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-β and Wnt/ β -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.


Introduction and background
Although drugs may slow its progression, the goal of genuinely curing Alzheimer's dementia (AD) has never been accomplished.Three inter-related reasons account for that failure: first is the wrong assumption that one drug will cure all cases; second, the causes of AD differ for different patients, and, therefore, AD is an umbrella term for multiple, phenotypically similar, conditions, each characterized by impairments of memory and cognition, and each requiring its own therapeutic formulation for a cure; third, in order to cure even one of those multiple dementias, a potentially curative compound requires accompaniment by partner drugs because, even though there are multiple ADs, each one is itself multi-causal.Some preliminary comments are apposite, regarding whether its pathogenesis implies that AD is a single disorder or is an umbrella term for multiple diseases; and how this consideration affects its curability.Since dementia involves disturbances affecting several neural circuits, the critical question is whether a single initiating mechanism, whether genetic, environmental, or both, would affect all of them.While not impossible, it would seem highly improbable that one initiating mechanism might affect all of the many relevant circuits although there would certainly be overlapping, biochemical changes.If that is correct, there are two inferences.First, is that several initiating mechanisms imply several separate diseases, albeit them all having a single phenotypic expression; the second, is that correcting a single mechanism will not cure all cases of dementia.These inferences have pragmatic importance, which is that no one formulation of treatment can be generalized to all cases.
Here, six general approaches to achieve cure are described: 1) in the first, are treatments addressing levels of TGF-β and Wnt/β-catenin, that become significantly reduced after MCI transitions to AD; and treatment 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) are treatments addressing the brain cells whose impaired functions result in MCI and dementia; 5) is the need to use partner drugs even when a particular drug addresses a single pathogenetic cause such as amyloid deposition; 6) enhances the likelihood of genuine cure by using combinations of approaches chosen from the foregoing.It is emphasized that although it is likely that each of the treatment formulations presented below, confers a high possibility of curing some cases, nevertheless, a particular formulation will not cure all cases.Further, regarding the six suggested approaches, the author recommends the famous advice of Sir Francis Bacon, 'Read not to contradict and confute, nor to believe and take for granted.but to weigh and consider'.
generalization, since there are many examples where apparently incurable conditions became curable with the advent of better treatment.For this reason, AD is not beyond the reach of curative therapy.
Cure of AD requires reversal of both the loss of memory and the impairment of cognition, to levels that are normal for the patient's age, educational attainment, and cultural background.It is emphasized that cure is not merely a lessened progression of the dementia but requires dementia's reversal.It is worth noting that the primary endpoint of the trial of lecanemab was stated as a 'Bayesian analysis of 12-month clinical change on the Alzheimer's Disease Composite Score (ADCOMS) for the ED90 dose, which required an 80 % probability of ≥25 % clinical reduction in decline versus placebo' (Swanson et al., 2021); that the primary endpoint of the trial of aducanumab was stated as a 'change from baseline to week 78 on the Clinical Dementia Rating Sum of Boxes (CDR-SB), an integrated scale that assesses both function and cognition' (Budd Haeberlein et al., 2022); and that the primary endpoint of the trial of donanemab was stated as 'the change from baseline in the score on the Integrated Alzheimer's Disease Rating Scale (ADRS; range, 0-144, with lower scores indicating greater cognitive and functional impairment) at 76 weeks' (Mintun et al., 2021).Thus, none of these primary objectives required a cure of the dementia.Totally new approaches to achieving true cures of AD are urgently required, some of which are described below.
Six approaches for curative treatment are suggested but there are, certainly, others.

Curative approach #1
This approach is based upon the paradox that spontaneous cure of AD has never been reported whereas spontaneous cure of Mild Cognitive Impairment (MCI) occurs in as many as half the patients (Fessel, 2023a).There are four explanations for the paradox, and addressing them all might lead to a cure for some patients with AD. 1), during MCI, levels of transforming growth factor-β (TGF-β) are normal but become significantly reduced in AD; 2), levels of Wnt/β-catenin also become significantly reduced after transition to AD; 3), there is reduced epidermal-mesenchymal transition (EMT) in neurons after that transition; and 4), if, at the time of transition there were risk factors that were either newly operative or pre-existing but worsened, they may participate in pathogenesis and correcting them may be required for cure of dementia.
The absolute level of TGF-β was not significantly reduced in MCI (Huang et al., 2013), but was greatly reduced in AD, where it was approximately 30-50 % lower than in controls (Huang et al., 2013;Mocali et al., 2004).Some ambiguous and conflictual data require exploration.TGF-β1 levels were found by Motta et al. to occur in the earliest AD stage, viz, 8-fold higher in mild, 3.8-fold higher in moderate, and slightly reduced in severe stage disease (Motta et al., 2007).Lippa et al. saw little difference between AD patients and controls in TGF-β receptors 1&2 in neurons but glia from patients with AD showed increased reactivity (Lippa et al., 1998).Zetterberg et al. saw significantly higher spinal fluid levels of TGF-β1 in AD than in controls (Zetterberg et al., 2004).The above ambiguous data are explicable.First, there is an impediment to the downstream effects of raised TGF-β1 levels.Activated TGF-β binds to Smad proteins; in the nucleus, TGF-β/Smad complex regulates target gene transcription (Lee et al., 2006;Dennler et al., 2002).Smad2 maintains neurons in an activated state (Ueberham et al., 2006) and both Lee et al. and Ueberham et al., showed that in AD there is significantly less Smad (Lee et al., 2006;Ueberham et al., 2006).Further, Smads 6 and 7 are major, negative regulators of TGF-β signaling (Park, 2005;Yan et al., 2009).For all of these reasons, increased levels of TGFβ in AD have less downstream consequences, and may be compensatory to that reduced downstream effect.Also, are differences in levels of the three isotypes of TGF-β.Plasma from AD subjects had reduced levels of TGF β1 (Mocali et al., 2004), and there was a 30 % reduction of TGF-β1 serum levels in AD but not in MCIHUANG (Huang et al., 2013).A final reason for variable data is that drugs received for treatment of comorbidities, may affect levels of TGF-β.E.g., acetyl salicylic acid (ASA) and statins raise levels of TGF-β (Peress and Perillo, 1995;Ren et al., 1997;Grainger et al., 1995), while other drugs may lower levels of TGF-β, e.g., losartan (Iñigo et al., 2001), and chloroquine, hydroxychloroquine, amodiaquine, and azithromycin (Basque et al., 2008).In brief: TGF-β and its isotypes, particularly β1, have levels in AD that are mostly reduced but even if raised they have reduced downstream effect.Raising TGF-β levels in conjunction with other measures described in this article, might contribute to curing AD.
Wnt/β-catenin signaling and cognition are positively correlated, which is why the normal levels in MCI but the low levels in AD may also contribute to explaining the reversibility of MCI and the irreversibility of AD.Wnt/β-catenin signaling in the brain, promoted neuronal survival and neurogenesis; its loss made neurons more susceptible to apoptosis; and its activation rescued both the neuronal apoptosis and the bloodbrain barrier (BBB) dysfunction caused by Aβ (Jia et al., 2019).Confirmatory studies by Inestrosa et al. showed that Wnt/β-catenin is involved in regulating synaptic plasticity and maintaining BBB integrity; that activated WNT/β-catenin signaling prevented the neural toxicity caused by Аβ; that WNT/β-catenin, via its (normal) phosphorylation of tau, is involved in the mechanisms of learning and memory; and that WNT/β-catenin dysfunction resulted in Aβ production and aggregation (Inestrosa et al., 2021).Tay et al. followed 14 subjects with MCI and 74 with mild to moderate AD and measured their scores for the Clinical Dementia-sum of boxes (CDR-SB), at baseline and after one year; they assessed the correlations between changes in the CDR-SB and serum levels of Dickkopf-1 (Dkk-1), which is an antagonist of Wnt (Tay et al., 2019).An increase of Dkk-1, indicating decreased levels of Wnt, was significantly associated with progressively higher CDR SB scores, among patients with AD but, critically, not among patients with MCI.As did Tay et al., Folke et al. saw a linear correlation between the decrement in Wnt7B levels and Braak stages (r = 0.794; P < .001); the control subjects had Braak stages 1-3, the AD patients had Braak stages 5&6 (Folke et al., 2019).These data suggest that correcting the decreased levels of Wnt, which are seen in AD but not in MCI, may assist in the cure of AD.The effects of EMT, are also relevant as to why MCI often undergoes spontaneous reversion to normal cognition but AD never does.EMT refers to the epithelial-to-mesenchymal transition, a differentiation process by which cells change their phenotype from being one that primarily typifies cells of epithelial lineage (E) to one that typifies cells of mesenchymal (M) lineage.Cadherins are involved in the formation and maintenance of the neuroepithelium, neurite extension and migration of neuronal cells (Suzuki and Takeichi, 2008).The majority of neurons in the brain either express E-cadherin and represent the E phenotype, or express N cadherin and represent the M phenotype.In AD, there is down-regulation of neurons with the M phenotype, reflecting less EMT.This was shown by Liu et al., who immuno-stained for FAM3C, that is a key molecule in causing the E-to-M transition, and found it 45 % lower in AD brains than in controls (Liu et al., 2016).Those findings were confirmed by Watanabe et al., who saw a reduction of FAM3C by 27 % in Braak stages 3-6, and by 51 % in Braak stages 5-6 (Watanabe et al., 2022).These data show that in AD there is reduced E-to-M transition.Interestingly, Hasegawa et al. demonstrated a role for TGF-β in EMT, by finding that TGF-β induced the neuronal expression of FAM3C (Hasegawa et al., 2014).Thus, the treatments that increase the levels of TGF-β should benefit the attempt to reverse AD, by leading to increase of FAM3C (thus, increased E-to-M transition), and of N-neurons (thus, increased neurogenesis).
Treatments are available that raise levels of Wnt/β-catenin and TGFβ.Doxycycline raised levels of both Wnt/β-catenin and TGFβ (Zhang et al., 2019); it also decreased the immunostaining of Dkk-1, the antagonist of Wnt/β catenin, by >60 %, and increased the immunostaining of Wnt-10b by as much as 150 % (Gomes et al., 2017).Several statins, including simvastatin, atorvastatin, and rosuvastatin, promote the actions of Wnt/β-catenin, one mechanism for which is the inhibition of Dkk-1 (Niedzielski et al., 2020).Statins also benefit other mechanisms: simvastatin raised the levels of the lipoprotein receptor, LRP-6, whose binding by Wnt initiates a number of intracellular signaling cascades; and the anti-apoptotic effect that simvastatin had on cultured neuronal cells was reduced after suppression of the Wnt/β-catenin pathway (Gao et al., 2016).Inhibition of Wnt signaling also reduced the release of several transcription factors from embryonic stem cells (Qiao et al., 2011).In brief, doxycycline and statins increase the efficacy of Wnt/β-catenin signaling, and both statins and ASA increase TGF-β.As indicated, EMT is enhanced by TGF-β, so benefits from treatments causing increased levels of TGF-β.

Curative approach #2
Using intranasal insulin and edaravone, this approach augments the body's natural counter-reactions to the changes in brain cell-types that produced the dementia, and supplements these benefits with pioglitazone plus fluoxetine or pioglitazone plus lithium; additionally, it treats new or worsened pre-existing AD risk factors that occurred either during the one year preceding or one year succeeding the transition from MCI to dementia.This approach to curing AD, augments what were inadequate counter-reactions to the event that initiated the dementia; had those counter-reactions been adequate, dementia would not have occurred.Augmentation of those counterreactions in order to make them become adequate, is produced by a combination of intranasal insulin and edaravone.Insulin restores cerebral glucose, that is the main nutrient for brain neurons whose depletion is one of the factors responsible for the dementia; and edaravone decreases the excess of free radicals and reactive oxygen species (ROS) that are consequences of the relative hypoglycemia of neurons and are well-known as being intrinsic causes of neuropathology in AD (Fessel, 2023a).In addition, two further drugs, either pioglitazone plus fluoxetine or pioglitazone plus lithium, are added because those address the brain cell-types whose changed functions contribute to causing the dementia (Fessel, 2023a).Further treatment may be beneficial if, during either the one year before or one year after the transition from MCI to dementia, one or more comorbid risk factors became either newly present or worse; then, addressing or correcting that factor or factors should be a beneficial supplement to intranasal insulin and edaravone (Fessel, 2023a).

Curative approach #3
This is identical to approach #2 except that instead of intranasal insulin, it supplies brain-derived neurogenic factor (BDNF), which would repair the ~70 % depletion of CA1 hippocampal neurons that is seen in AD (West et al., 1994).By itself, BDNF has poor BBB penetration but that was overcome by Vitiliano et al., who conjugated it to clathrin (Vitaliano et al., 2020).Clathrin is a natural protein found in bacteria, fungi, plants, and animals, that can serve as a stable nanoplatform onto which BDNF can be attached.When the clathrin-BDNF conjugate was administered intranasally, it increased hippocampal BDNF concentrations by 400-fold more than was achieved by unconjugated intranasal BDNF alone (Vitaliano et al., 2022).As with approach #2, edaravone and pioglitazone plus either fluoxetine or lithium, would accompany the administration of intranasal BDNF conjugated with clathrin.

Curative approach #4
This approach addresses the brain cells whose functions become changed as a result of the transcriptomal, epigenomal, metabolomal, and environmental, factors that are known to be involved in the pathogenesis of AD.This approach is discussed in detail in ref (Fessel, 2023b).The benefit of this approach to curing AD lies in the fact that at least eleven drugs are available from which to formulate rational therapy to correct those changes in brain cells.The five affected brain cell-types are astrocytes, oligodendrocytes, neurons (excitatory and inhibitory), endothelial cells/pericytes, and microglia.The available drugs include clemastine, dantrolene, erythropoietin, fingolimod, fluoxetine, lithium, memantine, minocycline, pioglitazone, piracetam, and riluzole.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, are also described in ref (Fessel, 2023b)).All five of the cell-types may be involved in the pathogenesis of AD; among the above 11 drugs, four of them, fluoxetine, lithium, memantine, and pioglitazone, each addresses all five of the brain cell-types.Memantine is the weakest of those four, and although fluoxetine and lithium are the strongest they cause the most adverse reactions, so should not be administered together, and should be used in low dosages.The two-drug combinations, pioglitazone plus lithium and pioglitazone plus fluoxetine.are those suggested as additions in approaches 2, and 3.

Curative approach #5
In this approach, single drugs for which the preclinical data were promising but which failed to cure AD in clinical trials, would be rescued by adding partner drugs.The obvious examples are the trials of antiamyloid compounds, which all failed to cure human AD.It remains possible that in some cases of human AD, amyloid may be essential to pathogenesis but insufficient.If that is the case, then anti amyloid compounds might still cure AD if their effect were supplemented by partner drugs.Several partner drugs are available, including clemastine, fingolimod, and rolipram, as discussed in ref (Fessel, 2022).

Curative approach #6
Combining two approaches enhances the likelihood of cure, and many permutations involving two approaches are possible.Thus, one pair of treatments might be doxycycline plus a statin plus two other drugs (pioglitazone plus fluoxetine or pioglitazone plus lithium).Another pair of treatments could be intranasal insulin, edaravone, pioglitazone with either fluoxetine or lithium, and BDNF conjugated with clathrin.Several other paired treatments are possible.

Trials to validate above approaches
There are two categories of trials to validate above approaches.The first category uses a multi-region, human brain organoid, which has been shown to be a predictive, model system (Fleck et al., 2022).This trial would have four arms to test the putative efficacy of a chosen drug combination: 1), saline; 2), Aβ; 3), the chosen drug combination; 4), Aβ plus the chosen combination.The degree by which the chosen combination of drugs minimizes the effects of Aβ upon the brain organoid, will be the measure of efficacy.
After the above trial shows benefit of the chosen combination, the second category would be a typical clinical trial in which participants would be aged 70-90 who have the diagnosis of AD.Exclusionary criteria would include a history of major psychiatric disease, cerebrovascular disease, any active psychiatric condition other than AD, untreated hepatitis C, or history of any cancer other than squamous cell cancer of skin.Cure would be determined by a neuropsychologist using standard tests of cognition, administered at baseline and then annually.Duration of the trial would be ≤ 5 years with option to stop sooner if calculations by a Data Safety Monitoring Board showed an earlier, significant benefit.The number of participants would be calculated by a biostatistician on the bases of a 25 % greater cure from active treatment than from standard of care and an annual reduction of 15 % in the number of participants caused by side effects and deaths.

Discussion
The goal of treatment for AD is, or should be, the reversal of dementia.Two considerations may apply to any approach that is aimed at curing AD.The first is that AD is an umbrella term for many conditions having the same phenotypic, clinical expression, and means that no particular treatment will cure all cases.The second consideration is that subtypes of risk factors for future AD may determine the need for an attempt at cure.For example, in some patients for whom amyloid deposition is an ultimate cause, its effect may be so modified as to defer the need for treatment.That occurred in the member of a kindred carrying the PSEN1-E280A mutation that led to dementia in the kindred at the age of approximately 45 years.The above member had carried that mutation, and autopsy showed an enormous amyloid load; but that individual also had a mutation in the RELN gene, the protein derived from which affects the maintenance of the cerebral cortex.Possession of that mutation seems to have caused a 25 years' delay in the expected onset of dementia so that had he died a few years earlier, then no treatment would have been required despite the massive intracerebral amyloid (Lopera et al., 2023).
To date, all trials of therapy for AD, none of which aimed to cure the dementia, have been based upon the hypothesis that postulates amyloid deposition as the major cause of AD.That hypothesis stimulated multiple studies that greatly increased understanding of mechanisms that underpin AD; but amyloid became widely misunderstood as being the sole cause rather than as being one among many possible causes, again emphasizing that one formulation of treatment cannot be expected to cure all cases.A further issue is that the focus of treatment trials has not been the cure of the dementia with full recovery of cognition and memory but, instead, merely a decreased progression of the impaired cognition and memory.
Three issues need discussion concerning the suggested approaches to a cure for AD: it could be argued that the presentations are overdetermined in that they are speculative, that they represent a fishing expedition, and that there are other approaches besides those described.This reminds of a poem by TS Eliot: "All our knowledge brings us nearer to our ignorance.Where is the wisdom we have lost in knowledge?Where is the knowledge we have lost in information?"(Eliot, 1999).
It may be true that the proposed approaches are speculative but there are degrees of speculation, such that those that are based upon robust data are the least speculative.It is more appropriate to view the proposals not as speculations but as best guesses based upon available data.In fact, best guesses are at the basis of virtually all the spectacular advances in medicine that have been achieved in the past six decades.Treatment for HIV/AIDS started in 1991 with the best guess that one antiretroviral drug might be curative; failure of one drug led to a trial of a combination of two drugs (Collier et al., 1993); and finally, when two drugs failed to cure, then three drugs including protease inhibitors were successfully used (Havlir et al., 1998).Control of HIV infection became possible after only 20 years of trying.In another example, Anthony Fauci et al. used best guess to treat Wegener's granulomatosis (Fauci and Wolff, 1973) that, hitherto, had been untreatable and uniformly fatal; the successful treatment by Fauci et al. led to the introduction of immune-suppressant treatment for rheumatoid arthritis.Trials of the treatments for Alzheimer's dementia that are suggested here, might finally cure the disease.As a last example, it was on the basis of speculation that thalidomide was first used in the treatment of myeloma; that speculation led to the formation of thalidomide derivatives, lenalidomide and pomalidomide (Shortt, 2023), that are integral to the current standard of care for patients with myeloma.A recent article observed that 'medical science is an iterative process of observation and hypothesis refinement' (Hunter and Holmes, 2023); it is this iterative process that makes the 'best guess' approach both acceptable and potentially productive.It might also be argued that the approaches are only a "fishing expedition"; but Craig Venter pointed-out in a recent interview, that this is how Darwin discovered so many species (Ledford, 2023).It is also the case that, besides the suggestions in this article, there may be other therapeutic formulations which could reverse AD.Such formulations include ones based upon remyelination of the depleted neural tracts in AD (Chen et al., 2021), or upon a vaccine that induces a tau antibody (Novak et al., 2019).Other therapeutic formulations are implied by the title of this article: 'The several ways to authentically cure Alzheimer's dementia'.

Conclusions and summary
• The goal of therapy for Alzheimer's dementia is cure, i.e., its total reversal.• Spontaneous reversal of MCI is frequent but is never seen in AD.
• While levels of TGF-β, Wnt/catenin, and EMT are normal in MCI, they become depleted in patients with AD, which may be why MCI converts to AD. • Six general approaches to curative therapy are described.One approach is to raise levels of TGF-β, Wnt/catenin, and EMT; another approach is to augment the body's natural counter-reactions to the changes in brain cell-types that produced the dementia by using intranasal insulin and edaravone, and supplement these with pioglitazone plus fluoxetine or pioglitazone plus lithium; a third approach is the same as the second but instead of insulin uses BDNF; the next approach uses drugs from among eleven that address the brain cells whose changed functions caused the dementia; the fifth approach uses those drugs for which the preclinical data were promising but which failed to cure AD in clinical trials, and supplements those by adding partner drugs; the sixth combines two of the above approaches, in order to enhance the likelihood of cure.• Supplements to the above, involve combinations from among doxycycline, statins, aspirin, and pioglitazone plus either lithium or fluoxetine.• Since the pathogenesis of AD has many and varied components, no therapeutic formulation can cure all cases.• Even when the main drug addresses a single pathogenetic cause, there is a need for partner drugs.• If a condition that is a risk factor for AD became either newly present or worse, in the 12 months before or after the diagnosis of AD, its treatment should be added to the six suggested approaches.• Clinical trials are necessary to establish the validity and safety of the suggested cures.