Caffeine Consumption and Dementia: Are Lewy Bodies the Link?

OBJECTIVE: The objective of this study was to examine the association between caffeine intake and cognitive impairment. Caffeine-neuropathology correlations and interactions with lifestyle and genetic factors impacting caffeine metabolism and response were also tested. METHODS: We included 888 participants aged 59+ years from the Rush Memory and Aging Project (MAP) and 303,887 participants aged 55+ years from the UK Biobank (UKB). MAP participants took part in annual cognitive testing. Diagnosis of dementia was based on clinical neurological examination and standardized criteria. A subset provided postmortem tissue for neuropathologic evaluation for common age-related diseases (eg, Alzheimer's disease [AD], Lewy bodies, and vascular). For UKB, dementia was determined by linked hospital and death records. Self-reported caffeine intake was estimated using food-frequency questionnaires in both cohorts. Cox proportional hazard ratio (HR), regression, and mixed models were used to examine associations of caffeine intake with incident dementia, cognitive decline, and neuropathology. RESULTS: In MAP, compared to ≤100 mg/day, caffeine intake >100 mg/day was associated with a significantly higher HR (95% confidence interval [CI]) of all-cause (HR = 1.35, 95% CI = 1.03-1.76) and AD (HR = 1.41, 95% CI = 1.07-1.85) dementia. Caffeine intake was not associated with cognitive decline. In UKB, compared to ≤100 mg/day, the HRs (95% CI) of all-cause dementia for consuming 100 ≤ 200, 200 ≤ 300, 300 ≤ 400, and > 400 mg/day were 0.83 (95% CI = 0.72-0.94), 0.74 (95% CI = 0.64-0.85), 0.74 (95% CI = 0.64-0.85), and 0.92 (95% CI = 0.79-1.08), respectively. Similar results were observed for Alzheimer's dementia. In MAP, caffeine intake was inversely associated with postmortem Lewy bodies but no other age-related pathologies. Caffeine intake >100 mg/day was associated with lower neocortical type Lewy bodies (odds ratio (95%CI): 0.40 (95% CI = 0.21-0.75). INTERPRETATION: Caffeine intake was inconsistently associated with clinical dementia; potentially explained by cohort differences in underlying dementia etiology. Lewy bodies may link caffeine to lower risk in some persons. ANN NEUROL 2022;91:834-846.