Summary People with psychotic disorders die 10-20 years prematurely, often after years of disability and declining health. Early-onset dementia is an important contributor to these problems. By age 65, 27% of people with psychotic disorders are already diagnosed with dementia. The nature of this premature cognitive decline is unclear, and RFA-MH-22-270 calls for studies to understand the increased risk of dementia in psychotic disorders. Specifically, it is unknown when the cognitive decline takes place, why it happens, and what are its functional consequences. The Suffolk County Mental Health Project, a longitudinal epidemiologic study of first- episode psychosis that begun in 1989, provides an unparalleled opportunity to study cognitive decline in psychotic disorder during midlife. The study enrolled 628 individuals with psychotic disorders. At Year 20, 261 demographically matched never-psychotic adults were added. The cohorts have been genotyped, and have received comprehensive psychiatric evaluations, medical exams, physical performance tests, EEG, and cognitive testing at regular intervals throughout the follow-up period. This created a rich dataset that has already been the basis of over 115 publications. We propose a 35-year follow-up, when participants will be 65 years old on average (expected N = 530). The proposed study has four aims. First, we will determine whether the cognitive decline from Year 20 to 35 is faster in cases than never-psychotic controls. Second, we will test if Year 20 risk factors for cognitive change are the same in cases and controls (e.g., metabolic syndrome, inactivity, tobacco use, low education, and APOE4) or some differ (e.g., antipsychotics, anticholinergics, and schizophrenia polygenic risk score). Third, we will investigate in cases whether cognitive decline is associated with worsening functioning in the real-world (role, social, and self-care), physical impairment, and neural deficits (EEG and plasma markers). Fourth, we will explore dementia incidence in cases vs. controls and risk factors for incident dementia. The proposed research will address scientific objectives highlighted in the RFA- MH-22-270. First, it will explicate trajectories and outcomes of psychotic disorders in mid- to late-life by studying cognitive and functional changes over 15 years (from mean age 50 to age 65). Second, it will identify promising targets for future development of preventive interventions by investigating modifiable risk factors. Third, it will shed light on mechanisms underpinning these trajectories by studying relevant genetic, molecular, neural, environmental, and behavioral factors.

Narrative Individuals with psychotic disorders, such as schizophrenia and bipolar disorder, are at a very high risk of premature cognitive decline and early dementia. However, reasons for this are unclear. The current proposal aims to understand this cognitive decline by following people with psychotic disorders and never psychotic individuals across the midlife.