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

Katrina A Wugalter1, Rebecca C Thurston2, Minjie Wu2

  • 1Department of Psychology, University of Illinois Chicago, Chicago, IL, USA.

Alzheimer'S & Dementia : the Journal of the Alzheimer'S Association
|December 24, 2025
PubMed
Summary
This summary is machine-generated.

Midlife women with the APOE4 gene variant show reduced brain activity and connectivity during memory tasks, even without cognitive decline. These early brain changes may precede later cognitive effects in Alzheimer's disease (AD) risk.

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Area of Science:

  • Neuroscience
  • Genetics
  • Cognitive Science

Background:

  • The APOE4 genotype is linked to neuroimaging differences, particularly in women, with effects becoming more pronounced with age.
  • Midlife is a crucial period for identifying early risk factors for cognitive decline, as the APOE4 genotype's impact on women's brain health is subtle at this stage.
  • Early biomarkers are needed to detect brain vulnerabilities in female APOE4 carriers.

Purpose of the Study:

  • To investigate APOE4-related differences in brain activation and hippocampal functional connectivity during word encoding in cognitively normal midlife women.
  • To explore the association of these brain patterns with verbal memory performance and plasma Alzheimer's disease (AD) biomarkers.

Main Methods:

  • Functional magnetic resonance imaging (fMRI) was used to assess brain activation and hippocampal functional connectivity during verbal encoding tasks in midlife women.
  • Generalized psychophysiological interaction (PPI) analyses were employed to examine functional connectivity, with corrections for multiple comparisons.
  • APOE4 group differences were analyzed using linear regression, adjusting for age, race, and education.

Main Results:

  • No significant differences were found between APOE4 carriers and non-carriers in verbal recognition performance, verbal memory measures, or plasma AD biomarkers.
  • APOE4 non-carriers exhibited greater activation and hippocampal functional connectivity in specific brain regions during verbal encoding compared to carriers.
  • Left inferior frontal gyrus activation was positively associated with verbal memory, and left hippocampal connectivity was linked to lower p-tau 181 levels.

Conclusions:

  • Female midlife APOE4 carriers demonstrate reduced activity and connectivity in memory-related regions during word encoding, despite comparable cognitive and biomarker profiles to non-carriers.
  • The observed functional brain patterns may serve as early indicators of APOE4-associated brain vulnerabilities.
  • These findings suggest that functional brain alterations related to the APOE4 genotype may manifest before detectable cognitive or plasma biomarker changes, highlighting their relevance to AD pathogenesis.