Interaction between Oligomeric Amyloid‐β and Cardiovascular Risk Factors is Associated with Executive and Dorsal Attention Network Dysfunction in Pre‐dementia

Abstract

AbstractBackgroundOligomeric amyloid‐β(OAβ) accumulation within brain tissue has been shown to be associated with major AD neuropathological features including tau pathology, synaptic loss, inflammation and oxidative damage; as well as cognitive impairment in dementia cohorts (Celine.E.N et.al.,2018). However, association of OAβ with functional connectivity (FC) and cardiovascular risk factors is not clearly known in the pre‐dementia stage. We aimed to examine association of FC with OAβ and other dementia risk factors in a pre‐dementia cohort to understand the underlying mechanisms related to OAβ.MethodsWe included 98 age and sex matched participants and classified them into OAβ+(28) and OAβ‐(70) subgroups using a OAβ cut‐off ratio of ≥ 0.9 (MDS‐ OAβ Test Kit, PeopleBio Inc, South Korea). Participants completed resting‐state functional MRI, clinical and lifestyle history questionnaires, blood, and neuropsychological assessments for global cognition on Montreal cognitive assessment and Visual Cognitive Assessment at Dementia Research Centre (Singapore). The Cardiovascular Risk Factors, Aging and Dementia (CAIDE) risk score was computed, and independent sample or chi‐squared analysis were performed to evaluate group‐level participant characteristics. Region‐of‐interest based FC analysis for 19 seeds from executive control (ECN), default‐mode, salience and dorsal‐attention networks (DAN) was performed to examine the network‐based FC differences in OAβ+ and OAβ‐ groups in association with CAIDE using ANCOVA model.ResultsMean age of OAβ+ and OAβ‐ were 62.04±8.84, and 62.05±8.07 (Table‐1). No significant FC differences were observed between OAβ+ vs OAβ‐ subjects. There were no significant FC differences related to CAIDE score in OAβ+ and OAβ‐ groups. Nonetheless, the OAβ*CAIDE interaction showed significant FC changes. The OAβ+*CAIDE interaction analyses showed reduced FC within ECN and DAN (Figure‐1a). Whereas OAβ‐*CAIDE interaction showed reduced FC only within ECN (Figure‐1b). Furthermore, OAβ interaction with apolipoprotein‐ε4 (OAβ*APOE4) was found to further influence FC trends in ECN and DAN (Figure‐1c,1d).ConclusionWhile no FC differences were observed between OAβ+ vs OAβ‐ subjects, the interaction between CAIDE and APOE4 moderated FC changes within the ECN and DAN. These observations in a pre‐dementia cohort suggest that the presence of cerebrovascular risk factors may result in differential FC dysfunction in ECN and DAN depending on APOE4 status.