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Neurodegenerative Disease Alzheimer’s Disease


Involvement of Nutrients in the Pathogenesis or Management of Alzheimer’s Disease


Richard J Wurtman, MD Cecil H Green Distinguished Professor Emeritus, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology


Abstract


The number of hippocampal and cortical synapses is diminished in early Alzheimer’s disease (AD) and this loss, which is well correlated with the onset of cognitive deficits, probably reflects both an acceleration in their breakdown and a slowing in their synthesis, perhaps consequent to the concurrent decrease in dendritic spines. No strategies have been identified for increasing the number of synapses. Synaptogenesis requires adequate amounts of highly specialized synaptic membrane and activation of a process for shaping this membrane, initially into dendritic spines and neurites and then into the synapses themselves. Both can be enhanced by providing, concurrently, three circulating compounds present in the diet—uridine (as its monophosphate), docosahexaenoic acid (DHA), and choline—which can be rate-limiting precursors in membrane phosphatide synthesis. The uridine, as uridine triphosphate (UTP), also activates brain P2Y receptors, which facilitate neuronal differentiation and affect the production of synaptic proteins. In two large-scale clinical trials, patients with early AD who received the precursors and cofactors orally for up to 24 weeks exhibited significant improvements in memory indices.


Keywords


Nutrients, synapses, synaptic membrane, phosphatides, synaptic proteins, dendritic spines, uridine, docosahexaenoic acid, choline, Alzheimer’s disease, cognition, memory


Disclosure: Richard J Wurtman, MD, is a member of staff at the Massachusetts Institute of Technology (MIT). MIT holds patents on the use of uridine and of docosahexaenoic acid (DHA) sources to promote synaptic membrane production and Dr Wurtman is one of the listed inventors. If MIT obtains royalties from a product that emerges from this research, Dr Wurtman will share in them according to the standard agreement that MIT makes with its staff. Dr Wurtman does not participate in any clinical trials on his inventions, he has had no involvement in the clinical trials described in this article, and does not own stock in companies that are trying to develop products based on his inventions. He has served as a research adviser to such companies, and advises Nutricia, a wholly-owned subsidiary of the Danone Company, on possible medical uses of mixtures to promote synaptogenesis. Dr Wurtman’s laboratory’s research on the use of nutrients to promote synaptogenesis has been largely or entirely supported by grants from the US National Institutes of Health. Funds for two to three postdoctoral fellows have also been obtained from the Center for Brain Sciences and Metabolism Charitable Trust. Received: November 17, 2011 Accepted: November 22, 2011 Citation: US Neurology, 2011;7(2):87–90 Correspondence: Richard J Wurtman, MD, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Building 46-5009, Cambridge, MA 02139. E: dick@mit.edu


This article examines the possible involvement of nutrients in the pathogenesis, prevention, or management of Alzheimer’s disease (AD). Nutrients are defined here as food constituents that are essential for preventing or treating the clinical syndromes that develop when they are deficient. In general, they act as substrates or cofactors for enzymes and thereby sustain growth and metabolism.


These effects might, for example, involve enzymes, transport proteins (e.g., in brain capillaries through which leucine suppresses the passage of blood tryptophan into the brain and thus diminishes serotonin synthesis),2


This article first considers the evidence that deficiencies involving individual nutrients, for example folic acid or docosahexaenoic acid


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Some nutrients can also produce pharmacologic effects if administered in doses higher than those needed to prevent their deficiency syndromes, or if given without the other compounds that usually accompany them in food sources.1


antagonism of receptors, synthesis of second messengers, ion channels, or even non-enzymatic processes (e.g., acting as antioxidants).


(DHA), might be risk factors for AD, or that administering each such compound might be useful in treating this disease. It then describes the pharmacologic effects of a mixture of nutrients on synapse formation and behavior in experimental animals, and on memory functions in patients with early AD and, presumably, deficiencies in cortical and hippocampal synapses.3–5


The course of AD, a very common and poorly treated neurodegenerative disease, is currently thought to involve three characteristic phases.6


In the earliest phase, memory disturbances are minor or even absent and there is no evidence of dementia; however, neurochemical abnormalities presumably exist which might be assessed by measuring putative biomarkers.6


These include subnormal levels of a characteristic


peptide, A-beta 1–42, in cerebrospinal fluid (CSF) and abnormal brain scans exhibiting, by magnetic resonance imaging (MRI), medial temporal lobe atrophy with loss of hippocampal, entorhinal cortical, and amygdalar volume, or, by positron emission tomography (PET), reduced


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