BBruce’s Hypothesis – “Prevent  Alzheimer’s Diseases” is that Late Onset Alzheimer’s Disease (LOAD) starts around mid-life (assume age 45 or 50 – without symptoms), progressing with increasing toxic soluble amyloid oligomers and amyloid plaque (AB42) load during a 10-year period (Beta Amyloid Plaque Disease – BAPD).  With the amyloid continuing, the load reaches a point to trigger Tau fibrils and tangles that initiates neuron loss in the Entorhinal Cortex (EC).  This neuron loss continues during the next 10-year Prodromal AD (AD-P) period without symptoms.  Then, during the next five years, as progression continues (tauopathy), symptoms occur and Mild Cognitive Impairment (MCI) is diagnosed.  The MCI period is assumed to last for five to seven years after symptoms begin.  Finally, neuron loss progression continues for possibly a 20-year period,during which AD evolves into Dementia.  Each period has specific conditions that required different strategies.


The amyloid cascade hypothesis has driven research of the symptomatic period since 1982 without success.  I believe there are two compounding contributors to the symptoms in this period that currently impede success.  They both involve neuron loss in the brain.  Once neurons are lost, they currently cannot be re-created.  The first contributor is normal aging.  The second contributor begins with Tau neuron loss in the Entorhinal cortex along with the hippocampus (memory), and then proceeds to the Neocortex (executive function) and throughout the brain.  There are probably many contributing issues, such as metabolic and vascular anomalies, cell energy decline in the mitochondria during aging, inflammation, and immune system unknowns.  Solutions to these issues are yet to be understood and will probably require decades or centuries of research.  Unless an intervention receives market approval to halt the loss of neurons,  realistic expectations should be initially aggressive lifestyle activities and later pursuing quality care.  An early intervention might prevent the severe stage of AD.


          MCI became a disease stage during the first decade of the twenty-first century.  It is currently defined by a Mini Mental State Exam (MMSE) score of 30 to 26.  However, cognitive symptoms are initially so unnoticeable that a patient could go undetected, or remain at a score of 30, for up to five years.  Even after a diagnosis, it could be five to seven years to reach a MMSE score of 26.  Unfortunately, Tau neuron loss continues during this period. Strategies during this period are aggressive active lifestyle and monitor research for a successful Tau intervention that could halt or slow the neuron loss (due to AD) which could be considered possible prevention or at least significant delay.  However, neuron loss would continue due to aging.


Results from the 2001 AN-1792 Phase I follow-up trial provided an “outside the box” indicator – reported but never emphasized or recognized.  Two patients with MMSE scores of 25 and 24, and whose immune systems generated antibodies, showed improvement, with new MMSE scores of 30 and 28 respectively (C. Hock et. al., May 2003).  Could this be the type of improvement or delay expected in presymptomatic patients if plaque is dissolved or prevented from aggregation?  Were these patients early enough in the disease decline process that damage was not too far advanced.   Was this a missed opportunity not to have followed these two?  How long would the anti-bodies remain effective (if they ever were) before neurodegeneration reappeared, if ever? 


          This may be the real start of Alzheimer’s disease.  Based on Bruce’s Hypothesis “Prevent Alzheimer’s Diseases”, a 55 or 60-year old patient could begin Prodromal AD (AD-P) without any symptoms or knowledge that it has started.  This hypothesis assumes AD-P begins to occur when the amyloid load is enough to initiate fibrils and tangles of the Tau protein in the Entorhinal Cortex (EC).  Think of the EC as a computer server, passing information from the body’s five senses to short term memory in the hippocampus and then back through EC to the neocortex for long term memory storage.  The EC neuron loss continues during a 10-year AD-P period when MCI is detected.  (ages 55 – 65 or 60 -70).  These postulated periods are assumed based on both current research evidence, along with the1991 autopsy report by Braak and Braak and the 1996 autopsy report by Tereasa Gomez-Isla et. al. in which they both stated: “AD must have started many years before symptoms appeared”.  Can a Tau intervention be found for this AD-P period to delay or prevent continued neuron losses or is it too late once the EC neuron loss starts?  Strategies during this period are a focus on halting or slowing EC Tau neuron loss and pursue patient diagnosis and prediction of decline progression along with identification of  an acceptable biomarker, that can confirm or dispel this hypothesis.


          This period begins with the first detection of toxic soluble amyloid oligomers and amyloid plaque (AB42) that continue to initiate tau fibrils and tangles and neuron loss in the EC.  Assuming a 10-year period, evidence seems to favor this period as the best target for an intervention.   In 2001,  AN-1792 vaccine trial for mild and moderate AD patient showed that amyloid plaque was dissolved, but amyloid was not removed from the brain, along with no impact on Tau or tauopathy, and neurodegeneration continued.  Neuron loss continued without amyloid plaque influence (possibly aging?).  If an intervention could receive market approval to dissolve and clear amyloid plaque, then BAPD  could be treated as a separate disease with an end-point of prevented amyloid load from triggering EC tau fibrils and tangles.  With such an end-point, market approval of a BAPD intervention could avoid the current FDA AD requirement of “meaningful cognitive benefits”.  Such strategy would provide hope for future candidates, along with the probability of preventing a future AD tsunami.


There are four drugs candidates currently targeting toxic soluble amyloid oligomers and amyloid plaque as well as clearance of soluble amyloid.    The candidates are Solanezumab, Crenezumab, Aducanumab, and BAN2401.  All the interventions are in trials using symptomatic AD patients who Bruce assumes have neuron loss in level 2 of their Entorhinal Cortex  (Braak’s 1991 evidence) along with a significant level two loss of neurons (30% per Gomez-Isla 1996 evidence).

Assuming these drugs do not demonstrate efficacy, but demonstrate dissolving amyloid plaque along with preventing aggregation for a significant time (say two years or more).  Then, could these drugs be considered for market approval for treatment of non-symptomatic patients in the BAPD period of “Bruce’s Hypothesis: “Prevent Alzheimer’s Diseases”?  Could this be a preventive option?


Pharmaceuticals could approach the FDA with the BAPD concept for market approval which probably fits the FDA Prodromal AD stage 1 guidance, along with a request for accelerated approval while continuing a parallel trial.  Then a blood test panel should be developed for use by primary care doctors during physical exams of patients (suggest 50 to 70).  Depending on the blood test results, Cerebral Spinal Fluid (CSF) and PET Scan could be a backup as needed.  This type approach could increase the public’s interest and awareness of AD since there would be a possible prevention option.


Research evidence over the last thirty years not only identified a) neuron loss in the temporal lobe’s Entorhinal Cortex (Braak 1991 and Gomez-Isla 1996 autopsy reports, b) Tau Pet Scan tracers in living human’s) c)  amyloid load impact to fibrils and tangles (Giannakopoulos 2003), and d) lack of benefits for dissolving amyloid plaque in mild and moderate AD patient (AN-1792 vaccine trial), but appears to support Bruce’s Hypothesis: “Prevent Alzheimer’s Diseases”.  In addition, the failed trials that targeted amyloid in mild and moderate patient suggests that once significant neuron loss occurs, neuron loss continues, whether by AD and/or aging.  

Figure 1 below provides an early Alzheimer’s period visual illustration of Bruce’s Hypothesis:  “Prevent Alzheimer’s Diseases”.

ibapd - jan.018
Evidence - Braak 7 Braak (1991) and Teresa Gomez-Isle et. al. (1996)
Bruce’s Hypothesis to prevent amyloid from accumulating before triggering Tau fibrils and tangles.

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