Carriers of of the apoE ε4 allele have significantly lower selenium levels in nails and brains. Selenoprotein P is a selenium transport protein. Apolipoprotein E receptor 2 by binding to selenoprotein P regulates uptake of selenium into cells. Both apolipoprotein E receptor 2 and apolipoprotein E regulate transport of selenoprotein P into cells. Selenoprotein P provides protection from amyloid β (Aβ), the main component of amyloid plaques seen in Alzheimer’s disease. The association of apoE ε4 with Alzheimer’s disease could be due to apoE ε4 not being as effective in regulation of selenium transport into cells via apolipoprotein E receptor 2 as other alleles of apoE.
Synthesis of acetylcholine requires acetyl-coenzyme A which donates an acetyl group to choline. With dysregulation of the transsulfuration pathway in Alzheimer’s disease, marked by high levels of homocysteine, L-cysteine is not synthesized at sufficient levels. See my paper A disease-modifying treatment for Alzheimer’s disease: focus on the trans-sulfuration pathway. With low levels of l-cysteine coenzyme A, which is synthesized from pantothenic acid and which requires l-cysteine for synthesis, is not synthesized at appropriate levels. With low levels of coenzyme A the E2 subunit of the pyruvate dehydrogenase complex is underactive. Acetyl-coenzyme A required for the synthesis of acetylcholine is derived from the pyruvate dehydrogenase complex. Dysregulation of the pyruvate dehydrogenase complex could lead to shortages of acetylcholine in Alzheimer’s disease. Shortages of acetylcholine are a hallmark of Alzheimer’s disease. Supplementation with pantothenic acid and sulbutiamine, a fat-soluble thiamine derivative, could improve symptoms of Alzheimer’s disease due to acetylcholine deficiencies such as poor memory. There is a lot askew in Alzheimer’s disease so supplementation with pantothenic acid and sulbutiamine would only be partly effective in Alzheimer’s disease. As always various supplements must be avoided. See the Treatment page on what supplements to avoid.
Reductions in cerebral metabolism sufficient to impair cognition in normal individuals also occur in Alzheimer’s disease (AD). The degree of clinical disability in AD correlates closely to the magnitude of the reduction in brain metabolism. Therefore, we tested whether impairments in tricarboxylic acid (TCA) cycle enzymes of mitochondria correlate with disability. Brains were from patients with autopsy-confirmed AD and clinical dementia ratings (CDRs) before death. Significant (p < 0.01) decreases occurred in the activities of the pyruvate dehydrogenase complex (-41%), isocitrate dehydrogenase (-27%), and the alpha-ketoglutarate dehydrogenase complex (-57%). Activities of succinate dehydrogenase (complex II) (+44%) and malate dehydrogenase (+54%) were increased (p < 0.01). Activities of the other four TCA cycle enzymes were unchanged. All of the changes in TCA cycle activities correlated with the clinical state (p < 0.01), suggesting a coordinated mitochondrial alteration. The highest correlation was with pyruvate dehydrogenase complex (r = 0.77, r2= 0.59). Measures to improve TCA cycle metabolism might benefit AD patients.
Bill Gates is looking for new ideas on the etiology of Alzheimer’s disease. A heightened focus on the citric acid cycle in Alzheimer’s disease is a new approach to the etiology of Alzheimer’s disease for which there is experimental backing.
There are infectious diseases subdivided into bacterial and viral diseases, there is cancer where there are many sorts of cancer, there is heart disease, lung disorders etc. There could be a new disease class. There could be epigenetic disorders where there is common origin for a wide range of epigenetic disorders. With epigenetic mechanisms dysregulated many different diseases can arise as there are many different ways genes and histones can become inappropriately methylated. My idea is that a dysregulation of aconitase 1 can dysregulate iron metabolism and decrease 2-oxogularate synthesis which will in turn dysregulate TET enzymes, which demethylate DNA, and dysregulate Jumonji domain-containing proteins, which demethylate histones. Dysregulation of TET enzymes and dysregulation of Jumonji domain-containing proteins can play out many different ways in terms of inappropriate DNA methylation and inappropriate histone methylation whereby many different diseases can arise. Though many different diseases can arise from dysregulations of aconitase 1, iron metabolism and 2-oxoglutarate synthesis prevention of a range of illnesses could be achieved by the same treatment. For example, a treatment than prevents schizophrenia could also prevent Alzheimer’s disease and Parkinson’s disease. The Treatment presented in the Treatment section is not ready for home use, however, a Moon shot would not be necessary to get the treatment to a state where family doctors could prescribe a treatment which would prevent a range of chronic illnesses from schizophrenia, to Alzheimer’s disease, to Parkinson’s disease. What is needed is a launch ten weather balloons into the high atmosphere then collect and analyze data kind of effort.
There could be some improvement in Alzheimer’s disease with appropriate treatment. I am making a logical point. I have no biological evidence that this is the case. Various illnesses that present as dementia’s can be treated. Major depressive disorder can appear to be a dementia, however, the dementia of major depressive disorder is treatable. There could be certain aspects of Alzheimer’s disease that arise from biochemical abnormalities which are not strictly related to death of neurons. With the biochemical abnormalities addressed various aspect of an Alzheimer’s dementia could be reversed. In my paper A disease-modifying treatment for Alzheimer’s disease: focus on the trans-sulfuration pathway I argue than Alzheimer’s disease can be prevented and stopped with appropriate Treatment, however, from a logical viewpoint some symptoms of Alzheimer’s disease could even be reversed especially in the early stages of the disease.
Iron chelators are being clinically tested in a number of neurodegenerative illnesses such as Alzheimer’s and Parkinson’s disease . I do not think iron chelation is going to work. In fact I think iron chelators will make Alzheimer’s and Parkinson’s worse. I very much hope I am mistaken. The difficulty isn’t iron per se but rather dysregulation of iron regulated biological processes. A sensible choice now is to stay away from iron supplements except for anemia. My ideas are very sensible but sensible ideas are wrong all the time. Iron chelation is a very sensible approach to treatment of Alzheimer’s and Parkinson’s which I think is going to be disastrous.