Personalized, Precision Medicine to Cure Alzheimer's Dementia: Approach #1.

The goal of the treatment for Alzheimer's dementia (AD) is the cure of dementia. A literature review revealed 18 major elements causing AD and 29 separate medications that address them. For any individual with AD, one is unlikely to discern which major causal elements produced dementia. Thus, for personalized, precision medicine, all causal elements must be treated so that each individual patient will have her or his causal elements addressed. Twenty-nine drugs cannot concomitantly be administered, so triple combinations of drugs taken from that list are suggested, and each triple combination can be administered sequentially, in any order. Ten combinations given over 13 weeks require 2.5 years, or if given over 26 weeks, they require 5.0 years. Such sequential treatment addresses all 18 elements and should cure dementia. In addition, any comorbid risk factors for AD whose first presence or worsening was within ±1 year of when AD first appeared should receive appropriate, standard treatment together with the sequential combinations. The article outlines a randomized clinical trial that is necessary to assess the safety and efficacy of the proposed treatments; it includes a triple-drug Rx for equipoise. Clinical trials should have durations of both 2.5 and 5.0 years unless the data safety monitoring board (DSMB) determines earlier success or futility since it is uncertain whether three or six months of treatment will be curative in humans, although studies in animals suggest that the briefer duration of treatment might be effective and restore defective neural tracts.

Formulating Treatment to Cure Alzheimer's Dementia: Approach #2.

There are two generic approaches to curing any medical condition. The first one treats every patient for all the known possible causes that contribute to pathogenesis; the second one individualizes potentially curative therapy by only identifying in each separate patient the components of pathogenesis that are actually operative and treating those. This article adopts the second approach for formulating a cure for Alzheimer's dementia (AD). The components of AD's pathogenesis are, in alphabetical order, as follows: circadian rhythm disturbances, depression, diabetes and insulin resistance, dyslipidemia, hypertension, inflammation, metabolic syndrome, mitochondrial dysfunction, nutritional deficiencies, TGF-ß deficiency, underweight, vascular abnormalities, and Wnt/ß-catenin deficiency. For each component, data are described that show the degree to which its prevalence is higher in patients with mild cognitive impairment (MCI) who did not revert to having normal cognition than in those who did because the former group is the pool of patients in which future AD may develop. Only addressing the components that are present in a particular individual potentially is a curative strategy. Published data indicate that curative therapy requires the number of such components that are addressed to be ≥3. Although structural brain changes cannot be directly addressed, the impaired neural tracts result from many of the reversible causal elements, so correcting them will benefit these tracts.

The several ways to authentically cure Alzheimer's dementia.

Although drugs may slow its progression, authentic cure of AD has never been accomplished. Here, six approaches are suggested that might achieve genuine cure. The six therapies include: 1) treatments addressing levels of TGF-ß and Wnt/ß-catenin, that become significantly reduced after MCI transitions to AD, and addressing also the impaired epithelial-to-mesenchymal transition (EMT) in AD's pathogenesis; 2) and 3) are two formulations that address the inadequate counter-responses to initial loss of cognition; 4) treatments addressing the brain cells whose impaired functions result in MCI and dementia; 5) the need for using partner drugs even when a particular drug addresses a single pathogenetic cause such as amyloid deposition; 6) enhancing the likelihood of genuine cure by using combinations of approaches chosen from the foregoing. Briefly, genuine cure of AD is possible; however, since AD denotes not one but multiple, phenotypically similar conditions, no one therapy can be generalized to all cases.

Formulating treatment of major psychiatric disorders: algorithm targets the dominantly affected brain cell-types.

BACKGROUND: Pharmacotherapy for most psychiatric conditions was developed from serendipitous observations of benefit from drugs prescribed for different reasons. An algorithmic approach to formulating pharmacotherapy is proposed, based upon which combination of changed activities by brain cell-types is dominant for any particular condition, because those cell-types contain and surrogate for genetic, metabolic and environmental information, that has affected their function. The algorithm performs because functions of some or all the affected cell-types benefit from several available drugs: clemastine, dantrolene, erythropoietin, fingolimod, fluoxetine, lithium, memantine, minocycline, pioglitazone, piracetam, and riluzole PROCEDURES/FINDINGS: Bipolar disorder, major depressive disorder, schizophrenia, Alzheimer's disease, and post-traumatic stress disorder, illustrate the algorithm; for them, literature reviews show that no single combination of altered cell-types accounts for all cases; but they identify, for each condition, which combination occurs most frequently, i.e., dominates, as compared with other possible combinations. Knowing the dominant combination of altered cell-types in a particular condition, permits formulation of therapy with combinations of drugs taken from the above list. The percentage of patients who might benefit from that therapy, depends upon the frequency with which the dominant combination occurs in patients with that particular condition. CONCLUSIONS: Knowing the dominant combination of changed cell types in psychiatric conditions, permits an algorithmically formulated, rationally-based treatment. Different studies of the same condition often produce discrepant results; all might be correct, because identical clinical phenotypes result from different combinations of impaired cell-types, thus producing different results. Clinical trials would validate both the proposed concept and choice of drugs.

Analysis of Why Alzheimer's Dementia Never Spontaneously Reverses, Suggests the Basis for Curative Treatment.

A paradox regarding Alzheimer's dementia (AD) and mild cognitive impairment (MCI) is thats spontaneous cure of AD has never been reported, whereas spontaneous cure for MCI occurs fequently. This article analyzes what accounts for this difference. It holds that it is not merely because, for any condition, a stage is reached beyond which it cannot be reversed, since even widely metastatic cancer would be curable were there effective chemotherapy and rheumatoid arthritis became controllable when immune-suppressant treatment was introduced; thus, so could AD be reversible via effective therapy. The analysis presented leads to an explanation of the paradox that is in four categories: (1) levels of transforming growth factor-ß are significantly reduced after the transition from MCI to AD; (2) levels of Wnt/ß-catenin are significantly reduced after the transition; (3) there is altered epidermal-mesenchymal transition (EMT) in neurons after the transition; (4) there may be risk factors that are either newly operative or pre-existing but worsened at the time of transition, that are particular to individual patients. It is suggested that addressing and ameliorating all of those four categories might cure AD. Medications to address and ameliorate each of the four categories are described.

Cure of Alzheimer's Dementia in Many Patients by Using Intranasal Insulin to Augment an Inadequate Counter-Reaction, Edaravone to Scavenge ROS, and 1 or 2 Other Drugs to Address Affected Brain Cells.

The goal of treatment for Alzheimer's dementia (AD) is the restoration of normal cognition. No drug regimen has ever achieved this. This article suggests that curing AD may be achieved by combination therapy as follows. First, with intranasal insulin to augment the body's natural counter-reaction to the changes in brain cell-types that produced the dementia. Second, with edaravone to decrease free radicals, which are increased and causal in AD. Third, as described elsewhere, with one or two drugs from among pioglitazone, fluoxetine, and lithium, which address the brain cell-types whose changed functions cause the dementia. Insulin restores cerebral glucose, which is the main nutrient for brain neurons whose depletion is responsible for the dementia; and edaravone decreases ROS, which are intrinsic causes of neuropathology in AD. This combination of drugs is a potential cure for many patients with AD, and should be tested in a clinical trial.

Cure of Alzheimer's Dementia Requires Addressing All of the Affected Brain Cell Types.

Multiple genetic, metabolic, and environmental abnormalities are known to contribute to the pathogenesis of Alzheimer's dementia (AD). If all of those abnormalities were addressed it should be possible to reverse the dementia; however, that would require a suffocating volume of drugs. Nevertheless, the problem may be simplified by using available data to address, instead, the brain cells whose functions become changed as a result of the abnormalities, because at least eleven drugs are available from which to formulate a rational therapy to correct those changes. The affected brain cell types are astrocytes, oligodendrocytes, neurons, endothelial cells/pericytes, and microglia. The available drugs include clemastine, dantrolene, erythropoietin, fingolimod, fluoxetine, lithium, memantine, minocycline, pioglitazone, piracetam, and riluzole. This article describes the ways by which the individual cell types contribute to AD's pathogenesis and how each of the drugs corrects the changes in the cell types. All five of the cell types may be involved in the pathogenesis of AD; of the 11 drugs, fingolimod, fluoxetine, lithium, memantine, and pioglitazone, each address all five of the cell types. Fingolimod only slightly addresses endothelial cells, and memantine is the weakest of the remaining four. Low doses of either two or three drugs are suggested in order to minimize the likelihood of toxicity and drug-drug interactions (including drugs used for co-morbidities). Suggested two-drug combinations are pioglitazone plus lithium and pioglitazone plus fluoxetine; a three-drug combination could add either clemastine or memantine. Clinical trials are required to validate that the suggest combinations may reverse AD.

Supplementary Pharmacotherapy for the Behavioral Abnormalities Caused by Stressors in Humans, Focused on Post-Traumatic Stress Disorder (PTSD).

Used as a supplement to psychotherapy, pharmacotherapy that addresses all of the known metabolic and genetic contributions to the pathogenesis of psychiatric conditions caused by stressors would require an inordinate number of drugs. Far simpler is to address the abnormalities caused by those metabolic and genetic changes in the cell types of the brain that mediate the behavioral abnormality. Relevant data regarding the changed brain cell types are described in this article and are derived from subjects with the paradigmatic behavioral abnormality of PTSD and from subjects with traumatic brain injury or chronic traumatic encephalopathy. If this analysis is correct, then therapy is required that benefits all of the affected brain cell types; those are astrocytes, oligodendrocytes, synapses and neurons, endothelial cells, and microglia (the pro-inflammatory (M1) subtype requires switching to the anti-inflammatory (M2) subtype). Combinations are advocated using several drugs, erythropoietin, fluoxetine, lithium, and pioglitazone, that benefit all of the five cell types, and that should be used to form a two-drug combination, suggested as pioglitazone with either fluoxetine or lithium. Clemastine, fingolimod, and memantine benefit four of the cell types, and one chosen from those could be added to the two-drug combination to form a three-drug combination. Using low doses of chosen drugs will limit both toxicity and drug-drug interactions. A clinical trial is required to validate both the advocated concept and the choice of drugs.

Fluoxetine plus lithium for treatment of mental health impairment in Long Covid.

Purposes: (1) To summarize the mental conditions that may accompany persistent symptoms following acute infection by SARS-CoV-2, often termed Long Covid; (2) to formulate treatment based upon the brain cells that are dominantly affected. Methods: (1) Review the reports relating to the mental symptoms occurring in Long Covid. (2) Review the drugs that address the brain cells affected in Long Covid, and suggest pharmacotherapy for those patients whose response to psychotherapy is suboptimal. Results: Long Covid affects ~ 10% of patients infected by SARS-CoV-2, and mental symptoms affect ~ 20% of persons with Long Covid. The brain cell-types that have been demonstrated as dominantly affected in Long Covid are astrocytes, oligodendrocytes, neurons, endothelial cells/pericytes, and microglia. Lithium and fluoxetine each address all of those four cell-types. Low dosage of each is likely to be well-tolerated and to cause neither clinically important adverse events (AE) nor serious adverse events (SAE). Conclusion: For those patients whose response to psychotherapy is suboptimal, lithium and fluoxetine should be administered in combination for both depth of benefit and reduction of dosages.

Abnormal oligodendrocyte function in schizophrenia explains the long latent interval in some patients.

A puzzling feature of schizophrenia, is the long latency between the beginning of neuropathological changes and the clinical presentation that may be two decades later. Abnormalities in oligodendrocyte function may explain this latency, because mature oligodendrocytes produce myelination, and if myelination were abnormal from the outset, it would cause the synaptic dysfunction and abnormal neural tracts that are underpinning features of schizophrenia. The hypothesis is that latency is caused by events that occur in some patients as early as in-utero or infancy, because clones of abnormal, myelinating oligodendrocytes may arise at that time; their number doubles every ~2 years, so their geometric increase between birth and age twenty, when clinical presentation occurs, is about 1000-fold plus the effect of compounding. For those patients in particular, the long latency is because of a small but ongoing increase in volume of the resulting, abnormally myelinated neural tracts until, after a long latent interval, a critical mass is reached that allows the full clinical features of schizophrenia. During latency, there may be behavioral aberrancies because of abnormally myelinated neural tracts but they are insufficiently numerous for the clinical syndrome. The occurrence of behavioral symptoms during the long latent period, substantiates the hypothesis that abnormal oligodendrocytes explain the latency in some patients. Treatment with fingolimod or siponimod benefits both oligodendrocytes and neural tracts. Clinical trial would validate their potential benefit in appropriate patients with schizophrenia and, concurrently, would validate the hypothesis.

Reversing Alzheimer's disease dementia with clemastine, fingolimod, or rolipram, plus anti-amyloid therapy.

A few anti-amyloid trials offer a slight possibility of preventing progression of cognitive loss, but none has reversed the process. A possible reason is that amyloid may be necessary but insufficient in the pathogenesis of AD, and other causal factors may need addressing in addition to amyloid. It is argued here that drugs addressing myelination and synaptogenesis are the optimum partners for anti-amyloid drugs, since there is much evidence that early in the process that leads to AD, both neural circuits and synaptic activity are dysfunctional. Evidence to support this argument is presented. Evidence is also presented that clemastine, fingolimod, and rolipram, benefit both myelination and synaptogenesis. It is suggested that a regimen that includes one of them plus an anti-amyloid drug, could reverse AD.

Supplemental thiamine as a practical, potential way to prevent Alzheimer's disease from commencing.

It is better to attempt stopping Alzheimer's disease (AD) before it starts than trying to cure it after it has developed. A cerebral scan showing deposition of either amyloid or tau identifies those elderly persons whose cognition is currently normal but who are at risk of subsequent cognitive loss that may develop into AD. Synaptic hypometabolism is usually present in such at-risk persons. Although inadequate adenosine triphosphate (ATP) may cause synaptic hypometabolism, that may not be the entire cause because, in fact, measurements in some of the at-risk persons have shown normal ATP levels. Thiamine deficiency is often seen in elderly, ambulatory persons in whom thiamine levels correlate with Mini-Mental State Examination scores. Thiamine deficiency has many consequences including hypometabolism, mitochondrial depression, oxidative stress, lactic acidosis and cerebral acidosis, amyloid deposition, tau deposition, synaptic dysfunction and abnormal neuro-transmission, astrocyte function, and blood brain barrier integrity, all of which are features of AD. Although the clinical benefits of administering supplementary thiamine to patients with AD or mild cognitive impairment have been mixed, it is more likely to succeed at preventing the onset of cognitive loss if administered at an earlier time, when the number of aberrant biochemical pathways is far fewer. Providing a thiamine supplement to elderly persons who still have normal cognition but who have deposition of either amyloid or tau, may prevent subsequent cognitive loss and eventual dementia. A clinical trial is needed to validate that possibility.

Does synaptic hypometabolism or synaptic dysfunction, originate cognitive loss? Analysis of the evidence.

Elderly persons with currently normal cognition who have cerebral hypometabolism as shown by low uptake of 18fluorine-fluorodeoxyglucose (18F-FDG), are at risk of future loss of cognition and, thus, of future Alzheimer's dementia (AD). Reduction of either 18F-FDG or cognition is assumed to reflect synaptic dysfunction, since synapses account for the majority of glucose use by the brain and cognition depends upon accurate synaptic function. The chronology of the connection between reduced cerebral synaptic function and hypometabolism is, therefore, a critical question, because if synaptic dysfunction came first, then correcting the hypometabolism would likely not benefit synaptic function; but if hypometabolism came first, then correcting the hypometabolism probably would benefit synaptic function. That correction might prevent initiation of the cognitive loss that eventuates in AD and, thereby, would benefit the vast numbers of persons in their eighth to tenth decades of life who are at risk for AD. Among the many citations reviewed in this presentation, seven show hypometabolism that precedes synaptic dysfunction, and two show the reverse. Thus the preponderance of evidence, 78%, suggests that the initiating event is synaptic hypometabolism and that it is 3.5-fold less likely that synaptic dysfunction is the initiator. In addition, it is inherently unlikely that synaptic dysfunction causes hypometabolism. This conclusion could be tested by a clinical trial whose primary objective would be to assess the benefit to cognition of improving synaptic metabolism in patients who are at risk for cognitive loss.

A vaccine to prevent initial loss of cognition and eventual Alzheimer's disease in elderly persons.

Prevention is better than cure and prevention of Alzheimer's disease (AD) may be possible. In elderly persons who are cognitively normal, synaptic hypometabolism as shown by reduced cerebral uptake of fluorodeoxyglucose (18F-FDG), provides a premonitory signal of potential, future loss of cognition if those individuals also have present evidence of amyloid deposition seen in the Pittsburgh compound B positron emission tomography (PIB-PET) scan for amyloid. Those are the persons who should be targeted if one aims to prevent AD. The synaptic hypometabolism implies that the brain's availability of adenosine triphosphate (ATP) is inadequate for performance of all required synaptic functions. This review first describes the basis for asserting that reduced cerebral uptake of 18F-FDG accurately reflects synaptic hypometabolism; second, explains the basis for asserting that hypometabolism implies inadequate ATP; third, shows that amyloid beta (Aß) itself, Aß modified by pyroglutamate to become a molecule termed pE(3)Aß, and cyclophilin-D, in concert are the main contributors to inadequate synaptic ATP and that, therefore, reducing all of their levels would neutralize their combined effect and correct the hypometabolism. pE(3)Aß is more neurotoxic than unmodified Aß; and cyclophilin D inhibits ATP synthase and reduces ATP formation. Finally, this review describes an mRNA self-replicating vaccine that will raise brain levels of ATP by reducing Aß, pyroglutamate-modified Aß, and cyclophilin-D, and thereby-in cognitively normal elderly persons who have synaptic hypometabolism-prevent initiation of the process that terminates in AD.

The potential for one drug, administered at the earliest preclinical stage, to prevent the subsequent decline of cognition that eventuates in dementia.

In the process that eventuates in mild cognitive impairment (MCI) and ultimately in Alzheimer's dementia, the earliest identifiable change is in the function of synapses. If started at that early point in time, when there is subjective but not objective memory loss plus abnormal brain imaging with fluorodeoxyglucose and Pittsburgh compound B, treatment with a single drug directed at synaptic dysfunction might prevent development of cognitive impairment. Each of four drugs, dantrolene, lithium, minocycline, and piracetam, benefits synaptic impairment. This presentation has two sections. In the first, evidence is discussed at length, for abnormality in the axo-spinous synapse as being the earliest change before objective cognitive decline. The second section explains the benefits to synapses provided by the four mentioned drugs. Dantrolene and lithium perhaps have the strongest supporting data for use as single agents: their efficacy should be subjected to clinical trial.

Caveolae, CD109, and endothelial cells as targets for treating Alzheimer's disease.

Reduced functionality of transforming growth factor ß (TGF-ß) is a major pathogenetic component of Alzheimer's disease (AD). The reduction is caused by an ≈50% decrease in the AD brain of the TGF-ß receptor, TGFBR, causing a bottleneck effect that reduces the downstream actions of TGF-ß, which is highly disadvantageous for brain function. Degradation of TGFBR occurs in caveolae with participation by caveolin-1 (Cav-1) and CD109. Mechanisms for this are discussed. In the cerebral microcirculation, endothelial cells (which are rich in caveolae) carry CD109 as a surface marker that co-precipitates with Cav-1. Atorvastatin reduced Cav-1 by 75% and, because Cav-1 and CD109 co-immunoprecipitate reciprocally, atorvastatin would also reduce the level of CD109. Administration of atorvastatin as a component of combination therapy would diminish the degradation of TGFBR and thereby benefit patients with AD.

If ineffective levels of transforming growth factors and their receptor account for old age being a risk factor for Alzheimer's disease, then increasing TGFBR2 might be therapeutic.

If it is correct that ineffective levels of transforming growth factors beta and their receptor account for old age being a risk factor for Alzheimer's disease (AD), then increasing TGFBR2 might be therapeutic. Pacltaxel is a direct way to increase TGFBR2 levels. Indirect ways that will increase TGFBR2, include decreasing the levels of c-myc because that will lower the miRNA cluster 17-92, particularly its miR-17 and miR-20a components; and raising EGFR because that also will increase TGFBR2. Metformin and desferrioxamine are drugs that decrease c-myc; and statins increase levels of EGF. Clinical trials using those drugs, would demonstrate whether they decrease the progression from amnestic mild cognitive impairment to AD.

The paradox of opposite directions of gene expressions in MCI and AD suggests possible therapy to prevent progression of MCI to AD.

One of the puzzling observations concerning mild cognitive impairment (MCI) and Alzheimer's disease (AD), is that many gene expressions in MCI may be in the opposite direction of those seen in AD. Several examples of this paradox are provided. The likely explanation lies in in the control mechanisms of gene transcription. These mechanisms include (1) modification of DNA and histones by methylation or acetylation, affecting the balance between the Compass group of proteins that enhances mRNA formation, and the Polycomb group that suppresses it; (2) compensation for the loss of one gene's function by another gene with overlapping functions; (3) reduced control of the entire neural RNA production; and (4) response to microRNAs (miRNA). Although data are inadequate to exclude with certainty any one of the indicated mechanisms, the available evidence favors overall reduced control of neural mRNA production, including the effect of miRNA. The switch occurs at a specific stage, somewhere between Braak 0-1 and Braak 2-3, in the progression from MCI to AD, which reduces the number of its likely causes. Two strong but related candidates are the repressor element-1 silencing transcription factor (REST), which in adult neurons impairs plasticity; and a miRNA, for example, miRNA124, that represses REST. Another possible explanation is that only those patients with MCI who will not progress to AD are the ones that have gene expressions in the opposite direction as in AD. The solution to the paradox may have pragmatic value.

Prevention of Alzheimer's disease by treating mild cognitive impairment with combinations chosen from eight available drugs.

Several hundred clinical trials of initially promising drugs have failed to produce meaningful clinical improvement of Alzheimer's disease (AD), which is probably because there are at least 25 biochemical pathways known to be aberrant that underpin the disease, and unless there is a single drug that addresses all or most of them, even promising drugs if given alone are unlikely to succeed. Because so many pathways are potentially at fault, it is quite possible that no treatment might succeed. However, because amnestic mild cognitive impairment (aMCI) often precedes AD and, assuming that those with aMCI who progress to AD commence with insufficient risk factors for AD but accrue them later, then it is likely that fewer pathways need addressing in aMCI than in AD to either prevent progression of aMCI to AD or effect its reversion. Published reports show that eight drugs, that is, dantrolene, erythropoietin, lithium, memantine, minocycline, piracetam, riluzole, and silymarin, address many of the pathways underlying MCI and AD. Among those eight drugs, combinations between either two or three of them have combined nonoverlapping actions that benefit enough of the approximately 25 pathways at fault so that their convergent efficacy has the potential to prevent aMCI from progressing to AD. The combinations should be subjected to a clinical trial in persons with aMCI to establish their safety and efficacy.

Ineffective levels of transforming growth factors and their receptor account for old age being a risk factor for Alzheimer's disease.

After the midninth decade of age, the incidence rates of Alzheimer's disease (AD) and the presence of active TGF-ß1 show comparable increases. The hypothesis is proposed that the reason why advanced age is a major risk factor for AD is a progressive decrease with advancing age in the numbers of TGFR2 receptors in the brain, with the consequence of a decline in the neurotrophic efficacy of TGF-ß1 and 2 despite their already increased levels in older persons. Alternative, possible reasons are discussed but rejected because either those reasons may also affect young persons or because they cannot be validated in a clinical trial. The proposed hypothesis may be validated in persons with aMCI after raising their brain levels of TGF-ß1 and 2 by using a combination of three drugs, lithium, memantine, plus either glatiramer or venlafaxine, and then assessing their progression to AD.