ABSTRACT

Objective:
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+ from the Rush Memory and Aging Project(MAP) and 303,887 participants aged 55+ from 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 (e.g. AD, Lewy bodies, 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 ≤100mg/d, caffeine intake >100mg/d was associated with a significantly higher HR(95%CI) of all-cause[1.35(1.03,1.76)] and Alzheimer's[1.41(1.07,1.85)] dementia. Caffeine intake was not associated with cognitive decline. In UKB, compared to ≤100mg/d, the HRs(95%CI) of all-cause dementia for consuming 100≤200, 200≤300, 300≤400 and >400mg/d were 0.83(0.72,0.94), 0.74(0.64,0.85), 0.74(0.64,0.85) and 0.92(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 >100mg/d was associated with lower neocortical type Lewy bodies[Odds ratio(95%CI): 0.40(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.

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