Volume 9, Number 4, August 2006 - Special Issue "Folate and Homocysteine in Alzheimer's Disease" (Guest Editor: Thomas Shea)

Pages 359-360
Thomas B. Shea
Folate, the Methionine Cycle, and Alzheimer's Disease

Pages 361-380
Andrew McCaddon
Homocysteine and cognition - a historical perspective
Abstract: The discovery of a relationship between homocysteine and cognition stems from clinical observations of an association between vitamin B12 and folate deficiency and cognitive dysfunction. This retrospective details the history of vitamin B12 and folic acid and the conceptual evolution of their association with dementia. The hematological and neuropsychiatric manifestations of these deficiencies are discussed, together with the nature of their relationship with dementia, generalized cognitive decline and discrete neuropsychological function. An evaluation of the potential of reversing 'homocysteine-associated' and/or 'vitamin-associated' cognitive decline raises questions as to whether current interventions can unequivocally determine if homocysteine independently impacts on cognitive function. Alternative approaches specifically designed to address this issue are discussed.

Pages 381-392
Aron M. Troen, Barbara Shukitt-Hale, Wei-Hsun Chao, Bina Albuquerque, Donald E. Smith, Jacob Selhub, Irwin H. Rosenberg
The cognitive impact of nutritional homocysteinemia in Apolipoprotein-E deficient mice
Abstract: Homocysteinemia is associated with cognitive dysfunction in the elderly ranging from subtle cognitive decline to dementia. Homocysteine is generated from methionine as a product of biological methylation reactions and is disposed of through reactions that require folate and vitamins B12 and B6. While different disruptions in these reactions can result in homocysteinemia, it is unclear if they will also result in homocysteine-mediated cognitive dysfunction. Young ApoE-deficient mice were fed one of four diets with differing methionine and B-vitamin content for eight weeks, before undergoing psychomotor tests, the Morris Water Maze test of spatial memory and learning, and measurement of home-cage activity. B-vitamin deficiency induced homocysteinemia and selectively impaired Morris Water Maze performance without affecting other behavioral measures. The cognitive deficits occurred in the absence of overt histologic neurodegeneration but in association with moderate impairments of brain methylation potential. Diets that yielded cognitive deficits were different from those that exacerbated aortic pathology. These findings are inconsistent with a single mechanism linking homocysteinemia to neurological dysfunctions mediated by homocysteine vasotoxicity. Instead, they indicate that different “types” of homocysteinemia, or in other words different impairments of nutritional metabolism affecting homocysteine levels, may lead to different end organ dysfunctions and/or diseases.

Pages 393-398
Sudha Seshadri
Elevated Plasma Homocysteine Levels: Risk Factor or Risk Marker For The Development Of Dementia and Alzheimer’s Disease?
Abstract: Elevated plasma homocysteine (tHcy) concentrations have been associated with an increased risk of developing dementia and Alzheimer’s disease (AD). It is not clear, however, if an elevation in tHcy concentration is a ‘risk factor’ with a direct pathophysiological role in the development of the disease or merely a ‘risk marker’ reflecting an underlying process such as oxidative stress responsible for both the high tHcy concentrations and the development of AD. Epidemiological studies have confirmed that elevations in plasma tHcy temporally precede the development of dementia and that there is a continuous, inverse linear relation between plasma tHcy concentrations and cognitive performance in older persons. Several potential biological pathways that could mediate the observed association are briefly reviewed. In light of these data and the growing parallel interest in plasma tHcy as an emerging vascular risk factor there was considerable hope that vitamin therapy with folate, B12 and B6, shown to lower plasma tHcy levels, could significantly reduce the risk of stroke and dementia permitting healthy brain aging. The results from recent trials addressing the secondary prevention of stroke and myocardial infarction trials have been disappointing. However, the role of vitamins and other homocysteine lowering treatments in the primary prevention of stroke and dementia, as well as their role in preserving cognition among persons with mild cognitive impairment and early dementia deserves to be fully pursued.

Pages 399-405
Amy Chan and Thomas B. Shea
Dietary and genetically-induced oxidative stress alter tau phosphorylation: influence of folate and apolipoprotein E deficiency
Abstract: One hallmark of AD is the deposition of neurofibrillary tangles which are comprised of phosphorylated isoforms of the microtubule-associated protein tau. We demonstrate herein that dietary deprivation of folate and vitamin E, coupled with iron as a pro-oxidant, fosters an increase in nonphospho- and-phospho-tau within brain tissue of mice homozygously lacking apolipoprotein E as assayed by monoclonal antibodies Tau-1 and PHF-1, respectively. Tau immunoreactivity in mice homozygously expressing murine apolipoprotein E was not affected. Supplementation of this challenge diet with s-adenosylmethinone, known to be depleted following folate deprivation and further known to restore a portion of the oxidative buffering capactity of these mice when maintained under this challenge diet, alleviates the increase in nonphospho-tau but does not attenuate the increase in phospho-tau. These findings suggest that the combined deleterious impact of dietary- and genetically-induced oxidative stress fostered a specific increase in phospho-tau. While some studies consider that increased levels of phospho-tau represents a hallmark of neuropathology, the findings of the present study also remain consistent with the alternative viewpoint that accumulation of phospho-tau instead represents an index of antioxidant compensation.

Pages 407-414
Sigfrido Scarpa, Rosaria A. Cavallaro, Fabrizio D'Anselmi, Andrea Fuso
Gene silencing through methylation: an epigenetic intervention on Alzheimer disease
Abstract: Alzheimer disease (AD) is among the few diseases that may display high homocysteine (HCY) and low B12 and folate in blood. This observation has raised the suspect that amyloid-ß overproduction and accumulation, which may be the cause of the disease, could be due to the loss of epigenetic control in the expression of the genes involved in AßPP (amyloid-ß protein precursor) processing. We have shown, in cell culture, that two of the genes responsible for amyloid-ß production are controlled by the methylation of their promoters. The process is strictly related to S-adenosylmethionine (SAM) metabolism. SAM is a natural compound, mainly produced by the liver, which has been found at very low concentrations in AD brains. A further support to this thesis came from the observation that in elderly DNA methylations are consistently lower than in young and mid aged people. We are actually experimenting in transgenic mice the possibility to prevent or to arrest amyloid-ß accumulation, through SAM administration, and therefore its significance and the use of this drug for the treatment of the disease.

Pages 415-419
Rosaria A. Cavallaro, Andrea Fuso, Fabrizio D’Anselmi, Laura Seminara, Sigfrido Scarpa
The effect of S-adenosylmethionine on CNS gene expression studied by cDNA microarrays analysis
Abstract: High homocysteine (Hcy) together with low S-adenosylmethionine (SAM) levels are often observed in Alzheimer disease (AD), and this could be a sign of alteration of SAM/Hcy metabolism. It has already been shown that DNA methylation is involved in amyloid ß-protein precursor (AßPP) processing and amyloid-ß (Aß production through the regulation of Presenilin 1 (PS1) expression and that exogenous SAM can silence the gene reducing Aß. To investigate whether SAM administration globally influenced gene expression in the brain, we analysed 588 genes of the central nervous system in SK-N-BE neuroblastoma cells, with cDNA probes derived from untreated (DM; Differentiation Medium) or SAM treated (DM+SAM) cultures. In these conditions only seven genes were modulated by SAM treatment (and therefore by DNA methylation); three were up-regulated and four down-regulated, showing low levels of modulation.

Pages 421-427
Flaubert Tchantchou
Homocysteine metabolism and various consenquences of folate deficiency
Abstract: Homocysteine is a neurotoxic non-proteinogenic amino acid, an abnormal increase of which in plasma has been implicated in many pathological conditions including cardiovascular diseases, neural tube defects and is now recognized and Alzheimer’s disease. Homocysteine elimination is regulated by the transmethylation and the transsulfuration pathways and is modulated by folate, a member of the B-vitamin family. A metabolic product of folate, 5 methyltetrahydrofolate, provides a methyl group that is used to reconvert homocysteine back to methionine through the transmethylation pathway. The efficiency of folate metabolism has an impact on the availability of S-adenosylmethionine (SAM), a compound that is known to activate homocysteine flux through the transsulfuration pathway. SAM is also necessary for utilization of the antioxidant glutathione via glutathione S-transferase. In this review, I will elaborate on different biochemical reactions that are implicated in the regulation of homocysteine elimination through the transmethylation and the transsulfuration pathways and on various consequences of folate deficiency on homocysteine metabolism.

Pages 429-433
Martha Clare Morris, Julie A. Schneider, Christine C. Tangney
Thoughts on B-Vitamins and Dementia
Abstract: The B-vitamins, including vitamins B12, B6, B1, B2, niacin (B3) and folate (B9), have been implicated as protective risk factors against cognitive decline and Alzheimer’s disease. This commentary reviews the evidence to support protective relations of these vitamins, including consideration of known vitamin deficiency syndromes, theories of underlying biologic mechanisms, and the epidemiologic evidence. We also comment on the potential benefits and harms of vitamin supplementation as well as make recommendations for the direction of future studies.

Pages 435-443
Martha Clare Morris, Denis A. Evans, Julie A. Schneider, Christine C. Tangney, Julia L. Bienias, Neelum T. Aggarwal
Dietary Folate and Vitamins B-12 and B-6 not Associated with Incident Alzheimer’s Disease
Abstract: Context: It is currently not known whether dietary intakes of folate and vitamins B12 and B6, co-factors in the methylation of homocysteine, protect against Alzheimer’s disease. Objective: To examine the association between risk of incident Alzheimer’s disease and dietary intakes of folate, vitamin B-12, and vitamin B-6. Design: Prospective cohort study. Setting: Geographically defined biracial Chicago community Participants: 1,041 residents, aged 65 years and older, initially free of Alzheimer’s disease and followed a median 3.9 years for the development of incident disease. Main Outcome Measure: Probable Alzheimer’s disease identified through structured clinical neurological evaluation using standardized criteria. Results: A total of 162 persons developed incident Alzheimer’s disease during follow-up. In logistic regression models adjusted for age, sex, race, education, cognitive activities, APOE-e4, and dietary intakes of vitamin E in food and total niacin, there was no association between risk of developing Alzheimer’s disease and quintiles of folate intake or of vitamin B-12 intake. The adjusted odds ratio was 1.6 (95% confidence interval: 0.5, 5.2) for persons in the highest quintile of total folate intake (median of 752.7 ug/d) compared with persons in the lowest quintile of intake (median, 202.8 ug/d). Compared with persons in the first quintile of total vitamin B-12 intake (median, 3.1 ug/d) the odds ratio was 0.6 (95% confidence interval: 0.2, 1.6) for persons in the fifth quintile of intake (median, 20.6 ug/d). Intake of vitamin B-6 was not associated with incident Alzheimer’s disease after control for dietary intakes of vitamin E and total niacin. Conclusion: Dietary intakes of folate, vitamin B-12, or vitamin B-6 do not appear to be associated with the development of Alzheimer’s disease.

Pages 445-448
Selected Abstracts from the "Wellness for Persons with Dementia" Symposium
Organizer and Chair, Nancy B. Emerson Lombardo, Boston University

Pages 449-457
Transcript: Alzheimer Research Forum Live Discussion
Lost in Translation? Charting the Course in Preclinical Therapeutic Development

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