Interaction Between COMT Genotype and MIND Diet, Cognitive Decline, and Incident Dementia: A Prospective Cohort Study

Background: Catechol-O-methyltransferase (COMT) metabolizes catecholamines and polyphenols unique to the Mediterranean-DASH Diet Intervention for Neurodegenerative Delay (MIND). The COMT Val158Met variant modified the effect of MIND on change in perceptual speed after 3 years in a randomized controlled trial. We aimed to evaluate and extend these findings to dementia incidence in a community-based prospective cohort. Methods: We included 745 older adults (mean age 80.0 years) from the Rush Memory and Aging Project. MIND adherence was estimated using a validated food-frequency questionnaire (0-15 points). Repeated cognitive assessments and dementia diagnoses were based on standardized clinical neurological examinations and criteria. Linear regression, linear mixed-effects, and Cox proportional hazards models examined associations of COMT Val158Met and its interactions with MIND with baseline cognition, cognitive decline, and incident dementia. Associations with neuropathology and COMT protein were also explored. Results: Significant COMT × MIND interactions were observed for Alzheimer's (p = 0.003) and all-cause (p = 0.004) dementia and for COMT × MIND × time interactions with declines in global cognition (p = 0.008), episodic memory (p = 0.009), and visuospatial ability (p = 0.01). Cognitive benefits associated with MIND adherence were greater among Met/Met carriers (lower COMT activity). The hazard ratio (95% CI) per MIND point for Alzheimer's dementia was 0.82 (0.69-0.98) for Met/Met, 1.00 (0.87-1.15) for Met/Val, and 1.05 (0.84-1.33) for Val/Val. Greater MIND adherence was associated with lower plasma COMT (p = 0.01), while each additional Val allele was associated with higher brain COMT (p < 0.0001). Conclusions: Individuals with genetically reduced COMT activity may be especially responsive to cognitive benefits of the MIND diet. Further study is needed to determine whether these effects differ across cognitive domains.