Ketogenic diet enhances cognitive-behavioral function and hippocampal neurogenesis while attenuating amyloid pathology in Tg-SwDI mice

Abstract

Background

The ketogenic diet (KD), characterized by high-fat, low-carbohydrate, and moderate protein intake, has gained attention for its therapeutic potential in patients with neurodegenerative diseases, including Alzheimer's disease (AD). Studies in AD rodent models report that KD and/or ketogenic supplements attenuate cognitive-behavioral impairments, neuroinflammation, amyloid-β (Aβ) plaques, and tau pathology. However, it is unknown whether KD can similarly benefit individuals with cerebral amyloid angiopathy (CAA), a prevalent condition in which Aβ accumulates in cerebral vessels. CAA is highly comorbid with AD and, on its own, increases the risk of stroke, cognitive impairment, and dementia, yet no effective treatments currently exist.

Objective

To determine whether KD can improve cognitive-behavioral and neuropathological outcomes in a mouse model with CAA.

Methods

Male Tg-SwDI mice were fed either a standard chow or KD from 3.5 to 7.5 months of age. Following ∼3 months of dietary intervention, glucose and ketone body levels were assessed, then mice underwent a battery of behavioral tests to evaluate locomotor activity, anxiety-related behaviors, and cognition. Immunohistochemistry was performed to assess amyloid pathology, vascular density, neuroinflammation, white matter integrity, and hippocampal neurogenesis.

Results

In addition to KD inducing nutritional ketosis and achieving metabolic benefits, mice on KD exhibited increased activity, enhanced spatial learning and memory, and a trend toward improved spatial working memory. These cognitive benefits were accompanied by an attenuation of amyloid pathology and increased hippocampal neurogenesis.

Conclusions

These findings suggest that a KD may be safe and effective in AD and dementia patients with CAA.