Homocysteine Induced Cerebrovascular Dysfunction: A Link to Alzheimer's Disease Etiology

A high serum level of homocysteine, known as hyperhomocystenemia (HHcy) is associated with vascular dysfunction such as altered angiogenesis and increased membrane permeability. Epidemiological studies have found associations between HHcy and Alzheimer's disease (AD) progression that eventually leads to vascular dementia (VaD). VaD is the second most common cause of dementia in people older than 65, the first being AD. VaD affects the quality of life for those suffering by drastically decreasing their cognitive function. VaD, a cerebrovascular disease, generally occurs due to cerebral ischemic events from either decreased perfusion or hemorrhagic lesions. HHcy is associated with the hallmarks of dementia such as tau phosphorylation, Aβ aggregation, neurofibrillary tangle (NFT) formation, neuroinflammation, and neurodegeneration. Previous reports also suggest HHcy may promote AD like pathology by more than one mechanism, including cerebral microangiopathy, endothelial dysfunction, oxidative stress, neurotoxicity and apoptosis. Despite the corelations presented above, the question still exists - does homocysteine have a causal connection to AD? In this review, we highlight the role of HHcy in relation to AD by discussing its neurovascular effects and amelioration with dietary supplements. Moreover, we consider the studies using animal models to unravel the connection of Hcy to AD.