Cerebral glucose uptake and cognitive functions: A phenome-wide Mendelian randomization study

Background Based on both physiological perspectives and observational findings, increasing cerebral glucose uptake appears to be a novel therapeutic strategy to preserve cognitive function in patients with Alzheimer’s disease (AD). However, the inherent limitations of observational studies make it difficult to establish clear causality. Objective To evaluate the potential of cerebral glucose uptake as a novel therapeutic strategy for AD through a systematic investigation of its causal relationship with cognitive function. Methods The [ 18 F] fluoro-2-deoxy-2- D -glucose positron emission tomography (FDG-PET) was used as an indicator of cerebral glucose uptake. Phenome-wide Mendelian randomization was performed to investigate the causal relationships between glucose uptake across 113 brain regions and 96 cognitive assessment scores using data from the Alzheimer's Disease Neuroimaging Initiative. Results In the primary analysis, employing the inverse-variance weighted method, genetically predicted increases in cerebral glucose uptake exhibited a consistent trend toward beneficial changes in cognitive assessment scores across brain regions independent of brain volume. Subsequent sensitivity analyses, horizontal pleiotropy assessments and corrections for multiple testing demonstrated robust causal relationships between cerebral glucose uptakes and cognitive assessment scores, including the Alzheimer's Disease Assessment Scale and the Clinical Dementia Rating, across multiple brain regions. Conclusions This study provides genetic evidence suggesting causal relationship between cerebral glucose uptake and cognitive function. These findings indicate that FDG-PET images in specific brain regions may serve as a surrogate marker for cognitive function and support the potential of therapeutic strategies targeting cerebral glucose uptake to preserve cognitive function in patients with AD.