The World is Not Flat

Debunking the Amyloid Hypothesis Myth in Alzheimer’s Disease

Amyloid plaques and tau tangles are ABSOLUTELY NOT the answer to find the solution in Alzheimer’s disease. We must challenge the amyloid hypothesis as the key reason for synaptic loss and neurodegeneration in Alzheimer’s disease. Period. END OF STORY.

Twenty years of research, conducted around the world, investigating beta-amyloid and tau tangles as the ‘cause’ of Alzheimer’s disease is like still trying to say that the world is flat. It is just not correct.

Some writers report that more than 100 drugs targeting beta amyloid have failed. A recent example is from Eli Lilly. So, amyloid plaques and tau tangles are definitely not the right clues in detecting Alzheimer’s disease.

By digging into the research around this hypothesis, one can uncover a myriad of ways to debunk this MYTH. It is essential that we expand our view of the pathogenesis beyond beta-amyloid and neurofibrillary tau tangle pathologies. And, it is critical to consider several (better) directions for Alzheimer’s disease research.

What is the amyloid hypothesis? The amyloid hypothesis suggests that faulty processing of the amyloid precursor protein (APP) in the brain is what triggers the production of beta-amyloid (Aβ), a short, mostly insoluble, sticky fragment of APP known as “amyloid plaque”. However, this is NOT the initiator of the disease and NOT the best way to address Alzheimer’s.

I like to explain it this way –> If I accidentally cut my skin with a knife, and the white blood cells race to the site, causing an inflammation, and a scab eventually forms … should I REMOVE the scab, to stop the bleeding? Would I remove the scab to stop from ever being cut by a knife, again!? Of course not. Well, this is what we are doing by trying to ‘eliminate’ the plaque and the tangles.

The theory then goes on to state plaque and tangles trigger an inflammatory response, as the brain tries to repair itself. Nope. The trigger starts earlier. The trigger causes the inflammation. This is so important that it needs to be repeated. The trigger starts earlier. The trigger causes the inflammation.

The tangles and plaque are not the primary cause of the inflammation. They are more likely the ‘scab’ that forms as a result of the inflammation. In more current theories, this inflammatory response is believed to be what leads to the production of neurofibrillary tangles (NTFs).

NTFs are made up of a protein called “tau”, which is why they are also known as tau tangles. The buildup of beta-amyloid and tau tangles is hypothesized to lead to neural synapse loss in the brain, neurodegeneration and, finally, to dementia.[1] (This ‘might’ be true, but the tangles and plaque are NOT the initiating event.)

Although some changes to the hypothesis have occurred since the original publications, the theory that beta-amyloid accumulation triggers Alzheimer’s disease, has largely remained the same – until NOW.[2]

So far, anti-amyloid treatments have broadly failed in achieving most all of their clinical goals. None of the tested treatments have produced an identifiable functional recovery, or altered the course of the disease.[7]

What’s wrong with the current amyloid hypothesis? Beta-amyloid plaques and tau tangles have been considered the diagnostic hallmarks of Alzheimer’s. But they are not the evidence that beta-amyloid is the prime cause of Alzheimer’s disease. (In fact, there are other diagnostic hallmarks, as will be outlined later.)

Amyloid plaque buildup occurs in cognitively normal individuals. So, there is a weak correlation between amyloid plaque load and cognition. The biochemical nature and presence of beta-amyloid oligomeric assemblies (proteins that contain more than one polypeptide chain) taking place in a living organism … is unclear.

Beta-amyloid has a normal role in the body. It’s in all of us! This implies that only targeting beta-amyloid may disrupt this natural role over the long term. We therefore see that the triggers of synapse loss, neuron loss and neuro-inflammation in Alzheimer’s disease are still unclear. Fundamentally, the relationship between beta-amyloid and tau pathologies, and their impact in causing Alzheimer’s, is unclear.

If we consider another ‘brain medical condition’, Down’s syndrome, the issue becomes even more complicated. 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 of life.[2]

As we can clearly see, the amyloid hypothesis is largely inadequate and unclear, hence demanding rapid strides in future research with more plausible hypotheses. We MUST go up-stream to get to the root cause(s) of Alzheimer’s disease.

Unfortunately, there are a number of drugs fighting to get ‘air time’ — that have nothing to do with beta amyloid. I am personally imploring the researchers of the world to pay attention – and give credence to some alternative stories that make a lot more sense.

Some hypotheses which are proving to be more impressive, are the Diminished Cerebral Glucose Metabolism (DCGM)-neurometabolic hypothesis – and the Neuroinflammatory hypothesis.

The DCGM-neurometabolic hypothesis suggests that a similar pathogenesis operates in Alzheimer’s Disease as in Type 2 diabetes (T2D), but in this case, the ‘disease’ is restricted to the brain. Thus, Alzheimer’s disease is described primarily as a result of the brain processing insulin poorly[3], fundamentally starving the brain of its nutrients because the brain cannot process glucose as an energy source. Cerebral insulin resistance is present in Alzheimer’s disease[4]; thus the potential for Alzheimer’s disease to be considered a neuro-metabolic disorder. In fact, some studies have shown that these issues in the metabolism of glucose occur decades before the onset of symptoms, suggesting that these issues may be an upstream event in at least some Alzheimer’s cases.

Check this out here. It’s a first-of-its-kind DCGM-based compound that has shown memory improvement in 53% of patients tested in early trials. Just phenomenal results.

The NeuroInflammatory hypothesis has now been acknowledged and suggests a possible role for neuro-inflammation in synapse pathology early in the disease[6]. Additionally, there is much evidence, from measuring a person’s genetic profile and comparing genetic profile variations, which indicates that inflammation occurs very early in Alzheimer’s disease. The inflammation is essentially in the right place, at the right time, to be CAUSATIVE for Alzheimer’s disease and likely to precede beta-amyloid and tau pathologies.

Is THIS the story!?
However, if I return to the ‘cutting my skin’ example – it would make more sense for Alzheimer’s if we said 1) the initial ‘insult’ to the brain is the lack of its ability to process glucose as an energy source, 2) with the body’s reaction (like sending in the white blood cells) being to rally with an inflammatory response to protect the brain, and 3) the third phase is that the brain puts up ‘super defenses’ by building a network, or wall, of plaque and tangles that are like the scab on my skin. Doesn’t it make sense for the body to act in a similar way to very different insults (a knife cut as compared to starvation of the brain)?

What can you do?
Over a year ago, we launched a $100 million campaign to find and fund a cure for Alzheimer’s disease. We received over 50 submissions, providing us with a unique ‘window’ into some amazing, transformative research happening all around the world. All of this work is convincing us that the ‘world is no longer flat’!

If you are working on some unique science to CURE Alzheimer’s disease – or, if you would like to FUND one of these initiatives, please contact us … we’re going to nail this one – soon!

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Additional References:

[1]Khan A “The amyloid hypothesis and potential treatments for Alzheimer’s disease”. The Journal of Quality Research in Dementia, Issue 4 (lay summary). Retrieved from https://www.alzheimers.org.uk/site/scripts/documents_info.php?documentID=383&pageNumber=6.

[2] Morris, Gary P, Ian A Clark, and Bryce Vissel. “Inconsistencies and Controversies Surrounding the Amyloid Hypothesis of Alzheimer’s Disease.” Acta Neuropathologica Communications 2 (2014): 135. PMC. Web.

[3]Craft S. Insulin resistance syndrome and Alzheimer’s disease: Age- and obesity-related effects on memory, amyloid, and inflammation. Neurobiol Aging. 2005;26:65–69. [PubMed]

[4]Liu Y, Liu F, Grundke Iqbal I, Iqbal K, Gong CX. Deficient brain insulin signalling pathway in Alzheimer’s disease and diabetes. J Pathol. 2011;225:54–62. [PMC free article] [PubMed]

[5]Talbot K, Wang HY, Kazi H, Han LY, Bakshi KP, Stucky A, Fuino RL, Kawaguchi KR, Samoyedny AJ, Wilson RS, Arvanitakis Z, Schneider JA, Wolf BA, Bennett DA, Trojanowski JQ, Arnold SE. Demonstrated brain insulin resistance in Alzheimer’s disease patients is associated with IGF-1 resistance, IRS-1 dysregulation, and cognitive decline. J Clin Invest. 2012;122:1316–1338. [PMC free article] [PubMed]

[6]195. Rao JS, Kellom M, Kim HW, Rapoport SI, Reese EA. Neuroinflammation and synaptic loss. Neurochem Res. 2012;37:903–910. [PMC free article] [PubMed]

[7]Mullane K, Williams M. Alzheimer’s therapeutics: continued clinical failures question the validity of the amyloid hypothesis-but what lies beyond? Biochem Pharmacol. 2013;85(3):289–305.