Methionine, Homocysteine, and Methylation Levels Predict Cognitive Decline in Alzheimer's Disease

Alzheimer's disease (AD), the most common cause of dementia, involves metabolic factors such as homocysteine, methionine, and DNA methylation in its pathogenesis. However, the precise interactions among these factors and their impact on cognitive function in AD require further elucidation.

A total of 191 AD patients and 200 cognitively normal (CN) individuals were selected from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database. Demographic, clinical, and metabolic data, including MMSE scores and white matter hyperintensity (WMH) volumes, were collected. Longitudinal cognitive changes over 1 year were also evaluated in 104 AD patients.

Compared to CN subjects, AD patients exhibited significantly lower MMSE scores, hippocampal volume, total brain volume, methionine levels, and methylation levels, alongside higher homocysteine levels and WMH volumes. Logistic regression and correlation analyses revealed that homocysteine, methionine, and methylation levels were significantly associated with cognitive function in AD patients but not in CN subjects. Elevated homocysteine levels in AD patients correlated with lower MMSE scores, higher WMH volumes, lower vitamin B12 levels, and older age. Similarly, low methionine and methylation levels were associated with more severe cognitive impairment and brain atrophy. Longitudinal analyses showed that AD patients with low methionine, high homocysteine, or low methylation levels experienced significantly greater cognitive decline over 1 year compared to those with more favorable biomarker profiles.

Our findings highlight the significant associations between homocysteine, methionine, and methylation levels and cognitive decline in AD patients. These results suggest that metabolic and epigenetic alterations may contribute to AD progression and could serve as potential biomarkers or therapeutic targets in AD.