# Sex Specific Effects of a High Fat Diet on Metabolism, Cognition, and Pathology in the Tg-SwDI Mouse Model of Alzheimer’s Disease

## TL;DR

This study shows that high-fat diets worsen Alzheimer's disease symptoms in female mice more than in males, affecting metabolism, memory, and brain pathology.

## Contribution

The study reveals sex-specific effects of high-fat diets on Alzheimer's pathology and cognition in a mouse model.

## Key findings

- HFD-fed AD female mice showed greater weight gain, glucose intolerance, and cognitive deficits compared to males.
- HFD-fed AD females had increased amyloid plaques and cerebral amyloid angiopathy in the thalamus.
- Neuroinflammation metrics correlated strongly with CAA pathology in HFD-fed AD females.

## Abstract

Alzheimer’s disease (AD) is the leading cause of dementia in the US, with over 80% of affected individuals experiencing comorbid metabolic disease. Along with age and sex, metabolic syndrome and prediabetes are known risk factors for developing dementia and AD, highlighting the complex nature of the disease. How these risk factors affect cerebral amyloid angiopathy (CAA) is less well studied. As such, we examined the effect of diet-induced metabolic syndrome and sex on cognition, neuroinflammation, and pathology in the Tg-SwDI mouse model of AD and CAA.

Male and female Tg-SwDI and WT mice were fed a low fat (LFD; 10% fat) or high fat (HFD; 60% fat) diet from 3 to 10 months of age. Metabolic, cognitive, and neuropathology outcomes were assessed.

All HFD-fed mice gained weight and exhibited impaired glucose tolerance. Metabolic disturbances were most severe in AD females receiving HFD. In both males and females, HFD-fed AD mice showed increased anxiety-like behavior, decreased locomotor activity, and impaired episodic memory in the open field and novel object recognition tests, respectively. HFD-fed AD females specifically exhibited spatial memory deficits in the Barnes maze. Hippocampal microgliosis, activated microglia, and astrogliosis were more severe in AD mice, but this effect was blunted by HFD in females in the cornu ammonis 1. HFD-fed AD females had greater amyloid plaques and CAA in the thalamus compared to LFD-fed AD controls. All metrics of neuroinflammation significantly correlated with CAA pathology in the thalamus.

AD females experienced greater metabolic, cognitive, and pathologic effects in response to a HFD compared to AD males and WT controls. These observations provide a better understanding of how metabolic disease may differentially affect the development of dementia in men and women.