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Background:  Higher 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.  Objective:  We 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).  Methods:  This 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.  Results:  The 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 ( P  interaction  = 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.  Conclusions:  Our 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.

human molecular genetics

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