The earliest and perhaps best example of an interaction between nutrition and dementia is related to thiamine (vitamin B1).
Throughout the last century, research demonstrated that thiamine deficiency is associated with neurological problems, including cognitive deficits and damage or disease that affects the brain. It happens when there’s been a change in the way your brain works or a change in your body that affects your brain. Those changes lead to an altered mental state, leaving you confused and not acting like you usually do.
Multiple similarities exist between classical thiamine deficiency and Alzheimer’s disease (AD) in that both are associated with cognitive deficits and reductions in brain glucose metabolism. Thiamine-dependent enzymes are critical components of glucose metabolism that are reduced in the brains of AD patients and by thiamine deficiency, and their decline could account for the reduction in glucose metabolism. In preclinical models, reduced thiamine can drive alzheimer’s disease-like abnormalities, including memory deficits, plaques, and hyperphosphorylation of tau. Furthermore, excess thiamine diminishes alzheimer’s disease-like pathologies.
In addition to dietary deficits, drugs, or other manipulations that interfere with thiamine absorption can cause thiamine deficiency. Elucidating the reasons why the brains of alzheimer’s disease patients are functionally thiamine deficient and determining the effects of thiamine restoration may provide critical information to help treat patients with AD.
A few thousand papers have been published with multiple permutations in treatments and duration, with the consistent conclusion that thiamine deficiency is associated with diminished memory.
Thiamine deficiency produces abnormalities that are similar to those in AD, and the results support the suggestion that increasing thiamine in the brain may be beneficial to patients with AD.
Thiamine has been implicated in neurological problems, delirium, and dementia. Even though a role for thiamine in neurological function has long been known, we have only a limited understanding of its multiple actions. The safety of thiamine and its analogues suggests that a carefully designed trial of thiamine analogues, with appropriate power, should be conducted in Alzheimers Disease patients.
Although thiamine deficiency has long been linked to memory deficits, the best way to increase the concentrations of thiamine and TPP in the brain is not well established. Thiamine administration does not lead to substantial changes in brain thiamine or TPP. On the other hand, if treatment is given early enough, thiamine does reverse deficits related to thiamine deficiency. Standard practice in the Western world is to treat delirious patients with thiamine and glucose. If only glucose is given, the brain can become damaged because of acidosis, and the results suggest that thiamine enters the brain to exert protective effects. In humans, administration of thiamine diminishes the symptoms of Wernicke–Korsakoff syndrome, and in animals, thiamine administration reverses the effects of thiamine deficiency on thiamine-dependent enzymes, behavior, and neuronal death, as long as thiamine is administered before the changes are irreversible. Nevertheless, thiamine is a relatively poor therapeutic in that after administration of exogenous thiamine, thiamine and TPP levels in blood rise slightly and do not remain high for a long time. On the other hand, other compounds, such as solbutaimine, benfotiamine, and fursultiamine, have been designed to increase thiamine 5 to 10 times higher than thiamine and maintain these high levels for hours.
The effects of benfotiamine on cognitive impairment and AD-like pathology alterations were tested in a mouse model of AD, where a chronic 8-week treatment of benfotiamine dose-dependently enhanced the spatial memory of mice in the Morris water maze test. Furthermore, benfotiamine effectively reduced both amyloid plaque numbers and phosphorylated tau levels.34 These effects were not mimicked by another lipophilic thiamine derivative, fursultiamine, although both benfotiamine and fursultiamine are effective in increasing the levels of free thiamine in the brain. Benfotiamine, but not fursultiamine, significantly elevates the phosphorylation level of glycogen synthase kinase (GSK)-3-α and -3-β, and reduces their enzymatic activities. Therefore, in animal models of AD, benfotiamine may improve cognitive function and reduce amyloid deposition via thiamine-independent mechanisms, or it may alter thiamine metabolism in a different manner than fursultiamine.
Benfotiamine has been shown to dramatically reduce plaques in the brain.34 In this study, a comparison with the effects of furusultiamine, which does not alter plaques, suggested to the authors that the effects of benfotiamine were independent of thiamine and likely occur through benfotiamine’s action on GSK. Although the data do raise this possibility, they are limited and leave room for alternative interpretations. One important limitation of the study is that thiamine levels were measured 1 hr after one injection or after ten days of daily administration, whereas the plaques and GSK activities were measured after daily administration for 8 weeks. Brain thiamine is well known to be resistant to short-term manipulation of peripheral thiamine. Thus, both benfotiamine and furusultiamine had only minimal effects on brain thiamine and no effects on TPP or TMP. However, benfotiamine was much more effective than fursultiamine in raising blood thiamine—blood thiamine was increased two to three times more by benfotiamine than by fursultiamine (0.1 to 15 as compared to 0.1 to 7), as well as after ten days (0.1 to 6 as compared to 0.1 to 12). Thus, over 8 weeks, these higher levels may have had a larger effect on brain thiamine. Also, the authors measured whole-brain thiamine. Mammillary bodies, which are very sensitive to thiamine deficiency, have ten times the concentration of thiamine than does the cortex.
Furthermore, endothelial cells are the cell type most sensitive to thiamine deficiency. Preventing these changes in endothelial cells protects against brain pathology, including neuronal loss. Benfotiamine has also been shown to benefit endothelial cells in diabetics by acting as thiamine. The authors suggested GSK as an alternative mechanism. However, dosages of benfotiamine that reduced plaques by 75% did not significantly alter GSK activity. Thus, although this paper is very important, the conclusion about the role of thiamine following benfotiamine requires further investigation.
Both thiamine and benfotiamine protect against the peripheral neuropathy that occurs in diabetes in humans. They both reduce advance glycation end products (AGEs) by activation of the non-oxidative portion of the pentose shunt. Benfotiamine is a better therapeutic than thiamine because it raises thiamine to much higher levels and for longer periods than does thiamine and may beneficially alter other processes as well. The pharamacokinetics of benfotiamine has been well studied and it is very safe in humans. These studies suggest that benfotiamine may be an effective treatment for AD and have stimulated a clinical trial of benfotiamine in AD patients, supported by both the Alzheimer’s Drug Discovery Foundation and the National Institutes of Health (see ClinicalTrials.gov).