Ketogenic Diet Enhances Cognitive-Behavioral Function and Hippocampal Neurogenesis While Attenuating Amyloid Pathology in Tg-SwDI Mice

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. Studies in Alzheimer’s rodent models report that KD and/or ketogenic supplements attenuate cognitive-behavioral impairments, neuroinflammation, amyloid-beta plaques and tau pathology. However, it is unknown whether KD can similarly benefit individuals with cerebral amyloid angiopathy (CAA), a prevalent condition in which amyloid accumulates in cerebral vessels. CAA is highly comorbid in patients with Alzheimer’s and, on its own, increases the risk of stroke, cognitive impairment, and dementia, yet no effective treatments currently exist. The objective of this study was to determine whether KD can improve cognitive-behavioral and neuropathological outcomes in a mouse model with CAA. 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. 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. These findings suggest that a ketogenic diet may be safe and effective in Alzheimer’s and dementia patients with CAA.