Tetrahydrobiopterin Effects on Cognitive Function in Alzheimer's Disease: Biochemical, Molecular and Cognitive Analysis

PROJECT SUMMARY Alzheimer?s disease (AD) is one of the most persistent and devastating dementias, eventually leading to a complete loss of memory and the inability to function independently. Despite the billions of US dollars invested in the development of drugs for AD, there have been more setbacks and failures than treatment successes. Drug repurposing has thus been proposed as one method to help advance AD drug development. Tetrahydrobiopterin (BH4) is a vital central nervous system (CNS) cofactor that maintains availability of the amine neurotransmitters and nitric oxide synthesis, and modulates the glutamatergic system. Previous studies have reported BH4 deficits in the periphery and CNS of AD patients; deficits comparable in size to those reported for BH4 deficiency disorders and psychiatric illness, supporting their characterization as having physiological significance. The GCH1 gene encodes the rate-limiting enzyme in BH4 biosynthesis, and GCH1 polymorphisms have been associated with cognitive ability in healthy individuals, and recently with AD. In our prelim studies, we showed that psychiatric patients who harbor a variant in the GCH1 promotor have significantly lower GCH1 expression in both the periphery and CNS, and concomitantly lower BH4. These data are particularly relevant given the exciting results obtained from our first trial of synthetic BH4 treatment for psychiatric patients. We found a significant genotype x treatment effect on the primary cognitive outcome (n=25, p=0.0093): Those patients with the GCH1 variant and low BH4 levels had greater cognitive deficits at baseline and showed significant improvement when treated with BH4, as compared to the other groups. Our trial data suggests that in those with a BH4 deficit, BH4 treatment impacts the relatively intractable cognitive core feature of psychiatric illness. Based upon these findings, we now hypothesize that differential expression of the GCH1 BH4 biosynthesis gene (via functional GCH1 polymorphisms), leads to BH4 dysregulation (for example a BH4 deficit) that will be associated with cognitive impairment in AD and MCI. We additionally hypothesize that synthetic BH4 or other molecules that can upregulate the BH4 biosynthesis pathway, are potential repurposing agents for targeting cognitive and functional impairments in patients with BH4 dysregulation. We will test these hypotheses under the following Aims: Specific Aim 1: To test the hypothesis that dysregulation of BH4 biosynthesis leads to physiologically-relevant dysregulation of BH4 availability, that predicts levels of cognitive impairment in patients with AD and MCI. Specific Aim 2: To test the molecular and biochemical efficacy of clinically available drugs to boost BH4 and rescue the neurotransmitter deficits observed in mouse models of Gch1 downregulation, overlaid onto an AD phenotype. Specific Aim 3: To target cognition via BH4 rescue in the AD animal models. Impact: If successful, this study would ascertain a population of patients whose cognition would benefit from therapeutics specifically targeting BH4 dysregulation, and would form the basis of future RCTs of AD and MCI.