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Dried Blood Spot Collection of Health Biomarkers to Maximize Participation in Population Studies
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Biomarkers.

McKenna E Williams1, Jeremy A Elman1, Tyler R Bell1

  • 1University of California San Diego, La Jolla, CA, USA.

Alzheimer'S & Dementia : the Journal of the Alzheimer'S Association
|December 25, 2025
PubMed
Summary
This summary is machine-generated.

Gray matter mean diffusivity (gMD) signatures show early Alzheimer's disease (AD) changes preceding structural atrophy. Increased cortical thickness may indicate future decline, especially in APOE-ε4 carriers, suggesting a biphasic AD progression model.

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Area of Science:

  • Neuroimaging
  • Alzheimer's Disease Research
  • Biomarker Development

Background:

  • Diffusion MRI metrics like gray matter mean diffusivity (gMD) may detect early, microstructural Alzheimer's disease (AD) changes before macrostructural atrophy.
  • A novel gMD signature can predict cognitive decline and identify at-risk subgroups, complementing cortical thickness/volume signatures.
  • Cortical thickness may exhibit dynamic, biphasic changes in early AD, with higher thickness potentially indicating pathology, especially in APOE-ε4 carriers.

Purpose of the Study:

  • To clarify early trajectories of AD signatures (gMD and cortical thickness/volume) to improve biomarker specificity and sensitivity.
  • To investigate the longitudinal relationships between gMD and cortical thickness/volume signatures in predicting cognitive decline.
  • To examine how APOE-ε4 status influences the relationship between AD signatures and cognitive outcomes.

Main Methods:

  • Utilized multilevel models on 286 male participants from the Vietnam Era Twin Study of Aging (VETSA).
  • Tested concurrent and lagged relationships between established thickness/volume and novel gMD AD signatures.
  • Investigated if longitudinal relationships differed based on APOE-ε4 carrier status and cognitive status.

Main Results:

  • gMD and thickness/volume signatures exhibited negative concurrent relationships across all timepoints.
  • Higher gMD signatures longitudinally predicted lower thickness/volume signatures six years later.
  • Higher thickness/volume signatures predicted higher gMD signatures and increased risk of mild cognitive impairment (MCI) six years later, specifically in APOE-ε4-positive individuals.

Conclusions:

  • gMD signatures serve as early AD markers, preceding changes in cortical thickness/volume.
  • Findings support a biphasic model of AD progression, where early increases in cortical thickness/volume, potentially with increased gMD, signal future decline risk.
  • These insights are particularly relevant for APOE-ε4 carriers, highlighting their potential role in early AD trajectories.