AbstractBackgroundAnxious depressive symptomatology and stress are associated with cognitive decline. Recent evidence suggests a relation between these factors and Alzheimer’s disease (AD) pathophysiology early in the continuum. With the current increases in anxiety, depression and stress due to the Covid19 pandemic ‐ notably in women ‐ unrevealing the biological mechanisms underlying these associations with a sex/gender approach appears fundamental.MethodWe included a total of 1170 participants in a series of observational cohort studies. Participants were cognitively unimpaired with increased risk of AD dementia (family history, APOE ε4, subjective cognitive decline). We investigated stressful life events with a lifespan perspective, stress perception, and changes in anxiety/depression in late life in relation to CSF, PET and MRI biomarkers of AD pathologies, neuroinflammation and brain atrophy. To that end, we performed multiple regression models adjusted by age, sex and education level. We also carried out stratified analyses by sex and explored sex differences in lifestyle and anxious‐behaviors (e.g., eating and sleep patterns).ResultThe accumulation of stressful life events as well as late‐life anxious depressive symptoms were associated with neuroinflammation markers, notably in women. Midlife stress was associated with increased tau and brain atrophy, together with lifetime history of anxiety/depression. In late life, amyloid positivity predicted longitudinal increases in anxiety and depression in the face of stressors, i.e., the covid19 pandemic, in women. Stress perception was not itself associated with any biomarker tested but mediated the increases in anxiety/depression. Women showed higher anxiety/depression and stress‐perception than men. While sex‐differences were identified in eating and sleep patterns, these did not explain the reported associations.ConclusionsOur results suggest that mental health factors and stress should be tackled from a life‐span and sex/gender perspective in people at risk for cognitive decline (Fig1): midlife stress may enhance tau pathology and brain atrophy. Accumulation of stress and anxiety/depression may enhance neuroinflammation pathways in women as well as brain atrophy. Once amyloid is present, women may be more prone to show increases in anxiety and depression in the face of stressors. Finally, stress‐perception represents an intervenable factor that may prevent increases in anxiety and depression.