APOE4 and Infectious Diseases Jointly Contribute to Brain Glucose Hypometabolism, a Biomarker of Alzheimers Pathology: New findings from the ADNI

Introduction We investigated the interplay between infections and APOE4 on brain glucose hypometabolism, an early preclinical feature of Alzheimer's Disease (AD) pathology. Methods Multivariate linear regression analysis was performed on 1,509 participants of the Alzheimer's Disease Neuroimaging Initiative (ADNI). The outcomes were the rank-normalized hypometabolic convergence index (HCI) and statistical regions of interest (SROI) for AD and mild cognitive impairment (MCI). Further, the HCI and its change in the presence and absence of APOE4 were evaluated. Results Infections were associated with greater hypometabolism [0.15, 95% CI: 0.03, 0.27, p=0.01], with a more pronounced effect among APOE4 carriers, indicating an interaction effect. A higher HCI (0.44, p=0.01) was observed in APOE4 carriers with multiple infections, compared to (0.11, p=0.08) for those with a single infection, revealing a dose-response relationship. The corresponding estimates for the association of infections with SROI AD and SROI MCI were -0.01 (p=0.02) and -0.01 (p=0.04) respectively. Conclusion Our findings suggest that infections and APOE4 jointly contribute to brain glucose hypometabolism and AD pathology, supporting a "multi-hit" mechanism in AD development.