Abstract
Background and Objectives Neuroimaging and biomarker studies in Alzheimer disease (AD) have shown well-characterized patterns of cortical thinning and altered biomarker concentrations of tau and β-amyloid (Aβ). However, earlier identification of AD has great potential to advance clinical care and determine candidates for drug trials. The extent to which AD risk markers relate to cortical thinning patterns in midlife is unknown. The first objective of this study was to examine cortical thickness change associated with genetic risk for AD among middle-aged military veterans. The second objective was to determine the relationship between plasma tau and Aβ and change in brain cortical thickness among veterans stratified by genetic risk for AD.
Methods Participants consisted of post-9/11 veterans (N = 155) who were consecutively enrolled in the Translational Research Center for TBI and Stress Disorders prospective longitudinal cohort and were assessed for mild traumatic brain injury (TBI) and posttraumatic disorder (PTSD). Genome-wide polygenic risk scores (PRSs) for AD were calculated using summary results from the International Genomics of Alzheimer's Disease Project. T-tau and Aβ40 and Aβ42 plasma assays were run using Simoa technology. Whole-brain MRI cortical thickness change estimates were obtained using the longitudinal stream of FreeSurfer. Follow-up moderation analyses examined the AD PRS × plasma interaction on change in cortical thickness in AD-vulnerable regions.
Results Higher AD PRS, signifying greater genetic risk for AD, was associated with accelerated cortical thickness change in a right hemisphere inferior parietal cortex cluster that included the supramarginal gyrus, angular gyrus, and intraparietal sulcus. Higher tau, but not Aβ42/40 ratio, was associated with greater cortical thickness change among those with higher AD PRS. Mild TBI and PTSD were not associated with cortical thickness change.
Discussion Plasma tau, particularly when combined with genetic stratification for AD risk, can be a useful indicator of brain change in midlife. Accelerated inferior parietal cortex changes in midlife may be an important factor to consider as a marker of AD-related brain alterations.
Glossary
- AD=
- Alzheimer disease;
- Aβ=
- β-amyloid;
- CV=
- coefficient of variation;
- DSM=
- Diagnostic and Statistical Manual of Mental Disorders;
- FWHM=
- full width half maximum;
- GWAS=
- genome-wide association study;
- LLOQ=
- lower limit of quantification;
- MP-RAGE=
- magnetization-prepared rapid gradient echo;
- mTBI=
- mild traumatic brain injury;
- PRS=
- polygenic risk score;
- p-tau=
- phosphorylated tau;
- PTSD=
- posttraumatic disorder;
- ROI=
- region of interest;
- TBI=
- traumatic brain injury;
- TRACTS=
- Translational Research Center for TBI and Stress Disorders;
- t-tau=
- total tau
Footnotes
Funding information and disclosures are provided at the end of the article. Full disclosure form information provided by the authors is available with the full text of this article at Neurology.org/NG.
The Article Processing Charge was funded by The Ohio State University.
Submitted and externally peer reviewed. The handling editor was Associate Editor Suman Jayadev, MD.
- Received September 8, 2022.
- Accepted in final form November 21, 2022.
- Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.
This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND), which permits downloading and sharing the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.
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