Ketogenic Diet Improves Cognitive Function and Hippocampal Neurogenesis While Reducing Amyloid Pathology in the Tg-SwDI Mouse Model of Dementia

Ketogenic Diet Improves Cognitive Function and Hippocampal Neurogenesis While Reducing Amyloid Pathology in the Tg-SwDI Mouse Model of Dementia

Alvin Sherman Library

Cerebral amyloid angiopathy (CAA), characterized by amyloid buildup in cerebral blood vessels, is highly comorbid with Alzheimer's disease (AD) and, on its own, increases the risk of stroke, cognitive impairment, and dementia. Despite its high incidence, no FDA-approved treatments currently exist to treat or prevent this condition. The ketogenic diet (KD), which is high in fats and low in carbohydrates, has shown promise for its therapeutic potential in patients with neurodegenerative diseases, including Alzheimer's. Studies in AD rodent models have found that KD and/or ketogenic supplements attenuate cognitive-behavioral impairments, neuroinflammation, and amyloid pathology. However, its effects on CAA remain unclear. This study sought to evaluate whether KD could improve cognitive-behavioral and neuropathological outcomes in an AD 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. After three months of dietary intervention, metabolic markers were assessed, followed by behavioral tests measuring activity levels, anxiety, and cognitive function. Immunohistochemistry was performed to assess amyloid pathology, vascular density, neuroinflammation, white matter integrity, and hippocampal neurogenesis. In addition to inducing nutritional ketosis and metabolic benefits, KD-fed mice exhibited enhanced spatial learning and memory, and a trend toward improved spatial working memory. These cognitive benefits were accompanied by reduced amyloid pathology and increased hippocampal neurogenesis. These findings suggest that KD may be a safe and effective intervention for AD and dementia patients with CAA, providing potential cognitive and neuropathological benefits.