Cerebrospinal fluid proteome alterations related to depressive symptoms in cognitive decline and Alzheimer's disease

BACKGROUND: Depressive symptoms are common in cognitive decline and Alzheimer's disease (AD), but their underlying pathology remains poorly understood. We aimed to investigate the pathophysiology of depressive symptoms in the context of AD. METHODS: Individuals with normal cognition (NC), mild cognitive impairment (MCI), or mild AD dementia from two independent, large cohorts were included. Untargeted mass spectrometry–based cerebrospinal fluid (CSF) proteomics, regression analyses, and pathway-enrichment analyses were applied. RESULTS: A total of 688 individuals (223 NC, 190 MCI, and 275 AD dementia) were included. The levels of 57 out of 946 robustly quantified CSF proteins were associated with depressive symptoms consistently across both cohorts. These proteins were enriched for cell adhesion/inflammation, synaptic signaling, and neurogenesis. In amyloid-positive subjects, cholesterol metabolism and transport were additionally associated with depressive symptoms. CONCLUSION: The identified proteome alterations may reflect shared biological mechanisms involved in both AD and depression in older people. Highlights: This is the first study to investigate cerebrospinal fluid proteome alterations associated with depressive symptoms in the context of cognitive decline and Alzheimer's disease (AD). Dysregulated proteins in patients with higher depression scores were related to pathways linked to cell adhesion/inflammation, synaptic signaling, and neurogenesis, as well as cholesterol metabolism in amyloid-positive individuals. The identified proteome alterations may represent shared biological mechanisms involved in both AD and depression in older people.