Abstract BACKGROUND: Subclinical depressive symptoms increase the risk of developing Alzheimer’s disease (AD). The neurobiological mechanisms underlying this link may involve stress system dysfunction, notably related to the hippocampus which is particularly sensitive to AD. We aimed to investigate the links between blood stress markers and changes in brain regions involved in the stress response in older adults with or without subclinical depressive symptoms. METHODS: This cross-sectional study was conducted using baseline data from the Age-Well trial. Cognitively unimpaired (CU) older adults with (DepS; n=73) or without (NoDepS; n=58) subclinical depressive symptoms (defined using the 15-item Geriatric Depression Scale) were included in the analyses. Blood cortisol, epinephrine and norepinephrine were measured; as well as the resting-state functional connectivity (rs-FC) between, and gray matter (GM) volume of, the hypothalamus, hippocampus and hippocampal subfields. Blood stress markers levels and neuroimaging measures were compared between groups; then regression analyses were conducted between these measures. RESULTS: DepS participants showed higher plasma epinephrine levels, which was associated with greater rs-FC between the CA1 and Subiculum hippocampal subfields and the hypothalamus. Lower GM volume in the CA1 and DG/CA2-3-4 subfields was also found in DepS. No between-group differences were observed for blood cortisol and norepinephrine. CONCLUSIONS: Our findings show that subclinical depressive symptoms are associated with increased sympatho-adrenomedullary axis activity, together with lower GM volume in a hippocampal subfield (i.e., CA1) particularly sensitive to AD. While causation cannot be inferred, these results suggest that screening and treating subclinical depressive symptoms in CU older adults could reduce AD risk. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02977819, Registration Date: 2016-11-25.