The role of ApoE and homocysteine in the pathogenesis of Alzheimer’s disease

Abstract

Alzheimer’s disease (AD) is the most common cause of dementia, followed by cerebrovascular disease (CVD). The two diseases occur together in ~20% of the demented population. AD and CVD share two risk factors: elevated plasma homocysteine (Hcy) and apolipoprotein E (ApoE) genotype. The aim of this study was to investigate the possible mechanism by which Hcy and ApoE may interact to alter cell cycle kinetics and neuronal physiology, potentially leading to the development of AD-related pathology. Using brain samples and clinical data collected from 252 patients (including preclinical, mild and severe AD patients and control patients) we investigated the effect of elevated levels of Hcy and ApoE genotype on cognitive deficit and AD-related pathology. Furthermore, using retinonic acid induced differentiated SH-SY5Y human neuroblastoma cells we investigated the effects of Hcy and ApoE isoforms on AD-related protein expression, cell proliferation, cell survival and the methylation pattern of cell cycle regulatory genes. The results from this study suggest that (i) Hcy affects the development of AD at multiple levels, cell cycle regulation, DNA methylation, induction of oxidative stress and direct effect on AD-type protein accumulation and (ii) these effects are modulated by the ApoE genotype.