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Clinical Manifestations.

Aurélie Garrone1, Yara Yakoub1,2, Alfonso Fajardo1,2

  • 1Douglas Mental Health University Institute, Centre for Studies on the Prevention of Alzheimer's Disease (StoP-AD), Montréal, QC, Canada.

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

Neuropsychiatric symptoms (NPS) are linked to Alzheimer's disease (AD) pathology in cognitively unimpaired individuals. Contrary to expectations, these associations were stronger in males, not females, for white matter hyperintensity volume.

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Area of Science:

  • Neurology
  • Neuroimaging
  • Psychiatry

Background:

  • Neuropsychiatric symptoms (NPS) are common in Alzheimer's disease (AD) and may indicate early disease stages.
  • Previous studies link NPS to increased amyloid-beta (Aβ) and tau pathology, particularly in vulnerable brain regions like the amygdala.
  • White matter hyperintensity (WMH) volume and sex differences are also implicated in AD progression and NPS severity.

Purpose of the Study:

  • To investigate the associations between NPS and key AD biomarkers: Aβ burden, amygdala tau deposition, and frontal white matter hyperintensity (WMH) volume.
  • To explore potential sex-based differences in these associations, hypothesizing stronger links in females due to their higher reported NPS prevalence.

Main Methods:

  • Utilized PET imaging (amyloid and tau) and MRI (WMH volume) in 208 cognitively unimpaired participants from the PREVENT-AD cohort.
  • Employed linear regression models with sex as an interaction term to analyze the relationship between NPS (apathy, anxiety, depression, stress, perseverative thinking, neuroticism) and biomarkers.
  • Controlled for age, education, APOE4 status, and cardiovascular risk factors in all analyses.

Main Results:

  • Found significant associations between NPS and AD markers, particularly WMH volume, which were more pronounced in males than females.
  • Observed associations between stress and depression with amyloid and amygdala tau in males.
  • Identified an association between perseverative thinking and amygdala tau in females.

Conclusions:

  • Confirmed associations between NPS and AD biomarkers (MRI and PET) in at-risk, cognitively unimpaired individuals.
  • Contradicted the initial hypothesis by revealing stronger associations in males for certain markers, despite females' higher NPS prevalence.
  • Highlights the complex interplay between NPS, sex, and AD pathology, warranting further investigation into sex-specific mechanisms.