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Basic Science and Pathogenesis.

Soheil Mohammadi1, Mahsa Dolatshahi1, Paul K Commean1

  • 1Mallinckrodt Institute of Radiology, Washington University in St. Louis, St. Louis, MO, USA.

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Midlife obesity and insulin resistance are linked to brain structure changes and increased amyloid burden in individuals at risk for Alzheimer's disease. These metabolic factors impact brain volume and amyloid accumulation, highlighting potential early intervention targets.

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Area of Science:

  • Neuroscience
  • Metabolic Health
  • Alzheimer's Disease Research

Background:

  • Midlife obesity and insulin resistance are known Alzheimer's disease (AD) risk factors.
  • Their specific impact on brain structure and AD biomarkers like amyloid and tau remains incompletely understood.

Purpose of the Study:

  • To investigate the associations between midlife obesity and insulin resistance with brain structure (cortical thickness, brain volume) and PET-detected amyloid and tau burdens.
  • To analyze these associations in cognitively normal, middle-aged adults.

Main Methods:

  • Eighty cognitively normal middle-aged participants underwent MRI, amyloid and tau PET scans, and metabolic assessments.
  • Participants were categorized into four groups based on obesity (BMI ≥ 30 kg/m²) and insulin resistance (HOMA-IR ≥ 1.9).
  • Statistical analyses (ANOVA, ANCOVA) evaluated differences in brain structure and biomarker burden across groups.

Main Results:

  • The metabolically abnormal obese (MAO) group showed significantly reduced right posterior cingulate and left temporal pole volumes compared to metabolically normal non-obese (MNNO) individuals.
  • The MAO group also exhibited significantly higher whole-brain amyloid and inferior temporal cortex amyloid burden compared to the MNNO group.
  • No significant differences in tau burden were observed between groups.

Conclusions:

  • Midlife obesity is associated with reduced brain volumes and increased amyloid burden in regions relevant to Alzheimer's disease.
  • The absence of tau differences may indicate the subclinical stage of the disease in this cohort.