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.