Disrupted role of the connectivity between the locus coeruleus and the hippocampus in cognition of healthy, middle-aged individuals at risk of dementia: the PREVENT-Dementia study



It is well acknowledged that Alzheimer’s Disease (AD) pathological processes start decades before clinical manifestations, but the brain mechanism of sporadic AD in midlife remains unclear. To address this gap, we examined whether risk factors for late-life AD are associated with disrupted connectivity between two key structures in AD pathophysiology – the Locus Coeruleus (LC) and hippocampus – and its role in cognition, in a cohort of middle-aged and cognitively healthy individuals. Detailed neuropsychological assessments and functional Magnetic Resonance Imaging were obtained at baseline (N=210), and two-years follow-up (N=188). Associations of cognition and LC–Hippocampus functional connectivity with apolipoprotein ε4 (APOE4) genotype, and dementia family history (FHD) were investigated using linear regression. Correlations between the Cardiovascular Risk Factors, Aging, and Incidence of Dementia (CAIDE) dementia risk score and cognitive and functional measures were further investigated. APOE ε4 allele was significantly associated with better performance in verbal, spatial and relational memory. Higher CAIDE scores were significantly associated with worse performance in verbal, visuospatial functions and short-term (conjunctive) memory. The CAIDE dementia risk score moderated the relationship between cognition and LC–Hippocampus functional connectivity. In individuals with low (=<3)/high (>=8) CAIDE scores, higher functional connectivity was significantly associated with better/worse cognition. These results shed light on the brain mechanism of incipient AD neuropathology in individuals, who are at high risk for late-life dementia on the cardiovascular risk score, but presently cognitively healthy.