Alzheimer’s Disease

Today over half of Americans who reach 85 will get an Alzheimer’s disease diagnosis and in less than 25 years, the Alzheimer’s Disease incidence will triple to what it is today. In England, where holistic lifestyle has not been well rooted,  Alzheimer’s Disease (heretofore AD) has replaced both cancer and cvd as the number one killer and the US is not far behind, in particular for the elderly. For those with the APOE 4 gene, the risk factors are higher and strike earlier. In order to better understand what health enthusiasts should do and what they should cease from doing, it’s useful to first look at etiology (pathogenesis or causation) (Section A). Thereafter, once we have determined what the correct chain of causation is with regard to AD’s progression, we will delve into where the Research should invest its resources (Section B). As for Holistic and Happiness Medicine Solutions that are available right now, See this link.

Section A

Pathogenesis

Introduction: The Heuristic Pathway to Fertile Research

For over 30 years, the primary focus for researchers studying Alzheimer disease has been centered on amyloid-beta, such that the amyloid cascade hypothesis has become the “null hypothesis.” Indeed, amyloid-beta is, by the current definition of the disease, a major player in pathophysiology, is toxic to neurons in vitro, and, perhaps most compelling, is increased by all of the human genetic influences on the disease. Therefore, targeting amyloid-beta has understandingly been the focus of considerable financial, basic and therapeutic interest.

However, for over 20 years, the emerging evidence has suggested that an “alternate hypothesis” may be more fruitful, one that would postulate that while amyloid-beta is still involved in the AD disease process, it is not an initiating event but rather is secondary to other pathogenic events, what can be called one of multiple symptoms. Furthermore and perhaps most contrary to current thinking, the alternate hypothesis proposes that the role of amyloid-beta is less as a harbinger of death than a protective response to neuronal dysfunction and toxemia that crosses the blood brain barrier.

Has Conventional Medicine’s central hypothesis been proven wrong ?

A focused reading of the publised data suggests that conventional neurological experts, just like with the conventional research experts in the cancer, cardiovascular and most other chronic disease fields, have wrongly postulated that the major culprit of AD is a symptom or group of symptoms that drives the disease.

In this case, the central hallmark of AD has been conventionally determined to be  the beta amyloid plaque, a form of misfolded proteins. Yet, after over 30 years and billions of dollars testing drugs in clinical trials, not one of these anti amyloidal drugs made a difference in terms of safely and efficiently treating this disease. (Source)  While the amyloid plaque did shrink with some of these drugs, just like cytotoxic chemo can shrink tumors, there has been no established correlation between plaque shrinkage and AD survivability, just like in conventional oncology. (Source).

What does the Evidence Show ?

On the other hand, holistic scientists, who tend to dig deeper and try to see the big picture beyond symptomatology and cash-flow,  have known for decades that the beta-amyloid plaque is a mere symptom, not the cause of Alzheimer’s Disease. (Source) Furthermore, the evidence suggests that the amyloid plaque, just like the arterial and dental plaques, appears to be a defense mechanism against other deeper causes that conventional medicine misses or refuses to investigate.

Yet, the emerging evidence shows more and more that beta amyloidosis arises in order to protect the brain against toxic proteins, heavy metals like mercury, copper, iron and even molds (mycotoxins). (Source). In effect, recent AD research experts have proposed the existence of a third type of AD based on these mycotoxins and Lyme-type bacteria. (Source)

Likewise with the tau proteins, the neurofibillary tangles and much of everything else the big pharmaceutical industries are investing in, the evidence suggests that “drugs targeting symptoms” versus “holistic medicine treating root causes” has not only don’t resolve the disease, but tend to make it worse. (Source)

For over twenty years now, we have known that the so called central “Alzheimer Disease hallmark”, the beta-amyloidal plaques is not the driver of the disease. Below, a 2004 piece from a group of scientists who are not fooled by conventional medicine’s approach.

“Ever since their initial description over a century ago, senile plaques and their major protein component, amyloid-beta, have been considered key contributors to the pathogenesis of Alzheimer disease. However, counter to the popular view that amyloid-beta represents an initiator of disease pathogenesis, we herein challenge dogma and propose that amyloid-beta occurs secondary to neuronal stress and, rather than causing cell death, functions as a protective adaptation to the disease. By analogy, individuals suffering from altitude sickness nearly always have elevated levels of hemoglobin. However, while hemoglobin is toxic to cells in culture and increased erythropoiesis at sea level can be deadly, it is clear that the increases in hemoglobin occurring at altitude are beneficial. Amyloid, like hemoglobin, may also be beneficial, in this case, following neuronal stress or disease. Although controversial, a protective function for amyloid-beta is supported by all of the available literature to date and also explains why many aged individuals, despite the presence of high numbers of senile plaques, show little or no cognitive decline. With this in mind, we suspect that current therapeutic efforts targeted toward lowering amyloid-beta production or removal of deposited amyloid-beta will only serve to exacerbate the disease process. (Ann N Y Acad Sci. 2004 Jun;1019:1-4). (Source) (1)

Well said. And the analogy on altitude hemoglobin is well taken. Instead of understanding why hemoglobin rises in high altitudes (ie, as a compensatory mechanism for the decrease in atmospheric pressure, which means less cellular oxygenation),  conventional neuroscience would propose drugs to combat this compensatory increase in hemoglobin, a chemical intervention that would necessarily lead to deleterious effects, just like most of today’s synthetic “pharmakia” (i.e., pharmakia is mentioned five times in the Bible and each time, this notion is interpreted to mean “witchcraft” or “poison”, Cf Source).

And since 2004, the evidence keeps on mounting that amyloid-beta plaques are protective. (Source) Yet most of big pharma and conventional medicine’s neurologists are either blinded by the research billions  or mentally impaired because they continue to prescribe anti-amyloid drugs that tend to  worsen clinical outcomes. (Source)

Below, another piece of published evidence from 2002, wherein the authors show that both amyloid-beta and tau, the major components of senile plaques and neurofibrillary tangles, are less the central mediators of the pathogenesis of Alzheimer disease than protectors from upstream biochemical events or assaults, including, but not limited to oxidative stress and toxemia.

“… in light of recent evidence, such “lesion-centric” approaches look to be inappropriate. In fact, rather than initiators of disease pathogenesis, the lesions occur consequent to oxidative stress and function as a primary line of antioxidant defense. (…) The notion that amyloid-beta and tau function as protective components brings into serious question the rationale of current therapeutic efforts targeted toward lesion removal”. Free Radic Biol Med. 2002 Nov 1;33(9):1194-9 (Source) (2)

Tentative Conclusion on Conventional AD Research

The Failure of AD monotherapeutics

Looking at the published data, I can assert with strong scientific confidence that neurodegenerative disease therapeutics has been all in all one of the greatest failures of biomedical therapeutics development. Patients with acute illnesses such as infectious diseases, or even with other chronic illnesses, such as cardiovascular disease, osteoporosis, human immunodeficiency virus infection, and even cancer, have access to more effective therapeutic options that can alleviate their conditions while patients with AD or other neurodegenerative diseases such as Lewy body dementia, frontotemporal lobar degeneration, psychosis and inter alia, amyotrophic lateral sclerosis don’t benefit from much if any relief. The hard facts in effect show that in the case of Alzheimer’s disease, there is not a single therapeutic that exerts anything beyond a marginal, unsustained symptomatic effect, with little if any effect on disease progression. Worse, emerging evidence suggests, like in conventional oncology, that most of conventional AD medicine worsens the AD experience.

Furthermore, in the past decade, hundreds of clinical trials have been conducted with regard to AD, at an aggregate cost of billions of dollars, all in vain. (Source)

Holistic Scientists suggests alternative hypotheses

In contradistinction to conventional allopathic Researchers who are more focused on finding drugs that will destroy some of AD’s symptomatology, in particular the tau proteins and beta-amyloids, holistic scientists are looking out of the conventional “box” and finding more significant events that are upstream of these amyloidal “senile” plaques.

The Vascular Hypothesis

One of these mechanisms is based on  vascular degeneration. In this perspective, the emerging evidence shows that the formation of each AD amyloid plaque is initiated by bleeding from a cerebral capillary, that which creates the conditions for formation of an amyloid-rich plaque. Specifically, it is argued that ischaemia caused by the haemorrhage upregulates the expression of beta-amyloid by local neural cells, and that haemoglobin released into the neuropil binds to the beta-amyloid and promotes its oligomerisation.

“The premise that the event that initiates plaque formation is vascular explains why the risk factors for ALDs and cardiovascular diseases overlap; why drugs and lifestyle changes with vaso-protective effects protect against dementia; and why oxidative stress is prominent early in the genesis of Alzheimer-like dementias. The vascular premise also suggests that the anatomical substrate for the spread of plaque formation is the capillary bed of the cerebral cortex, and provides an explanation of why plaque formation is age-related, occurring as the capillary bed becomes fragile with age. The more specific premise, that haemorrhage creates the conditions for plaque formation, explains many of the features of plaques: their small and relatively uniform size, each being the site of a capillary bleed; why plaques form around capillaries; why haem is found in every plaque; why an inflammatory response is prominent where plaques form; why plaque formation and haemorrhagic stroke commonly co-occur in both sporadic and familial dementias; why plaques form around vessels in mouse models of plaque formation induced by transgenes that mimic the mutations that cause familial disease; why the acute petechial bleeding caused by brain trauma can lead to the formation of plaques. The hypothesis also suggests an explanation of how ALD’s can occur without plaque formation, as when the cerebral capillaries become blocked or constricted in flow, without haemorrhage. Advances in the prevention of dementia will be gained, it is argued, from understanding of why the cerebral capillary bed becomes unstable with age, and how that instability can be prevented, delayed or slowed. Advances in the treatment of dementia will be gained from techniques that minimise the neural damage caused by a multitude of tiny strokes. (Cf, Med Hypotheses. 2008 Sep;71(3):347-59,”What initiates the formation of senile plaques? The origin of Alzheimer-like dementias in capillary haemorrhages”. (Source) (3)

The Inflammation Hypothesis

Another upstream AD event that is connected  the vascular degradation is the inflammation cascade process, in particular in the AD patients who have acquired the APOE4 allele, which has been a known genetic risk factor for sporadic AD. (4) It has been linked to the amyloid hypothesis by indications it is involved in the clearance pathway of Aβ, with deficits causing a toxic Aβ accumulation and aggregation (5).

However, a more fertile heuristic avenue of alternative Research  shows that APOE4 has intimate connections with innate immunity, as a consequence thereto, it is necessarliy associated with the inflammatory cascade.  One observation is that APOE suppresses TNF secretion from inflammatory cells (6, 7). Importantly an APOE mimetic that suppresses TNF secretion has successfully treated experimental models of neurodegenerative disease, including traumatic brain injury (8), stroke (9) and AD (10). As well as reducing behavioral deficits, in the study of AD, the APOE mimetic also reduced Aβ plaques and tau tangles. (ibid, 10).

The inflammation cascade mechanism therefore appears to be one of the major causative players in AD pathogenesis independently of Aβ. (11). Thus, the next question to ask is what drives inflammation.

Insulin resistance and Inflammation

It is suggested that a similar pathogenesis operates in AD as in Type 2 diabetes (T2D), but restricted to the brain, thus describing AD primarily as a result of cerebral insulin resistance [183]. Certainly cerebral insulin resistance is present in AD just as in T2D [184], and the appropriate alterations in post-insulin receptor intracellular signalling have been impressively demonstrated in fresh AD autopsy brains [185]. This idea is likely inseparable from the argument that AD is an inflammatory disease, since evidence that excessive TNF induces insulin resistance is biochemically precise [186] and, as has been reviewed [187], is widespread across many inflammatory diseases, infectious and sterile. Moreover an agent that inhibits TNF production [188] and another that controls insulin resistance [189] have both been shown to reverse AD in experimental models [190].

Toxemia and oxidative stress: Two of the big Drivers of Inflammation that can be controlled via a Holistic Approach

Toxemia

Under construction

Oxidative Stress

Under construction

Brain Signaling Disruption and Genes

The transgenic mouse studies suggest that APP signaling can be manipulated to inhibit AD pathophysiology. However, the mouse models feature mutations in APP or other familial AD-related genes such as presenilin-1, whereas the large majority of patients with AD suffer from sporadic AD, without an APP or PS1 mutation (although the majority do express the ε4 allele of ApoE).

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Given the many inputs to the APP signaling balance in humans (e.g., estrogen, netrin-1, Aβ, etc.), and the minimal success with each of many potentially therapeutic agents (e.g., estrogen, melatonin, exercise, vitamin D, curcumin, Ashwagandha, etc., see Holistic Solutions Link), the pathobiology of AD dictates the use of a more holistic approach rather than than a single targeted agent as conventional medicine has invested in for decades.

Holistic Solutions

By using a more holistic approach, AD has been shown to be reversed. Among others, Dr Bredensen was able to achieve a 90 percent AD reversal using simple naturaopathic interventions in a holistic way.  Successes with other chronic illnesses such as cardiovascular disease, neoplasia, and HIV support the efficacy of multiple-component holistically-based approach.

“This report describes a novel, comprehensive, and personalized therapeutic program that is based on the underlying pathogenesis of Alzheimer’s disease, and which involves multiple modalities designed to achieve metabolic enhancement for neurodegeneration (MEND). The first 10 patients who have utilized this program include patients with memory loss associated with Alzheimer’s disease (AD), amnestic mild cognitive impairment (aMCI), or subjective cognitive impairment (SCI). Nine of the 10 displayed subjective or objective improvement in cognition beginning within 3-6 months, with the one failure being a patient with very late stage AD. Six of the patients had had to discontinue working or were struggling with their jobs at the time of presentation, and all were able to return to work or continue working with improved performance. Improvements have been sustained, and at this time the longest patient follow-up is two and one-half years from initial treatment, with sustained and marked improvement. These results suggest that a larger, more extensive trial of this therapeutic program is warranted. The results also suggest that, at least early in the course, cognitive decline may be driven in large part by metabolic processes. Furthermore, given the failure of monotherapeutics in AD to date, the results raise the possibility that such a therapeutic system may be useful as a platform on which drugs that would fail as monotherapeutics may succeed as key components of a therapeutic system”. Aging . 2014 Sep; 6(9): 707–717. Reversal of cognitive decline: A novel therapeutic. (Source)

Discussion

 Successes with other chronic illnesses such as cardiovascular disease, neoplasia, and HIV support the efficacy of multiple-component holistically-based approach.

The emergence of more holistic approaches to understanding AD pathogenesis

As suggested by Figure 3, the amyloid hypothesis is at least incomplete, and quite possibly largely incorrect. Therefore it follows that therapies targeting Aβ or APP processing may not treat LOAD, and possibly may not even work in some cases of EOAD. Given this conclusion, it is worthwhile to consider alternative possibilities. There are a number of theories in the literature that must be given serious consideration and ultimately integrated into a holistic view of disease. We will elaborate on just some of these, below.

Controversies and Inconsistencies Within the Current Amyloid Hypothesis. 1. Aβ deposition occurs in cognitively normal individuals; 2. There is a weak correlation between plaque load and cognition; 3. The biochemical nature and presence of Aβ oligomeric assemblies in vivo is unclear; 4. Pre-clinical AD models based on EOAD-linked mutations are biased toward the amyloid hypothesis; 5. Pathological heterogeneity and comorbidities are unexplained by the amyloid hypothesis; 6. Aβ has a normal physiological role and targeting Aβ may disrupt these roles over the long term; 7. Genetic factors linked to AD can be interpreted independently of amyloid; 8. APP cleavage and function is more complex than solely the production of Aβ, indicating other APP family members may play a role in disease progression; 9. The triggers of synapse loss, neuronal loss and neuroinflammation in AD are still unclear; 10. The relationship between Aβ and tau pathologies is unclear; 11. The onset of dementia in Down’s Syndrome is highly variable, despite the presence of fibrillar plaques in 100% of Down’s individuals by the fifth decade; 12. The APOE4 genotype has numerous functional effects, rather than solely relating to reduced Aβ clearance, including links to enhanced inflammatory phenotypes.

The basic tenets for such a comprehensive therapeutic system are the following:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4221920/#R5

Just as for other chronic illnesses such as atherosclerotic cardiovascular disease, the goal is not simply to normalize metabolic parameters, but rather to optimize them. As an example, a serum homocysteine level of 12 μmol/l is considered to be within normal limits, but is well documented to be suboptimal [27]. Similar arguments can be made for many other metabolic parameters.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4221920/#R27

Based on the hypothesis that AD results from an imbalance in an extensive plasticity network, the therapy should address as many of the network components as possible, with the idea that a combination may create an effect that is more than the sum of the effects of many monotherapeutics [5].

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4221920/#R5

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4221920/#
Screen Shot 2017-11-08 at 8.31.42 AM

Conclusion

Alternative and holistic therapeutic strategies are needed

5. Bredesen DE and John V. Next generation therapeutics for Alzheimer’s disease. EMBO Mol Med. 2013; 5:795-798. [PubMed]

 

The pharmacological treatment of Alzheimer’s disease (AD) is often limited and accompanied by serious drug side effects. (Source)

network-based therapeutics approach, rather than a single target-based approach, may be feasible and potentially more effective for the treatment of cognitive decline due to Alzheimer’s disease.

1

Future Directions
The emergence of more holistic approaches to understanding AD pathogenesis
As suggested by Figure 3, the amyloid hypothesis is at least incomplete, and quite possibly largely incorrect. Therefore it follows that therapies targeting Aβ or APP processing may not treat LOAD, and possibly may not even work in some cases of EOAD. Given this conclusion, it is worthwhile to consider alternative possibilities. There are a number of theories in the literature that must be given serious consideration and ultimately integrated into a holistic view of disease. We will elaborate on just some of these, below.
fig ft0fig mode=article f1
fig/graphic|fig/alternatives/graphic mode=”anchored” m1

Figure 3
caption a7
Controversies and Inconsistencies Within the Current Amyloid Hypothesis. 1. Aβ deposition occurs in cognitively normal individuals; 2. There is a weak correlation between plaque load and cognition; 3. The biochemical nature and presence of Aβ oligomeric assemblies in vivo is unclear; 4. Pre-clinical AD models based on EOAD-linked mutations are biased toward the amyloid hypothesis; 5. Pathological heterogeneity and comorbidities are unexplained by the amyloid hypothesis; 6. Aβ has a normal physiological role and targeting Aβ may disrupt these roles over the long term; 7. Genetic factors linked to AD can be interpreted independently of amyloid; 8. APP cleavage and function is more complex than solely the production of Aβ, indicating other APP family members may play a role in disease progression; 9. The triggers of synapse loss, neuronal loss and neuroinflammation in AD are still unclear; 10. The relationship between Aβ and tau pathologies is unclear; 11. The onset of dementia in Down’s Syndrome is highly variable, despite the presence of fibrillar plaques in 100% of Down’s individuals by the fifth decade; 12. The APOE4 genotype has numerous functional effects, rather than solely relating to reduced Aβ clearance, including links to enhanced inflammatory phenotypes. Each of these points are discussed in detail in the text.
Insulin resistance and Inflammation
It is suggested that a similar pathogenesis operates in AD as in Type 2 diabetes (T2D), but restricted to the brain, thus describing AD primarily as a result of cerebral insulin resistance [183]. Certainly cerebral insulin resistance is present in AD just as in T2D [184], and the appropriate alterations in post-insulin receptor intracellular signalling have been impressively demonstrated in fresh AD autopsy brains [185]. This idea is likely inseparable from the argument that AD is an inflammatory disease, since evidence that excessive TNF induces insulin resistance is biochemically precise [186] and, as has been reviewed [187], is widespread across many inflammatory diseases, infectious and sterile. Moreover an agent that inhibits TNF production [188] and another that controls insulin resistance [189] have both been shown to reverse AD in experimental models [190].
The inflammatory hypothesis of AD is a valid alternative to the amyloid hypothesis
We and others have long proposed a role for neuroinflammation, driven by microglia and astrocytes, as a trigger for Alzheimer’s pathogenesis [46,125,187,191]. The case for chronic inflammation, as classically defined, rather than Aβ, being the primary initiator of AD has a long history, with new evidence continuing to accumulate. From 1989 it has been reported that inflammatory cytokines are essential for the excess APP required for the amyloid hypothesis of AD [192], as well as up-regulating its cleavage to form Aβ [187]. In addition, parallel studies demonstrating that oligomeric Aβ influences synapses through inducing the inflammatory cytokine TNF [187,193,194] have been enlightening. A possible role for neuroinflammation in synapse pathology early in disease has now been acknowledged [195] and there is much evidence, from genetics and measuring indicatory of inflammation very early in AD, that it is in the right place at the right time to be causal, and likely to precede Aβ and tau pathologies [187]. More recently, the clinically approved specific anti-TNF agent, etanercept, is reported to prevent changes caused by administering Aβ to mice intracerebroventricularly [196].
The tau hypothesis of AD
The concept of hyperphosphorylated tau being a primary mediator of AD, like amyloid, has a long history, which continues to grow [197]. Much interest still exists in where tau sits in the pathogenesis of AD [198]. In our view, AD is sufficiently diverse that it is conceivable that the role of tau, and where it sits in AD pathology, could vary among individuals. If tau is a primary activator of disease in some cases, it is imperative that the reported harmlessness of phosphorylated tau to neurons during mammalian hibernation [199] be discussed in AD research circles. Furthermore, hyperphosphorylated tau can be considered another histological sign of cytokine activity [187].
Redefining ‘neuroinflammation’ through viewing the synapse as a complex multicellular structure is important in future AD research
The inflammatory hypothesis is an example of how amyloid and tau research can be integrated into a novel set of ideas, both expanding the amyloid hypothesis and including it. However, while we use the term ‘neuroinflammation’ throughout this text and elsewhere, we note that neuroinflammation is poorly defined. In its simplest form neuroinflammation is currently defined by altered glial cell morphology and excess pro-inflammatory cytokine release [46]. This must ultimately give way to a more complex and subtle view of glial function/dysfunction within the multicellular synapse [200].
Stepping back to consider the multitude of factors we have summarised above, a complex picture emerges that consistently points to synaptic dysfunction and loss as a major link between the diverse characteristics of the disease. We have recently pointed out the synapse needs to be re-defined and understood as a multicellular structure where glia play a critical role [46]. This allows us in turn to re-imagine AD.
Microglia and astrocytes are essential to normal synapse biology, including the removal [201,202] and formation of synapses [203,204], and maintenance of synaptic function [205,206]. Disruptions in signalling between glia and synapses, which may involve several known cytokines such as TNF, could therefore drive the well-known synapse loss in AD, either independently of, or in conjunction with Aβ [46].
A consequence of this interpretation is that the issue may not be an upregulation of neuroinflammatory signalling from these cells per se, that is involved in disease. Rather, expression of pro-inflammatory cytokines and other neuronal and glial derived molecules regulating the synapse could be disrupted subtly for a host of reasons, well before frank inflammation is apparent. APP, along with presenilin and indeed numerous other factors, may exert effects on the synapse through actions on glial function, leading to either excess synapses (as occurs in autism) or synapse loss (as occurs in AD). This would modify glial function at synapses, and potentially drive synapse loss. Thus, we propose that many of the factors thought to cause inflammation are more likely to cause a dysregulation of glial function at the synapse in the first instance, long before changes in cell morphology become obvious. Consequently, more subtle mechanisms may underpin AD.
Clearly, understanding the physiological roles of microglia and astrocytes at synapses, as opposed to simply considering them as cells with key roles in innate immunity and ‘neuroinflammation’ , is a critical avenue for future research. We suggest future research will reveal that the entire current concept of ‘neuroinflammation’ is poorly understood, defined and characterised. This concept will require profound rethinking before we can truly understand the role of glia in the unperturbed brain and in AD pathogenesis [46].
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Conclusion
In the words of Joseph Lister (1876)
“In investigating nature you will do well to bear ever in mind that in every question there is the truth, whatever our notions may be. This seems, perhaps, a very simple consideration, yet it is strange how often it seems to be disregarded. I remember at an early period of my own life showing to a man of high reputation as a teacher some matters which I happened to have observed. And I was very much struck and grieved to find that, while all the facts lay equally clear before him, those only which squared with his previous theories seemed to affect his organs of vision.” Lister

Lister’s quote is salient. Hypotheses are an important part of any scientific method, but the sentiment of Karl Popper, quoted earlier in this article, should be taken seriously. Keeping Popper’s views in mind may prevent us from becoming over-reliant upon, and blinkered by, any single hypothesis for AD.
It has been said the amyloid hypothesis, like certain banks, may have become too big to fail [101]. The hypothesis may yet prove its merit, at least in some cases, through early intervention trials with amyloid-directed therapeutics [70,71]. However, on the basis of the data discussed here, the role of Aβ as a primary cause of all AD remains debatable. We are therefore concerned by the suggestion that, if anti-Aβ treatments are successful in patients with EOAD, this would support an argument for treating all AD with anti-Aβ drugs [207]. Such a conclusion would merit questioning without direct clinical evidence that the treatments are effective in LOAD.
We are not arguing that Aβ has no role. In fact it may be a player in a more complex view of disease and, further, its role may even be variable. We suggest instead that to solve the complex riddle of AD, theoretical models must expand beyond Aβ as the central cause of dysfunction, instead including Aβ in a wider theory that accounts for the extensive data and advances in neuroscience that have accumulated over the last decade. Ultimately it is critical that any role for Aβ must be placed in the context of a holistic view of the disease that accounts for all the data.
Even more so, with recent meta-analyses highlighting some major pitfalls with experimental design and statistical power in neuroscience [208,209], we need to be wary. Conclusions drawn from any experiment must be replicated before accepting them as fact, especially considering the difficulty in replicating in vivo studies when using different background animal strains, and different methodological approaches [210,211].
An important suggestion we make is that the concept of neuroinflammation mediated by glia may need to give way to a more subtle understanding of how aberrant glial function at synapses drives AD. We suggest an alternative view that, given evidence for synapse dysfunction as an early event in AD, synapse dysfunction may ipso facto be the cause of AD. We recently suggested [46] a new definition of the synapse as “…a complex, dynamic and often transient structure involving several cells interacting within a sophisticated extracellular matrix and milieu.” Within this framework, one of the normal roles of glia in synapse structural plasticity is to modulate and also remove synapses. Improving our understanding of how dysregulation of the multicellular synapse leads to aberrant synapse elimination will likely produce novel insights into mechanisms of synaptic degeneration in AD, and provide insights into the relationship between synaptic degeneration and other pathological hallmarks of the disease. The corollary of this is that if we can identify signaling pathways that reverse glial mechanisms leading to synapse removal, we may identify approaches that could halt or even reverse AD, independent of specific cause. Regardless, if synapse loss is one of the earliest events in disease then we must go back to first principles and understand what drives this loss.
The primary point of our review is to suggest it is inappropriate to ignore equally valid interpretations of data. There are many thousands of papers on Alzheimer’s disease, and many of these papers can be interpreted in alternative ways, while still more are contradictory to, and/or inconsistent with, the amyloid hypothesis. There are also many thousands more investigating mechanisms driving synapse function and dysfunction that could be linked to AD literature, given synapse dysfunction is a key early event and accurate correlate of AD progression. We conclude by suggesting the students, post-docs and young faculty who will determine the course of AD research in the next decade, must spend time reading this literature extensively, and thinking deeply, and thus become the next generation of leaders that, at the expense of time away from the lab bench, determine the best pathway forward.

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In order to determine a satisfactory course of remedial action, it is necessary to know Alzheimers’ etiology (causes). In Alzheimer’s disease, a peptide called amyloid beta forms aggregates (oligomers), which accumulate in the brain and form deposits known as amyloid plaques. (Source) Inflammation and oxidative damage are also associated with the progession of Alzheimer’s disease. (Source). Recent research at the Brown University in Rhode Island and elsewhere (Source), suggests that the development of Alzheimers is connected to lifestyle assaults, in particular to that which causes diabetes, the lack of insulin sensitivity. To read more, click here….

Non-invasive brain stimulation. Few studies have demonstrated that transcranial direct current stimulation (tDCS), a method of neuromodulation with consecutive robust excitability changes within the stimulated cortex area, is beneficial in AD. There is also evidence that tDCS enhances memory function in cognitive rehabilitation in depressive patients, Parkinson’s disease, and stroke. tDCS improves working and visual recognition memory in humans and object-recognition learning in the elderly. AD’s neurobiological mechanisms comprise changes in neuronal activity and the cerebral blood flow (CBF) caused by altered microvasculature, synaptic dysregulation from ß-amyloid peptide accumulation, altered neuromodulation via degenerated modulatory amine transmitter systems, altered brain oscillations, and changes in network connectivity. tDCS alters (i) neuronal activity and (ii) human CBF, (iii) has synaptic and non-synaptic after-effects (iv), can modify neurotransmitters polarity-dependently, (v) and alter oscillatory brain activity and (vi) functional connectivity patterns in the brain. It thus is reasonable to use tDCS as a therapeutic instrument in AD as it improves cognitive function in manner based on a disease mechanism. Moreover, it could prove valuable in other types of dementia. Future large-scale clinical and mechanism-oriented studies may enable us to identify its therapeutic validity in other types of demential disorders” .Front Psychiatry. 2012;3:48. doi: 10.3389/fpsyt.2012.00048. Epub 2012 May 15. Action mechanisms of transcranial direct current stimulation in Alzheimer’s disease and memory loss. Hansen N. Source Department of Neurophysiology, Ruhr University Bochum Bochum, Germany. (Source). There are 13 studies in pub med on tDCS and Alzheimier like conditions (source) and source a.  Clinical trial ongoing. For Israel research, see source. For technique modalities, source. This technique is also good for pain source and source b and source c

 

 

 

Reference and Precision Notes

(1). Ann N Y Acad Sci. 2004 Jun;1019:1-4. (Source

(2). Free Radic Biol Med. 2002 Nov 1;33(9):1194-9 (Source)

(3). Med Hypotheses. 2008 Sep;71(3):347-59,”What initiates the formation of senile plaques? The origin of Alzheimer-like dementias in capillary haemorrhages”. (Source)

(4). Corder EH, Saunders AM, Strittmatter WJ, Schmechel DE, Gaskell PC, Small GW, Roses AD, Haines JL, Pericak-Vance MA. Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer’s disease in late onset families. Science. 1993;261:921–923. (Source). “Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer’s disease in late onset families”. Abstract: “The apolipoprotein E type 4 allele (APOE-epsilon 4) is genetically associated with the common late onset familial and sporadic forms of Alzheimer’s disease (AD). Risk for AD increased from 20% to 90% and mean age at onset decreased from 84 to 68 years with increasing number of APOE-epsilon 4 alleles in 42 families with late onset AD. Thus APOE-epsilon 4 gene dose is a major risk factor for late onset AD and, in these families, homozygosity for APOE-epsilon 4 was virtually sufficient to cause AD by age 80.”.

(5). Castellano JM, Kim J, Stewart FR, Jiang H, DeMattos RB, Patterson BW, Fagan AM, Morris JC, Mawuenyega KG, Cruchaga C, Goate AM, Bales KR, Paul SM, Bateman RJ, Holtzman DM. Human apoE isoforms differentially regulate brain amyloid-beta peptide clearance. Sci Transl Med. 2011;3:89ra57. (Source)

(6). Laskowitz DT, Goel S, Bennett ER, Matthew WD. Apolipoprotein E suppresses glial cell secretion of TNF-alpha. J Neuroimmunol. 1997;76:70–74. [PubMed]

(7). Vitek MP, Brown CM, Colton CA. APOE genotype-specific differences in the innate immune response. Neurobiol Aging. 2009;30:1350–1360. [PMC free article] [PubMed]

(8). Hoane MR, Kaufman N, Vitek MP, McKenna SE. COG1410 improves cognitive performance and reduces cortical neuronal loss in the traumatically injured brain. J Neurotrauma. 2009;26:121–129. [PMC free article] [PubMed]

(9) Tukhovskaya EA, Yukin AY, Khokhlova ON, Murashev AN, Vitek MP. COG1410, a novel apolipoprotein-E mimetic, improves functional and morphological recovery in a rat model of focal brain ischemia. J Neurosci Res. 2009;87:677–682. [PMC free article] [PubMed]

(10). Vitek MP, Christensen DJ, Wilcock D, Davis J, Van Nostrand WE, Li FQ, Colton CA. APOE-mimetic peptides reduce behavioral deficits, plaques and tangles in Alzheimer’s disease transgenics. Neurodegener Dis 2012. 2012;10(1–4):122–126. [PMC free article] [PubMed]

(11). The relationship of APOE4 to inflammation therefore opens a channel of enquiry directed to explain why stimulation of APOE expression in mice enhances normal Aβ clearance (both soluble oligomers and plaques) and reverses behavioural deficits. In line with the observation of the link between presenilin mutations and inflammation, the links between APOE4 and inflammation further point to inflammation as a major player in AD pathogenesis independently of Aβ

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