(PTFS10-04-26) Genotype-Specific Efficacy of Time-Restricted Feeding in Alzheimer’s Disease: Role of Hepatic Ketogenesis and ApoE Lipidation

Objectives: Apolipoprotein E (ApoE) polymorphisms are primary genetic determinants of Alzheimer’s disease (AD) risk, with the ε4 allele significantly exacerbating pathogenesis. While time-restricted feeding (TRF) shows promise as a metabolic intervention, its genotype-dependent efficacy and the precise metabolic underpinnings remain poorly defined. This study investigated whether TRF attenuates AD-related neurodegeneration via modulation of ketone metabolism and evaluated the modifying influence of ApoE genotype.

Methods: A translational approach was employed: For clinical association, A cross-sectional analysis assessed the correlation between circulating beta-hydroxybutyrate (BHB) levels and cognitive performance in AD patients stratified by ApoE status. For preclinical mechanistic study, humanized ApoEε3- and ApoEε4 -targeted replacement 5xFAD (EFAD) mice underwent a 3-month TRF regimen to evaluate cognitive function, amyloid pathology, and cerebral bioenergetics. For pilot intervention, a 4-month clinical TRF trial was conducted to assess longitudinal changes in cognitive scores (MoCA) among AD patients.

Results: In AD patients, serum BHB levels were positively associated with cognitive performance, with a stronger correlation in ApoEε4 non-carriers. Consistently, TRF in EFAD mice promoted a shift toward cerebral ketone utilization, reduced amyloid deposition, and improved cognition, with more pronounced effects in E3FAD than E4FAD mice. Mechanistically, these benefits depended on hepatic ketogenesis and preserved brain ApoE lipidation. Similar genotype-specific improvements were observed in the pilot clinical trial, where TRF-related cognitive benefits were mainly evident in ApoEε4 non-carriers.

Conclusions: TRF mitigates AD progression through a genotype-specific enhancement of brain ketone utilization and ApoE lipidation. These findings underscore ketone metabolism as a viable therapeutic target and suggest that dietary interventions for AD may require ApoE-based precision nutrition strategies, with ε4 non-carriers potentially deriving the greatest benefit.

Funding Sources: This work was supported by the Sci-Tech Innovation 2030 Brain Science and Brain-Like Intelligence Technology Project (2022ZD0208100 to Z. L.).