A ketogenic diet improves memory in females in the APOE4 mouse model of Alzheimer's disease.

The ε4 allele of apolipoprotein E (APOE4) is the strongest genetic risk factor for Alzheimer's disease (AD), increasing AD risk about fourfold in ~ 34 million American and ~ 75 million European females. APOE4 carriers exhibit cerebral metabolic deficits decades before clinical onset. We previously demonstrated that ketogenic diet (KD), a low-carbohydrate, high-fat diet promoting ketone metabolism, confers cognitive benefits in aged C57BL/6 mice, and in the PS1/APP mouse model of early-onset AD. Here, we evaluated the effects of KD in a humanized APOE4 AD mouse model. KD significantly improved composite cognitive performance and spatial working memory, with pronounced effects in females. Synaptic plasticity, measured via long-term potentiation (LTP), was likewise enhanced exclusively in females. Transcriptomic and protein analyses revealed KD-induced activation of CREB pathway, marked by increased phosphorylation of ERK and CREB in female brains. Moreover, KD selectively reduced pro-inflammatory cytokine levels in females. These findings demonstrate sex-specific neuroprotective effects of KD in APOE4 mice and suggest its potential therapeutic role in mitigating AD risk in APOE4-positive women.