This supplement is supported by Pamlab LLC.

Dr. Cummings is director of the Mary S. Easton Center of Alzheimer’s Disease Research in the Departments of Neurology and Psychiatry and Behavioral Sciences, David Geffen School of Medicine, at the University of California, Los Angeles.

Disclosure: Dr. Cummings has provided consultation to Abbott, Acadia, Accera, ADAMAS, Astellas, Avanir, Bristol-Myers Squibb, CoMentis, Eisai, Elan, Eli Lilly, EnVivo, Forest, GlaxoSmithKline, Janssen, Lundbeck, Medivation, Merck, Merz, Myriad, Neuren, Neurokos, Novartis, Noven, Orion, Pfizer, Prana, reMYND, Schering Plough, Signum Bioscience, Sonexa, Takeda, Toyama, and Wyeth; has been a speaker/lecturer on behalf of Eisai, Forest, Janssen, Novartis, Pfizer, Lundbeck, Merz; owns stock in ADAMAS, Neurokos, Prana, and Sonexa; owns the copyright of the Neuropsychiatric Inventory; and has provided expert witness/legal consultation regarding olanzapine and ropinirole.

Acknowledgment: Dr. Cummings is supported by the Sidell-Kagan Foundation and the Jim Easton gift.


 

Abstract

Alzheimer’s disease (AD) and dementia have enormous financial and social impacts on society. It is predicted that almost 36 million people will have dementia in 2010, a figure which is anticipated to double every 20 years as the world population ages.  Prevention of AD or slowing of the progression of AD would provide significant benefits. There are multiple ways in which vitamin B12, vitamin B6, folate, and homocysteine (Hcy) play a role in the pathogenesis of AD. Vitamin B12, vitamin B6, and folate deficiencies are associated with various cognitive disorders, including dementia. Neuroinflammatory oxidative stress occurs early in AD pathology. Total blood Hcy levels are utilized as a marker to assist in diagnosing such deficiencies. Hcy contributes to pathological cascades involving amyloid plaques and neurofibrillary tangles (NFTs). This review provides a thorough description of several factors involved in the development of the pathological changes associated with AD, such as neuroinflammatory oxidative stress and methylation, apoptosis, NFTs, amyloid plaques, and cerebrospinal fluid biomarkers. The review also considers the rationale for a combined B-vitamin and antioxidant supplement (Cerefolin NAC) in treating and slowing AD-related cognitive decline.


In this Expert Review Supplement, Andrew McCaddon, MD, and Peter R. Hudson, PhD provide a comprehensive review of factors involved in AD pathology as well as evidence supporting the use of a combined B-vitamin and antioxidant supplement (Cerefolin NAC) for AD-related cognitive decline. A commentary on this article is provided by leading AD expert Jeffrey L. Cummings, MD.

 

Drs. McCaddon and Hudson provide a thorough review of the multiple ways in which vitamin B12, vitamin B6, folate, and homocysteine (Hcy) are implicated in the pathogenesis of Alzheimer’s disease (AD). They noted that Hcy is more often elevated in AD and in mild cognitive impairment (MCI) than in cognitively healthy elderly; phosphatases needed to limit tau hyperphosphorylation and neurofibrillary tangle formation require methylation and are dependent on folate and methylation status; cerebrospinal fluid (CSF) tau levels correlated with markers of methylation status; reduced folate and B12 levels lead to increase b-secretase and pesenilin 1 (PS1) actions leading to greater amyloid-b production in in vitro models; elevated Hcy levels in rats are associated with increased PS1 activity and spatial memory deficits that are reversed following treatment with B12 and folate; raised Hcy levels in vitro increase amyloid-b protein neurotoxicity; methylation impacts transmitters and transmitter function relevant to AD; in cultured neurons, Hcy induces injury in DNA and stimulates cell death pathways. B12 deficiency leads to accumulation of methyl malonic acid, which inhibits mitochondrial function and may compromise energy generation and impair maintenance of synaptic plasticity. Methylation abnormalities result in excessive generation of reactive oxygen species that contribute importantly to cell injury. Biomarkers of oxidative injury, such as isoprostanes, are elevated in AD and suggest excess oxidation. Thus, there are multiple pathways through which deficient methylation may contribute to AD. In some cases, the observations are derived from models with B12 or folate deficiency and some in vitro observations have not been tested in in vivo models. There are no biomarkers specific to some of the pathways implicated and the magnitude of the impact of the deficiency or its treatment has not been established for all the relationships. Two open-label experiments in early- and late-stage AD patients have suggested benefit.

Epidemiologic data support a role for Hcy elevation as a contributing factor to AD. Based on data from the Framingham study,1 persons with elevated Hcy were at increased risk for developing AD; plasma levels >14 mmol/liter nearly doubled the risk of AD. In a consecutive series of 126 patients with AD, the patients were shown to have reduced CSF levels of L-methylfolate compared to healthy elderly controls.2 

Double-blind, placebo-controlled trials support a role for folate supplementation in older persons with elevated levels of serum Hcy. Durga and colleagues3 assigned 818 elderly individuals to 800 mcg of folic acid or placebo and treated them for 3 years. Subjects had 13–26 mmol/liter of Hcy at baseline. Those receiving folate supplementation performed better on tests of memory and sensory motor speed at the end of the trial. Patients had normal cognition at baseline. Aisen and colleagues4 performed a randomized trial of folic acid 5 mg/day, vitamin B12 1 mg/day, vitamin B6 25 mg/day in patients with mild-to-moderate AD. Hcy levels declined significantly; there was no corresponding cognitive, functional, global, or behavioral benefit.  Prespecified analyses of those with baseline Hcy levels in the highest quartile also showed no clinical benefit. The study shows that AD patients with normal levels are not improved by vitamin supplementation at these doses when used for 18 months and measured with standard clinical trial outcomes. Definitive conclusions about the utility of treatment of pathologically elevated Hcy levels awaits further study.

Cerefolin NAC, the compound described by Drs. McCaddon and Hudson, is available in the United States by prescription as a medical food. Medical foods are not supplements (which are taken by normal individuals, do not address a specific metabolic abnormality, and do not require a prescription) and they are not drugs (shown in rigorous double-blind, placebo-controlled trials to significantly improve a disease state).   Medical foods address a specific metabolic condition associated with a disease state. Cerefolin NAC reduces hyerhomocysteinemia that has been associated with memory impairment, AD, and cerebrovascular disease. The package insert for Cerefolin NAC describes the intended treatment population as individuals under a physician’s treatment for early memory loss with particular emphasis for those individuals diagnosed with or at risk for neurovascular oxidative stress and/or hyperhomocysteinemia, mild-to-moderate cognitive impairment with or without vitamin B12 deficiency, vascular dementia, or AD. Available data do not address all these conditions. The available data support use in older persons with elevated Hcy; studies in other populations are warranted. Cerefolin NAC is safe, with no important adverse events having been identified. 

Cerefolin NAC is currently being studied in a double-blind, placebo-controlled trial to determine its effect on cognition and other biomarkers for patients with early memory loss. This study is being conducted at Rush University in Chicago and the results for the first phase (6-month data) are due in early 2010. The patients will continue in the study for 18 months.

Clinicians must base treatment recommendations on the available pathophysiological and epidemiologic studies until more definitive clinical trial data are available. 

 

References

1. Seshadri S, Beiser A, Selhub J, et al.  Plasma homocysteine as a risk factor for dementia and Alzheimer’s disease. New Engl J Med. 2002;346:476-483.
2. Serot JM, Christmann D, Dubost T, Bene MC, Faure GC. CSF-folate levels are decreased in late-onset AD patients. J Neural Transm. 2001;108:93-99.
3. Durga J, von Boxtel MPJ, Schouten EG, et al.  Effect of 3-year folic acid supplementation on cognitive function in older adults in the FACIT trial: a randomized double-blind, controlled trial. Lancet. 2007;369:208-216.
4. Aisen PS, Schneider LS, Diaz-Arrastia R, et al.  High-dose vitamin B supplementation and cognitive decline in Alzheimer’s disease. JAMA. 2008;300:1774-1783.
 

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