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Basic Science and Pathogenesis.

Mary Hill1, Aaron Y Lai1, Dustin Loren V Almanza1

  • 1Sunnybrook Research Institute, Toronto, ON, Canada.

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|December 25, 2025
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A high-carbohydrate, high-fat diet shows mixed effects on Alzheimer's disease (AD) in rats. While initially protective in females, long-term consumption led to neuronal loss and increased AD pathology.

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Area of Science:

  • Neuroscience
  • Metabolic Disorders
  • Aging Research

Background:

  • The impact of high-carbohydrate-high-fat (HCHF) diets on Alzheimer's disease (AD) risk is debated, with conflicting evidence regarding body mass index.
  • Understanding AD pathogenesis during the early symptomatic phase, when the brain's energy demands increase, is crucial.

Purpose of the Study:

  • To investigate the effects of a HCHF diet on AD progression in a rat model during the early symptomatic phase.
  • To differentiate the relationship between high energy intake and AD pathology and cognitive function.

Main Methods:

  • TgF344-AD rats, modeling early symptomatic AD, were fed a HCHF diet for 3 and 6 months.
  • Cognitive function was assessed using the Barnes Maze.
  • Histological analyses examined neuronal density, amyloid-beta plaques, hyperphosphorylated tau, myelin, and glial markers.

Main Results:

  • A 3-month HCHF diet increased brain glucose metabolism, slowed cognitive decline, and enhanced myelin/oligodendrocyte density.
  • However, the 3-month diet also decreased neuronal density and promoted amyloid-beta and tau pathology.
  • After 6 months, detrimental effects persisted, while beneficial effects on cognition and myelin showed reduced impact.

Conclusions:

  • Sex-specific effects were observed, with obesity impacts being more pronounced in female rats.
  • High energy diet consumption during early symptomatic AD appears protective in female rats, suggesting potential sex-based therapeutic strategies.