I present a theory of Alzheimer's disease (AD) that explains its symptoms, pathology, and risk factors. To do this, I introduce a new theory of brain plasticity that elucidates the physiological roles of AD-related agents. New events generate synaptic and branching candidates competing for long-term enhancement. Competition resolution crucially depends on the formation of membrane lipid rafts, which requires astrocyte-produced cholesterol. Sporadic AD is caused by impaired formation of plasma-membrane lipid rafts, preventing the conversion of short- to long-term memory and yielding excessive tau phosphorylation, intracellular cholesterol accumulation, synaptic dysfunction, and neurodegeneration. Amyloid β (Aβ) production is promoted by cholesterol during the switch to competition resolution, and cholesterol accumulation stimulates chronic Aβ production, secretion, and aggregation. The theory addresses all of the major established facts known about the disease and is supported by strong evidence.

Background. Amyotrophic Lateral Sclerosis (ALS) is a devastating disease involving motor neuron degeneration. The few drugs approved for treatment have at most a marginal benefit, and death usually occurs 2-5 years after diagnosis. Methods. A thorough manual examination of the relevant literature, covering over 35,000 papers. Results. Two major phenomena that are generally not known to clinicians were found. First, insulin signaling is impaired in ALS even in patients not diagnosed with diabetes (DB). Almost all studies that have explicitly tested insulin function in non-DB ALS patients using glucose tolerance tests (18 out of 20, 1964-2022, different groups) have found it to be impaired. Second, there is strong evidence for excessive insulin-independent glucose uptake (IIGU) in ALS. In addition, (i) early/late diabetes are associated with increased/decreased risk, respectively; (ii) insulin-based diabetes drugs are protective in ALS in large retrospective human studies; and (iii) strong animal and human evidence shows that insulin opposes all of the major pathological processes in ALS. Conclusion. Most ALS patients have insulin impairment, yet this is commonly not diagnosed, likely because excessive IIGU normalizes glucose levels. The impairment promotes disease progression. Late diabetes is associated with decreased risk because high glucose levels indicate non-excessive IIGU, and because diabetes drugs are protective. Insulin-based treatment (e.g., GLP1 agonists, insulin) is beneficial and can be disease-modifying in ALS and in frontotemporal dementia variants comorbid with ALS. ALS patients should be routinely tested for insulin function and treated if test results are positive.

This paper presents a new theory explaining the pathological mechanisms of multiple sclerosis (MS). MS is triggered by persistently activated immune cells, mainly B cells, as in reactivated Epstein-Barr virus infection. Activated immune cells release cytokines, the main one here being TNFa. A major role of TNFa is to support immune cell motility and tissue penetration, by promoting the breakdown of ceramide products that stabilize membranes (sphingomyelin (SPM) and galactosylceramide (GalCer)), by stimulating membrane breakdown via ceramide 1-phosphate-induced liberation of arachidonic acid, and by promoting the production of sphingosine 1-phosphate, a ceramide product that promotes immune motility. These ceramide products are expressed in endothelial cells, including the blood-brain barrier, and have a large presence in myelin. Thus, excessive cytokine release both allows immune penetration into the brain, and impairs existing myelin sheaths. SPM and GalCer are essential for myelin maintenance but not for its synthesis, explaining the dominant relapsing-remitting nature of the disease. The theory is supported by diverse evidence, and supports modern B cell-based treatment directions.

Understanding brain function is one of the most important open problems in science today. At present, there is no concrete theory for how the brain works. Here, a theory is presented that provides a detailed mechanistic biological account of the brain’s capacities. Brain function is managed by a response (R) process that is structurally similar to the immune response, and shows anatomical and molecular specificity. Different R process stages utilize different cortical layers, hippocampus fields, basal ganglia paths, GABAergic interneurons, cerebellum paths, and molecular agents such as dopamine, serotonin and opioids. We show how the R process supports hierarchical action sequences, language and thought. The theory is supported by a large body of experimental evidence in many modalities, and accounts for virtually all of the major facts known about the brain at the system level.

I present a complete theory of Parkinson’s disease (PD). PD involves an abundance of gut microbiota that degrade mucin, resulting in elevated brain uptake of galactose (a mucin component) and reduced uptake of glucose. Since galactose is not efficiently used for glycolysis, this decreases the production of glutathione, which is essential for countering oxidative iron toxicity. The brain cells that are most sensitive to this effect, as attested by their expression of the iron chelator neuromelanin, are those that continuously secrete dopamine and norepinephrine, and they eventually degenerate. This account explains the etiology, symptoms (including prodromal autonomic symptoms), pathology and risk factors of the disease. The theory is supported by strong evidence, and gives rise to several relatively simply directions for early identification and treatment of the disease.

This paper presents a complete theory of autism spectrum disorder (ASD), explaining its etiology, symptoms, and pathology. The core cause of ASD is excessive stress-induced postnatal release of corticotropin-releasing hormone (CRH). CRH competes with urocortins for binding to the CRH2 receptor, impairing their essential function in the utilization of glucose for growth. This results in impaired development of all brain areas depending on CRH2, including areas that are central in social development and eye gaze learning, and low-level sensory areas. Excessive CRH also induces excessive release of adrenal androgens (mainly DHEA), which impairs the long-term plasticity function of gonadal steroids. I show that these two effects can explain all of the known symptoms and properties of ASD. The theory is supported by strong diverse evidence, and points to very early detection biomarkers and preventive pharmaceutical treatments, one of which seems to be very promising.