Warfarin treatment is associated with lower post-mortem brain vitamin K concentrations in older adults.

Abstract

Objective: Menaquinone 4 (MK-4) is the primary form of vitamin K found in the brain. In rodent studies, treatment with the vitamin K antagonist warfarin lowered brain MK-4 concentrations. It is not known if brain MK-4 levels are influenced by warfarin treatment in humans. To address this, we compared post-mortem brain MK-4 concentrations in older adults treated with warfarin prior to death to older adults not treated with warfarin. We also determined the likelihood of having mild cognitive impairment (MCI) or dementia in warfarin users, compared to non-users.

Methods: We utilized data from 381 autopsied participants (76% female, mean±SD age at death 92±6 years) in the Rush Memory and Aging Project (MAP) in whom MK-4 was measured in 4 brain regions: mid-frontal and temporal cortices, anterior watershed (AWS), and cerebellum. Brain MK-4 concentrations were compared between those treated with warfarin and those not treated, using linear regression adjusted for age, sex, and cognitive diagnosis at death. 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 = 585 (479-656) days) had 68-79% lower brain MK-4 concentrations in all measured regions, including the mean across all regions, compared to non-warfarin users (unstandardized β -1.538 to -1.140; all p<.001, fully adjusted). The likelihood of having MCI or dementia, versus no cognitive impairment, at death did not significantly differ between those treated with warfarin prior to death and those not [OR (95%CI) for MCI: 0.82 (0.41, 1.62), dementia: 1.04 (0.57, 1.93), fully adjusted].

Conclusions: These findings suggest that warfarin treatment influences MK-4 concentrations in the human brain. Future studies are needed to elucidate the mechanisms underlying this effect and the clinical implications.