A proof-of-concept study: Investigating the impact of COMT genotype and proline on negative symptoms in Alzheimer’s Disease

Previous studies have reported that levels of fasting plasma proline and catechol-O-methyltransferase ( COMT ) Val ¹⁵⁸ Met genotype influence negative symptoms in patients with severe psychiatric illness and those at-risk for psychosis. Parallel negative neuropsychiatric symptoms are also a core feature of Alzheimer’s disease (AD). In this proof-of-concept cross-sectional study of dementia patients, we explored the relationship between COMT and proline on negative neuropsychiatric symptoms. The proline x COMT interaction significantly predicted symptoms as assessed via the negative items of the Positive and Negative Symptom Scale (n=50, interaction coefficient=0.025, p=0.031): Higher proline was beneficial for both Val/Val and Val/Met dementia patients, but detrimental to Met/Met patients. That high proline also has opposing effects on negative symptoms by COMT genotype in patients with dementia, further supports the development of therapeutics to specifically target the interaction pathway across neuropsychiatric disorders.