The dihydrofolate reductase 19-bp deletion modifies the beneficial effect of B-vitamin therapy in mild cognitive impairment: pooled study of two randomized placebo-controlled trials.

backgroundHigher serum homocysteine is associated with cognitive decline in older people. But homocysteine-lowering trials including folic acid (FA) show inconsistent results on cognitive decline. The reduction of FA to dihydrofolate by dihydrofolate reductase (DHFR) is slow in humans.

objectiveWe examined the effects of the DHFR 19-bp deletion/insertion (del/ins) polymorphism on FA-containing treatment on cognitive decline and brain atrophy in older people with mild cognitive impairment (MCI).

methodsThis study used pooled data from two randomized B-vitamin trials on 545 MCI subjects who received either FA-containing B vitamins or placebo for 24 months. Subjects were typed for the DHFR genotype. Primary outcome was the Clinical Dementia Rating scale-global score (CDR-global). Secondary outcomes were CDR-sum of boxes score (CDR-SOB), memory and executive Z-scores and whole brain atrophy rate by serial MRI.

resultsThe proportions of subjects with del/del, del/ins and ins/ins genotype were 29.5, 44.3 and 26.1%, respectively. DHFR genotypes modified the effects of B vitamins on CDR-global, CDR-SOB and executive function Z-score (Pinteraction = 0.017, 0.014 and 0.052, respectively), with significant benefits being observed only in those with ins/ins genotype (Beta = -1.367, -0.614 and 0.315, P = 0.004, 0.014 and 0.012, respectively). The interaction was not significant for memory Z-score and whole brain atrophy rate. Notably, the supplements only slowed brain atrophy in members of the 'ins/ins' group who were not using aspirin.

conclusionsOur data indicate that the beneficial effects of B vitamins including FA on cognitive function are only apparent in those with ins/ins genotype, i.e. relatively better preserved DHFR activity.