Abstract
INTRODUCTION: Tau pathology impacts neurodegeneration and cognitive decline in Alzheimer's disease (AD), with the dorsal raphe nucleus (DRN) being among the brain regions showing the earliest tau pathology. As a serotonergic hub, DRN activity is altered by selective serotonin reuptake inhibitors (SSRIs), which also have variable effects on cognitive decline and pathology in AD. METHODS: We examined N = 191 subjects with baseline (18)F-fluorodeoxyglucose positron emission tomography and plasma biomarker data to study the effects of SSRIs on tau pathology, cognitive decline, and DRN metabolism. RESULTS: Plasma phosphorylated tau 181 (p-tau181) was lower with SSRI use. The effect of SSRIs on cognition varied by cognitive assessment. The DRN was hypometabolic in AD patients relative to healthy controls; however, SSRI use restored the metabolic activity of this region in AD patients. DISCUSSION: Long-term SSRI use may reduce the pathological presentation of AD but has variable effects on cognitive performance. HIGHLIGHTS: Tau pathology spreads throughout the brain during AD pathogenesis. The DRN is among the first regions to develop tau pathology during this process. SSRI use restores the metabolic activity of the DRN and reduces plasma p-tau181.