One-Carbon Metabolism in Alzheimer's Disease and Parkinson's Disease Brain Tissue

Disruptions in one-carbon metabolism and elevated homocysteine have been previously implicated in the development of dementia associated with Alzheimer's disease (AD) and Parkinson's disease (PD). Moreover, a PD diagnosis itself carries substantial risk for the development of dementia. This is the first study that explores alterations in one-carbon metabolism in AD and PD directly in the human brain frontal cortex, the primary center of cognition. Applying targeted liquid chromatography-tandem mass spectrometry (LC-MS/MS), we analyzed post-mortem samples obtained from 136 subjects (35 AD, 65 PD, 36 controls). We found changes in one-carbon metabolites that indicate inefficient activation of cystathionine β-synthase (CBS) in AD and PD subjects with dementia, the latter seemingly accompanied by a restricted re-methylation flow. Levodopa-carbidopa is known to reduce available vitamin B6, which would explain the hindered CBS activity. We present evidence of temporary non-protein-bound homocysteine accumulation upon levodopa intake in the brain of PD subjects with dementia but not in non-demented PD subjects. Importantly, this homocysteine elevation is not related to levodopa dosage, disease progression, or histopathological markers but exclusively to the dementia status. We hypothesize that this levodopa-induced effect is a direct cause of dementia in PD in susceptible subjects with reduced re-methylation capacity. Furthermore, we show that betaine best correlates with cognitive score even among PD subjects alone and discuss nutritional recommendations to improve one-carbon metabolism function.