Synergistic Effect of Cardiometabolic Multimorbidity and Depression on Longitudinal Cognitive Decline: Results from two Longitudinal Asian Elderly Cohorts

Introduction: Cardiometabolic multimorbidity (CMM) and depression are risk factors for cognitive decline and dementia. We investigated the independent and synergistic associations of CMM and depression on longitudinal cognitive deterioration in two Asian cohorts of elderly at varying cognitive status with differed underlying neuropathology. Methods: Eligible memory clinic (Harmonization) and stroke patients (Coast) aged ≥50 completed cognitive and clinical assessments at baseline and up to 5 follow-up visits in 6 years. Cardiometabolic diseases (CMDs), including hypertension, hyperlipidemia, diabetes mellitus, stroke and other cardiovascular diseases were assessed. Presence of CMM was defined as having two or more CMDs. Depression was defined by Geriatric Depression Scale (GDS) of ≥5. Biomarkers including cerebral beta-amyloid, cerebrovascular disease and ApoE genotype, were assessed by MRI and laboratory tests. Cognitive outcomes included cognitive trajectory patterns identified by the group-based trajectory model (GBTM) and the rate of change of global cognitive z-score. Multivariable logistic models and mixed models were conducted to assess the associations of CMM(+) and depression(+) with longitudinal cognitive decline. Stratification analysis by demographics and biomarkers was conducted. Results: Among a total of 809 (Harmonization: 586, Coast: 223) participants, three cognitive trajectories were identified by the GBTM in each cohort. CMM(+) was independently associated with longitudinal cognitive decline. There was a significant interaction among CMM, depression and time with longitudinal cognition in both cohorts (ps of β(CMM*depression*time) < 0.05). Compared with reference group, CMM(+) and depression(+) were associated with patterns of rapid decline (OR=3.58, =95%CI=(1.64,7.81)) and slow decline (OR=3.32, 95%CI=(1.20,9.19)) in Harmonization, and decline/low stable (OR=4.01, 95%CI=(1.03,15.50)) in Coast. Participants with CMM(+) and depression(+) had a 0.24 (95%CI= -0.49, -0.01) and 0.13 (95%CI=-0.24,-0.01) units decline per year on global cognitive z-scores in Harmonization and Coast, respectively, compared with those with CMM(-) and depression(-). The combined effect between CMM and depression was more pronounced among older and male participants, as well as APOEε4 carriers. Discussion: Our study demonstrated a synergistic effect between CMM and depression on longitudinal cognitive decline among elderly with differed underlying neuropathology. Targeting both CMM and depression in preventing cognitive decline may lead to greater effectiveness.