Hyperhomocysteinemia in Alzheimer's Disease
Principal Investigator: Ramon Diaz-Arrastia
Abstract: In the past years, two independent case control studies have established a correlation between elevated homocysteine levels and Alzheimer's Disease (AD). Since vitamin supplementation with folic acid, vitamin B12, and pyridoxine can lower homocysteine levels, this association raises the exciting possibility that polyvitamin therapy may decrease the incidence of AD. The goal of this proposal is to obtain pilot data necessary to design a large multicenter trial to determine whether vitamin therapy lowers the risk of AD. We plan to do this through the following specific aims: (a) Determine whether fasting or post-methionine load (PML) are best associated with AD. The published studies analyzed homocysteine levels in fasting or randomly drawn serum samples. Since many patients have elevations in homocysteine levels only after a methionine load, and both fasting and PML hyperhomocysteinemia may be associated with dementia, we will determine whether fasting hyperhomocysteinemia, PML hyperhomocysteinemia, or both, are linked to a higher risk of AD. We will also determine whether plasma levels of S-adenosylhomocysteine (SAH) and S- adenosylmethionine (SAM) are nire sensitive markers of functional hyperhomocysteinemia (b) Determine the relative importance of nutritional and genetic factors as determinants of hyperhomocysteinemia. Elevated homocysteine levels result from a complex interplay of genetic and acquired factors, and the link between hyperhomocysteinemia and AD has so far been reported only in Europeans. In an attempt to determine which of these factors is most important in an ethnically and culturally heterogeneous US population, we will administer a nutritional questionnaire and measure vitamin levels in our patients, as well as determine the allelic frequency of the C677T polymorphism of MTHFR, a major genetic determinant of hyperhomocysteinemia. (c) Determine whether vitamin therapy is effective in lowering homocysteine levels in patients with hyperhomocysteinemia. All subjects will be treated sequentially for 12 weeks first with low dose vitamin supplementation, followed by high-dose vitamin supplementation. The effectiveness, compliance rates, and potential side effects of these therapies will be monitored. Each of these specific aims is essential to rationally design a large multicenter trial to determine whether polyvitamin therapy lowers AD risk.
Funding Period: 2001-08-15 - 2005-07-31
more information: NIH RePORT
- Hyperhomocysteinemia and cognitive function: more than just a casual link?Teodoro Bottiglieri
Am J Clin Nutr 82:493-4. 2005
- Association of homocysteine with plasma amyloid beta protein in aging and neurodegenerative diseaseM C Irizarry
The Massachusetts Alzheimer Disease Research Center, Massachusetts General Hospital, Boston, MA, USA
Neurology 65:1402-8. 2005..tHcy may potentiate neurotoxic and vasculopathic processes, including amyloid beta protein (Abeta) metabolism, implicated in neurodegenerative diseases...
- Clinical course in Parkinson's disease with elevated homocysteinePadraig E O'Suilleabhain
Department of Neurology, Southwestern Medical Center at Dallas, University of Texas, 5323 Harry Hines Boulevard, Dallas, TX 75390 9036, USA
Parkinsonism Relat Disord 12:103-7. 2006..03). We conclude that hyperhomocysteinemia does not predict significantly worse progression over 2 years in early PD. The data raised the possibility of higher mortality, but the number of deaths was small...
- Protein phosphatase 2A methyltransferase links homocysteine metabolism with tau and amyloid precursor protein regulationEstelle Sontag
Department of Pathology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA
J Neurosci 27:2751-9. 2007..The link between homocysteine, PPMT, PP2A methylation, and key CNS proteins involved in AD pathogenesis provides new mechanistic insights into this disorder...