Blood and CSF Homocysteine Levels in Alzheimer's Disease: A Meta-Analysis and Meta-Regression of Case-Control Studies

Objective: Hyperhomocysteinemia (HHcy), as an important risk factor for Alzheimer's disease (AD), would aggravate cognitive dysfunction. This study aimed to investigate whether and to what degree the homocysteine (Hcy) levels in blood and cerebrospinal fluid (CSF) were elevated in AD patients compared with healthy controls and to explore the factors related to the elevated Hcy levels in AD patients.

Methods: PubMed and Embase databases were searched to identify eligible studies, and study quality was evaluated using the Newcastle-Ottawa Quality Assessment Scale. Ratio of mean (RoM) Hcy concentrations was used as a measure of fold-change between AD patients and healthy control subjects.

Results: We identified 35 eligible studies, consisting a total of 2172 patients with AD and 2289 healthy controls. The pooled results showed that patients with AD had a significantly higher blood level of Hcy (RoM, 1.32; 95% CI, 1.25-1.40; p<0.001) than controls did, with large heterogeneity across studies (I=81.4%, p<0.001). Hcy level in CSF did not differ significantly between patients with AD than controls (RoM, 1.12; 95% CI, 0.90-1.39, p=0.293; I=69.4%, p=0.02). A random effects meta-regression analysis revealed that there was an inverse correlation between the blood levels of Hcy and folate (p=0.006). There was no link found between the blood levels of vitamin B or the Mini-Mental Status Examination scores reflecting the degree of cognitive impairment, and blood levels of Hcy.

Conclusion: Regardless of dementia severity, there is an approximate one-third increase in blood Hcy in AD patients, which is robustly associated with a decreased level of blood folate in AD, but not with that of blood vitamin B nor the degree of dementia. Future investigation on the cause-and-effect link between Hcy and folate is warranted to clarify this issue.