(PTFS07-01-24) Warfarin Treatment Is Associated With Lower Post-mortem Brain Vitamin K Concentrations

Objectives: Menaquinone 4 (MK4) is the primary form of vitamin K in the brain. Brain MK4 concentrations were significantly lower in mice treated with Warfarin, a vitamin K antagonist. Further, higher brain MK4 concentrations have been positively correlated with cognitive function. However, it is not known if brain MK4 levels are influenced by warfarin treatment in humans. To address this, we compared post-mortem brain MK4 concentrations in older adults treated with warfarin to older adults not treated with warfarin.

Methods: We utilized data obtained from 380 autopsied participants (76% female, mean (SD) age 92 (6 years) of the Rush Memory and Aging Project (MAP) in whom MK4 was measured in the mid-frontal and temporal cortices ((MTC) averaged for statistical analysis), anterior watershed (AWS), and cerebellum. Linear regression was used to compare (natural log) brain MK4 concentrations between those treated and not treated with warfarin (based on self-report), adjusted for age, sex, and cognitive diagnosis at death (categorized as no cognitive impairment, mild cognitive impairment (MCI), or dementia). The association of warfarin use prior to death with cognitive diagnosis at death was evaluated using logistic regression, adjusted for age, sex, education, and apoE4 status.

Results: Warfarin users (n=73, median (IQR) duration of warfarin use = 218 (142-292) days) had 68-79% lower brain MK4 concentrations in all measured regions including the mean across all regions compared to non-Warfarin users (β= -1.352, -1.357, -1.538, -1.140; all p< .001, fully adjusted). Participants diagnosed with dementia prior to death had significantly lower MK4 concentrations in the MTC and AWS (β=-0.278 (p=0.04), β= -0.389(p=0.01), respectively). However, the odds of having MCI or dementia, compared to no cognitive impairment, at death did not differ between warfarin users and non-users (odds ratio (95% confidence interval) MCI = 0.82 (0.41, 1.62), dementia = 1.05(0.57, 1.93)).

Conclusions: These findings suggest that Warfarin treatment influences MK4 concentrations in the human brain. MK4 concentrations were lower in Warfarin users compared to non-users, however the odds for dementia did not differ with warfarin use due to lower risk of stroke and other cerebrovascular (CV) sequelae due to atrial fibrillation and other CV risk factors.

Funding Sources: USDA  58 1950 7 707
NIH R01AG051641