Summary/Abstract Cognitive, emotional, interpersonal, and physical functioning are profoundly impacted by Alzheimer's disease (AD) and related dementias. AD poses enormous public health and societal challenges, and the number of affected individuals is expected to rise if an effective intervention to stop or at least slow AD progression is not found. Research on the biological and psychosocial mechanisms that lead to dementia is essential to identify appropriate targets for interventions. The scientific premise of the proposed study is based on robust evidence for an association between long-standing personality traits and dementia-related outcomes. The mechanisms through which these traits lead to cognitive changes, however, are not well understood. Furthermore, with the onset and progression of AD, personality turns from a risk factor to a clinical sign of the disease, but the timing and trajectory of such changes are not well understood. By integrating multiple theoretical perspectives (five- factor model, lifespan models of personality and health, pathoplastic approaches to psychopathology, and cognitive reserve), the proposed research will test three innovative aims. The first aim is to advance a mechanistic understanding of the association between personality and dementia. We will test neurobiological (e.g., MRI brain region volumes and white matter integrity), physiological (e.g., cortisol and cardiovascular burden), behavioral (e.g., physical inactivity and smoking), and psychosocial (e.g., depressive symptoms and loneliness) factors in the pathway from personality to cognitive decline and dementia. The second aim is to test whether personality uncouples AD neuropathology from clinical dementia: We expect that, in the presence of neuropathological changes, a resilient personality profile (low neuroticism, high conscientiousness) will delay the time to onset of mild cognitive impairment (MCI) and dementia. The third aim is to identify the timing and trajectory of personality change during the prodromal phase of AD and related dementias. To address the study aims, we will leverage data from the Baltimore Longitudinal Study of Aging (BLSA). This ongoing prospective study include measures of the five major personality traits, along with in-depth assessments of relevant risk factors and AD biomarkers, and they involve long-term follow-ups (up to 40 years of serial assessments of personality in the BLSA). By leveraging rich prospective data, the proposed project will identify the biological and psychosocial mechanisms that underlie personality-based vulnerability and resilience to dementia and identify inflection points for personality change in the earliest symptomatic phase of the disease.