway scores were associated with smaller subcortical volumes, such as smaller hippocampal volume, in UK Biobank older adults. There was also evidence of positive association between subcortical volumes in Avon younger adults. For example, the tau protein binding pathway score was negatively associated with left hippocampal volume in UK Biobank (p = 8.35 x 10-05; Beta = -11.392; CI -17.066, -5.718) and positively associated with hippocampal volume in the Avon study (p = 0.040; Beta = 51.952; CI 2.445, 101.460).
The immune response score had a distinct pattern of association, being only associated with reduced thickness in the right posterior cingulate in older and younger adults, (p = 0.011; Beta = -0.003, CI -0.005, -0.001 in UK Biobank; p = 0.034; Beta = -0.016, CI -0.031, -0.001 in the Avon study). The immune response score was associated with smaller subcortical volumes in the older adults, but not younger adults.
The disease pathway scores showed greater evidence of association with imaging phenotypes than the genome-wide score. This suggests that pathway specific polygenic methods may allow progress towards a mechanistic understanding of structural changes linked to polygenic risk in pre-clinical Alzheimer’s. Pathway specific profiling could further define pathophysiology in individuals, moving towards precision medicine in Alzheimer’s disease.
| Original language | English |
|---|---|
| Article number | fcad229 |
| Journal | Brain Communications |
| Volume | 5 |
| Issue number | 5 |
| DOIs | |
| Publication status | Published - 25 Aug 2023 |
Bibliographical note
Funding Information:UK Biobank was established by the Wellcome Trust medical charity, Medical Research Council, Department of Health, Scottish Government and the Northwest Regional Development Agency. A full list of organisations funding UK Biobank is available on their website: https://www.ukbiobank.ac.uk/learn-more-about-uk-biobank/about-us/our-funding . For the Avon Longitudinal Study of Parents and Children (ALSPAC), core support is provided by the UK Medical Research Council and Wellcome (Grant ref: 217065/Z/19/Z) and the University of Bristol. This publication is the work of the authors, and Harrison et al. will serve as guarantors for the contents of this paper. A comprehensive list of grants funding (PDF, 330 KB) is available on the ALSPAC website. The Medical Research Council (MRC) and the University of Bristol support the MRC Integrative Epidemiology Unit [MC_UU_00011/1]. This research was funded in whole, or in part, by the Wellcome Trust. For the purpose of Open Access, the author has applied a CC BY public copyright licence to any Author Accepted Manuscript version arising from this submission. This research was specifically funded by the following grants: J.R.H. was supported by a Wellcome Trust GW4 Clinical Academic Fellowship (203918/Z/16/Z); V.E.-P. was funded by the Dementia Research Institute DRI (UKDRI-3003), DPUK (MR/L023784/2), Alzheimer’s Research UK, Alzheimer’s Society, Joint Programming for Neurodegeneration (MRC: MR/T04604X/1), Dementia Platforms UK (MRC: MR/L023784/2) and the MRC Centre for Neuropsychiatric Genetics and Genomics (MR/L010305/1); D.K.J. was supported by a Wellcome Trust Investigator Award and a Wellcome Trust Strategic Award (104943/Z/14/Z).
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© 2023 The Author(s). Published by Oxford University Press on behalf of the Guarantors of Brain.