Theses and Dissertations

Date of Award

8-1-2026

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Human Genetics

First Advisor

Joanne Curran

Second Advisor

Jacob Galan

Third Advisor

John Blangero

Abstract

Alzheimer's disease and related dementias (ADRD) disproportionately affect Mexican American populations, who also carry a disproportionate burden of type 2 diabetes (T2D), yet this population remains substantially underrepresented in large-scale multiomic studies of neurodegenerative diseases. We integrated genetic, lipidomic, and proteomic data from the Genetics of Brain Structure and Function Study (GOBS) to characterize the shared molecular architecture of ADRD biomarkers and T2D.

We first estimated the heritability of three emerging ADRD biomarkers: TDP-43, p-tau181, and p-tau217, and their genetic, phenotypic, and environmental correlations with established ADRD biomarkers and T2D. TDP-43 showed high heritability (h2= 0.49), while p-tau181 and p-tau217 showed moderate yet significant heritability (h2= 0.26 and 0.27, respectively). Bivariate analyses revealed strong genetic correlations among p-tau181, p-tau217, total tau, and neurofilament light chain (NfL), while T2D showed a genetic correlation with NfL, p-tau181, and p-tau217, supporting shared genetic pathways between metabolic disease and tau-related neurodegeneration.

Comprehensive plasma lipidomic profiling of 807 lipid species across 47 lipid classes in 2,085 individuals identified phosphatidylserine (PS) species as the strongest individual correlates of ADRD biomarkers, led by associations between TDP-43 and PS (40:5) and PS (38:4). A substantial 226 biomarker-lipid associations overlapped with T2D-associated lipid species, with PC (42:8) and SM (44:1) each linked to five ADRD biomarkers, pointing to a metabolically driven component of ADRD pathology in this population.

Finally, untargeted serum proteomic profiling of 752 circulating proteins in 489 individuals from the same cohort showed that most proteins (85.9%) were significantly heritable, with CFHR2, TAGLN2, and LPA showing the strongest genetic determination. Phenotypic correlations with ADRD biomarkers were robust, particularly for TDP-43 (139 correlated proteins), while discovery-based genetic correlation analyses identified CDH1, SERPINA7, and B4GAT1 as shared tau associated protein and SELENOP as a candidate shared across four of the five biomarkers examined.

This multiomic analysis extends on ADRD biomarker research to a historically underrepresented population and nominates specific genetic lipid, and protein candidates including phosphatidylserine metabolism, selenium transport, and cell-adhesion/ clearance pathways for future studies of comorbid ADRD and T2D.

Comments

Copyright 2026 Stephanie Noel Vindell. All Rights Reserved. https://proquest.com/docview/3409129292

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