Hyperhomocysteinemia, intima-media thickness and C677T MTHFR gene polymorphism: a correlation study in patients with cognitive impairment.

OBJECTIVE Intima-media thickness (IMT) seems associated with risk of Alzheimer disease (AD). Homocysteine (hcy) is a risk factor for vascular diseases and dementia. This study aimed at investigating the possible relationship among IMT, plasma hcy and C677T methylentetrahydrofolate reductase (MTHFR) polymorphism in relation to cognitive status. METHODS Sixty-three patients with cognitive impairment and 64 controls underwent biochemical, neuropsychological and carotid ultrasound assessment. RESULTS After age and folate adjustment, plasma hcy correlated with both Mini Mental State Examination (MMSE) score (r=-0.7, p<0.01) and IMT (r=0.7, p<0.01). Among patients with cognitive impairment, carriers of TT677 MTHFR genotype had plasma hcy (p<0.001) and IMT (p<0.01) values higher than non carriers. Furthermore, multiple regression analysis showed that MMSE scores were associated with plasma hcy (beta=-0.3, p=0.01), IMT (beta=-0.3, p=0.01) and TT677 MTHFR genotype (beta=-0.3, p=0.02). Structural equation modelling showed that the relation between hcy levels and MMSE score was partly direct (parameter estimate=-0.6; p=0.01) and partly mediated by IMT values (parameter estimate=-0.4; p=0.03). Finally, IMT resulted associated with hypertension (parameter estimate=0.8; p<0.0001). CONCLUSION Our findings suggest that TT677 MTHFR genotype promotes plasma homocysteine increase which in turn may favour intima-media thickening in patients with cognitive impairment. Hcy may promote neuronal damage through multiple mechanisms, including a micro-vascular damage, mediated by IMT increase, and a direct neuro-toxic effect.