Subclinical depressive symptoms are associated with increased risk of Alzheimer’s disease (AD), but the brain mechanisms underlying this relationship are still unclear. We aimed to provide a comprehensive overview of the brain substrates of subclinical depressive symptoms in cognitively unimpaired older adults using complementary multimodal neuroimaging data. We included cognitively unimpaired older adults from the baseline data of the primary cohort Age-Well (n = 135), and from the replication cohort ADNI (n = 252). In both cohorts, subclinical depressive symptoms were assessed using the 15-item version of the Geriatric Depression Scale; based on this scale, participants were classified as having depressive symptoms (>0) or not (0). Voxel-wise between-group comparisons were performed to highlight differences in gray matter volume, glucose metabolism and amyloid deposition; as well as white matter integrity (only available in Age-Well). Age-Well participants with subclinical depressive symptoms had lower gray matter volume in the hippocampus and lower white matter integrity in the fornix and the posterior parts of the cingulum and corpus callosum, compared to participants without symptoms. Hippocampal atrophy was recovered in ADNI, where participants with subclinical depressive symptoms also showed glucose hypometabolism in the hippocampus, amygdala, precuneus/posterior cingulate cortex, medial and dorsolateral prefrontal cortex, insula, and temporoparietal cortex. Subclinical depressive symptoms were not associated with brain amyloid deposition in either cohort. Subclinical depressive symptoms in ageing are linked with neurodegeneration biomarkers in the frontolimbic network including brain areas particularly sensitive to AD. The relationship between depressive symptoms and AD may be partly underpinned by neurodegeneration in common brain regions.

Objective:Physical activity has been associated with a decreased risk for dementia, but the mechanisms underlying this association remain to be determined. Our objective was to assess whether cardiovascular risk factors mediate the association between physical activity and brain integrity markers in older adults.Methods:Participants from the Age-Well study underwent, at baseline, a physical activity questionnaire, cardiovascular risk factors collection (systolic blood pressure, body mass index [BMI], current smoker status, HDL-cholesterol, total-cholesterol, insulin) and multimodal neuroimaging (structural-MRI, diffusion-MRI, FDG-PET, Florbetapir-PET). Multiple regressions were conducted to assess the association between physical activity, cardiovascular risk factors, and neuroimaging. Mediation analyses were performed to test whether cardiovascular risk factors mediated the associations between physical activity and neuroimaging.Results:134 cognitively unimpaired older adults (≥65 years) were included. Higher physical activity was associated with higher grey matter (GM) volume (ß=0.174, p=0.030) and cerebral glucose metabolism (ß=0.247, p=0.019), but not with amyloid deposition or white matter integrity. Higher physical activity was associated with lower insulin and BMI, but not with the other cardiovascular risk factors. Lower insulin and BMI were related to higher GM volume, but not to cerebral glucose metabolism. When controlling for insulin and BMI, the association between physical activity and cerebral glucose metabolism remained unchanged, while the association with GM volume was lost. When insulin and BMI were entered in the same model, only BMI remained a significant predictor of GM volume. Mediation analyses confirmed that insulin and BMI mediated the association between physical activity and GM volume. Analyses were replicated within Alzheimer’s disease-sensitive regions, and results remained overall similar.Conclusions:The association between physical activity and GM volume is mediated by changes in insulin and BMI. In contrast, the association with cerebral glucose metabolism seems to be independent from cardiovascular risk factors. Older adults practicing physical activity have cardiovascular benefits, through the maintenance of a lower BMI and insulin, resulting in greater structural brain integrity. This study has strong implications as understanding how physical activity affects brain health may help developing strategies to prevent or delay age-related decline.Trial Registration Information:EudraCT: 2016-002441-36; IDRCB: 2016-A01767-44; ClinicalTrials.gov Identifier: NCT02977819.

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