Alzheimer’s disease cerebrospinal fluid biomarker levels and APOE genetic status are associated with hippocampal-cerebellar functional connectivity

Recent research suggests that hippocampal-cerebellar (Hp-CB) functional connectivity may be altered early in the course of Alzheimer's disease (AD), given the early accumulation of AD pathology in the hippocampi and emerging evidence of cerebellar changes in early AD. This study analyzed the role of AD genetic risk (via APOE ε4 carrier status) and cerebrospinal fluid (CSF) biomarkers of AD pathology (ratio of phosphorylated tau (p-tau₁₈₁) to amyloid beta (Aβ₄₂/Aβ₄₀)) on the relationship between age and functional Hp-CB resting state fMRI connectivity in 161 cognitively unimpaired older adults (M age =67.3; SD =9.0; 37 % APOE ε4 +). In multiple regression analyses with Hp-CB connectivity as the outcome, there were significant interactions between age and APOE ε4 status, and between age and CSF AD biomarkers. Older age was associated with greater Hp-CB connectivity in APOE ε4 non-carriers and participants with less abnormal CSF AD biomarkers. In contrast, Hp-CB connectivity was marginally lower with older age in ε4 carriers and those with more abnormal AD biomarkers. Furthermore, greater Hp-CB connectivity was associated with better episodic memory performance across all groups. These findings suggest that age-related increases in Hp-CB connectivity among APOE ε4 non-carriers and those with low AD biomarker levels reflect age-related changes that are largely unrelated to AD, while age-related decreases in Hp-CB connectivity in APOE ε4 carriers may reflect AD-related alterations. These findings also highlight the importance of cerebellar contributions to cognitive performance among older adults and suggest that Hp-CB connectivity may be altered in preclinical AD.