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Basic Science and Pathogenesis.

Alexander J T Yang1, Ahmad Mohammad2, Robert W E Crozier3

  • 1University of Kansas Medical Center, Kansas City, KS, USA.

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

Alzheimer's disease (AD) brains show altered metabolic and synaptic markers, with unique changes in females. This study reveals sex-specific differences in brain signaling and mitochondrial function in AD.

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Area of Science:

  • Neuroscience
  • Biochemistry
  • Pathology

Background:

  • Alzheimer's disease (AD) is linked to inflammation and mitochondrial dysfunction, impacting synaptic integrity.
  • Metabolic dysfunction is a proposed driver of neuroinflammation and synaptic damage in AD.
  • Investigating sex-specific differences is crucial, as post-menopausal females have a higher prevalence of AD.

Purpose of the Study:

  • To compare metabolic, synaptic, and inflammatory markers in human Alzheimer's disease (AD) brains versus age-matched controls.
  • To identify sex-specific differences in these markers, given the higher AD prevalence in females.
  • To explore the role of metabolic dysfunction and inflammation in AD pathogenesis.

Main Methods:

  • Analysis of prefrontal cortex samples from post-mortem donors (10 per sex and condition).
  • Utilized immunofluorescence, western blot, ELISA for cytokine panels, and mitochondrial respiration assays.
  • Examined markers of Akt/mTOR signaling, mitochondrial complexes, synaptic proteins, inflammation (IL-2, Iba-1), and microglial morphology.

Main Results:

  • Alzheimer's disease (AD) brains exhibited altered Akt phosphorylation and increased mitochondrial complex III and V content.
  • AD females showed reduced Complex IV respiration, while both sexes had altered synaptic marker expression (AMPA GluA1, synaptophysin).
  • Sex-specific differences were observed, with greater metabolic signaling changes in females and altered Iba-1 expression in AD females.

Conclusions:

  • Significant differences in Akt signaling and mitochondrial content exist in the prefrontal cortex of AD donors.
  • Metabolic signaling dysregulation in AD appears to be more pronounced in females, suggesting a unique female-specific pathway.
  • These findings highlight the complex interplay of metabolic, inflammatory, and synaptic changes in AD pathogenesis, with notable sex differences.