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Are Amyloid and the Neuron Innocent Accomplices in Alzheimer’s Disease?

By: , Posted on: April 27, 2015


Since Alzheimer’s disease was first identified as a neurological disorder, one far worse than simple dementia, prevailing wisdom has maintained that the trademark neuronal death is primarily caused by toxic accumulations of extracellular amyloid. This single sustained hypothesis has been the scientific engine driving Alzheimer’s research for decades, prompting clinical trials that seek to prevent the extracellular accumulation of amyloid before it kills neurons.  Unfortunately, these trials have yet to demonstrate efficacy in curing or even suppressing the disease. Those scientists still committed to this hypothesis are now redefining their target population to treat patients before behavioral symptoms are clinically manifested.  At the same time, a growing body of researchers looks to other hypotheses that may provide a more promising roadmap.  In light of these recent circumstances, more scientists are raising the question: have we looked too closely at the resulting pathology (i.e. plaques and tangles) of Alzheimer’s without considering other events leading to neuronal death?

One such omitted consideration is the apparently beneficial role of amyloid (specifically the Aβ42 variant) in the healthy body, specifically in synaptic wiring from learning processes. Most scientists in the field insist on the toxicity of amyloid, and few even acknowledge its relation to other physiology besides Alzheimer’s pathology. As a result, if amyloid does indeed become toxic to the body, the field has yet to confidently address how and when this occurs.  Some proposed mechanisms include aberrant processing, mutations, and excessive accumulation of amyloid.  However, aberrant genetic causes of Alzheimer’s only account for roughly 5% of all cases, and the consequences of excessive accumulation of amyloid are poorly understood.

One school of Alzheimer’s research has studied the alpha-7 nicotinic acetylcholine receptor on neurons and reported its especially high affinity to amyloid. This suggests that amyloid is not typically abundant in the healthy brain, but is normally produced selectively and sparingly by neurons in the processes of synaptic plasticity. Contributing to this picture is the beneficial application of nicotine-like therapies to reduce the risk of Alzheimer’s in some reports. Furthermore, while many in the field believe that all intracellular amyloid is synthesized by the neuron, there is no empirically sound research that backs this claim. These data together raise the question: what might happen to neuron-amyloid dynamics if extracellular amyloid becomes ubiquitous in the brain?

Another oft-ignored pathological component of Alzheimer’s is the role of the vascular system. Hundreds of studies cite vascular health, diet, exercise, and other non-CNS activities as risk factors for dementia and Alzheimer’s disease, as well as the progression of patients from mild cognitive impairment to Alzheimer’s.  Despite these numerous claims, research that considers vascular pathology in the scope of disease therapy is scarce at best.

Considering the role of vascular pathology as a cause of Alzheimer’s, leads to a compelling, unifying, and satisfyingly simple version of events.  Should the vascular system fail to inhibit the passage of amyloid from the bloodstream into the brain, introducing an unfamiliar and unaccommodated large amount of amyloid, the high-affinity alpha-7 receptors would perhaps accumulate the excess amyloid, causing neurons to stockpile the protein to the point of neuronal failure and lysis.

To complete this picture, consider the question: what would these overburdened, lysed neurons leave behind?  The enzyme-resistant neuronal “guts” and the amyloid, which are suspiciously the components of so-called dense-core amyloid plaques that are hallmarks of the Alzheimer’s diseased brain.  What’s worse, other neurons with their extending processes through this toxic area of neuronal debris would die from irreversible structural damage (i.e. neurofibrillary tangles), while additional neurons would die from inflammation through factors released by the activated microglia and reactive astrocytes that are triggered by the lysed neurons. This proposed, fatal sequence of events presents a sound, compelling hypothesis of the pathology observed in Alzheimer’s. Perhaps the amyloid and the neuron are simply innocent accomplices to vascular insecurity that wrongly lets amyloid into the brain and sets off the entire process of neuronal death.  This sequence of pathological events, of course, would imply an entirely different and novel course of therapy to reduce the risk of and even cure Alzheimer’s disease, one that may finally warrant more careful consideration.

About the Book:

Advances in Alzheimer’s disease (AD) research have been challenging and without major breakthroughs in understanding its pathological basis. The reigning hypothesis suggests AD is the result of extracellular amyloid deposition that seed to form amyloid plaques, which then grow and kill neighboring neurons.

However, there are several inconsistencies with this hypothesis, not to mention the inability to show clinical benefit in several failed clinical trials by pharmaceuticals (i.e., from Pfizer, Eli Lilly, etc.), and it is in the field’s best interest to explore and test multiple hypotheses for pathology rather than drive the majority of research on this single amyloid theory.

However, there are several inconsistencies with this hypothesis, not to mention the inability to show clinical benefit in several failed clinical trials by pharmaceuticals (i.e., from Pfizer, Eli Lilly, etc.), and it is in the field’s best interest to explore and test multiple hypotheses for pathology rather than drive the majority of research on this single amyloid theory.

9780128019795Reviewing many scientifically peer-reviewed publications, Bursting Neurons and Fading Memories in Alzheimer’s Disease describes the “Inside-Out” hypothesis on how amyloid escapes the circulatory system through a dysfunctional blood-brain barrier to bind to the alpha 7 nicotinic acetylcholine receptor on pyramidal neurons.

Over time, excessive amounts of amyloid appear to be internalized, resulting in neuron death and lysis. This simple mechanism readily explains plaque composition, size, shape, and location. Based on the current direction of research in the field, this hypothesis appears years from any research and development.

If you are interested in further understanding of the details and evidence of this alternative approach, the book is available on the Elsevier Store. Use discount code “STC215″ at checkout and save up to 30% off the list price.

About the author:

 Michael R. D'AndreaMichael R. D’Andrea received his PhD in Cell and Developmental Biology and his MS in Molecular Biology at Rutger’s University, New Brunswick, NJ, and his BA in Psycho-Biology at Western Maryland College, Westminster, MD. His dissertation work utilized molecular and histological assays to study the regulation of DNA topoisomerases in human cancers. His earlier career concerned the use of the high magnification electron microscopy to support oncogenesis in preclinical models, and then moved into a new field where he and his peers co-invented the chorionic villus sampling method at Thomas Jefferson for clinical chromosomal analysis. In the late 1980s and early 1990s, he mastered immunohistochemical methods at the light and electron microscopy levels when he began publishing his work in scientific journals.

However, it wasn’t until the mid-1990s, while working at Johnson & Johnson’s Pharmaceutical Research & Development as the Target Validation Team Leader, did he become engaged in Alzheimer’s disease (AD) research. His Team was responsible for supporting target discovery and validation, while supporting biomarker discovery in preclinical and experimental models using genomic, proteomic, and histopathological methods across many therapeutic areas and was honored with over a dozen Leadership and Scientific awards. Currently, he has over 100 scientifically peer-reviewed scientific publications and invited reviews, about a third of which concern the neuropathology of AD, and holds 11 scientific patents. He has reviewed hundreds of papers for many scientific journals, reviewed international grants in the AD field, and is currently on the editorial board of the journal, Biotechnic & Histochemistry.

He has been invited to speak at numerous International, National, and Regional meetings, as well as at Universities and other companies to discuss his novel observations concerning the origin of amyloid plaques, the existence of various plaque types, and most recently that AD is also an autoimmune disease; all of which is presented in this book. Recently, Michael established a contract research company, Slidomics, LLC ( to apply his histopathological and target validation expertise by providing high quality data and analysis much like what you see in this book.

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