The major focus of my research has been molecular and biochemical mechanisms in diseases of the nervous system. My particular interest has been in identifying biochemical and genetic abnormalities in patients with specific diseases and then studying how the abnormality in the molecule contributes to the clinical manifestations of the disease. About 70% of my publications have been on biochemical and molecular research and about 30% on clinical research.

From 1967-1978, my research emphasized inborn errors of metabolisms which affect the nervous system. I was part of the team that characterized the defect in Refsum's disease. I described the first inborn error in the quantitatively major pathways of energy metabolism, namely pyruvate dehydrogenase (PDHC) deficiency;. This is now a well known and well studied inborn error. The phenotype includes cases of subacute necrotizing encephalopathy. My coworkers and I described the existence of an abnormality in a specific thiamin pyrophosphate dependent enzyme, transketolase, in a form of thiamin deficiency affecting the nervous system (Wernicke-Korsakoff syndrome). The existence of such a defect has been extensively confirmed, although the molecular basis is still not worked out. My coworkers and I demonstrated the existence of mitochondrial abnormalities in many patients with hereditary ataxias, including a subgroup of patients with PDHC deficiency. These results have been confirmed, and are in recent textbooks.

Since coming to Cornell in 1978, my colleagues and I have concentrated on degenerative neurological diseases of aging and particularly on Alzheimer's disease. We are closely identified with a hypothesis that there is an inherent mitochondrial defect in this disorder. The existence of such a defect, as demonstrated by confirmations of our studies on 2 mitochondrial multienzyme complexes (PDHC and KGDHC) has been widely reproduced. Recent studies (with Dr Gary Gibson) indicate that the degree of clinical dementia correlates better with the deficiency in KGDHC activity than with plaque or tangle counts in Alzheimer patients who carry the APOE4 gene. We and others have found that polymorphisms (SNPs) in one of the genes encoding KGDHC occur in a subgroup of patients with AD. Other recent studies, with Dr Arthur Cooper, have implicated transglutamination as a mechanism of damage in the (CAG)n/Qn disorders. Aberrant transglutamination also seems to be important in Alzheimer's Disease. We are also trying to develop therapeutic modalities for Alzheimer's Disease based on our observations.