General Overview

            Alzheimer’s Disease (AD) is currently view in two parts, which are AD Dementia with symptoms  and Presymptomatic AD with an unawareness of symptoms

            AD symptomatic diagnostic grew out the pyschiatric discipline of medicine where signs and symptoms  associated with areas of the brain define various mental disorders.  This pyschiatric diagnostic methodology evolved to guide the research approach for AD interventions.  Most notably is the FDA requirement for an intervention market approval, which is demonstrating “Meaningful Cognitive Benefits”.  

            This propelled cognitive testing that provides subjective inputs from either the patient or caregiver.  Such tests introduce complexity because of a population varied both in diversity and education which adds uncertainty to trial efficacy goals and data analysis.  Unfortunately, this is the best available method without metabolic markers.

            In 2011, research refocused to presymptomatic AD, where AD occurs without cognitive symptoms or signs.  Measurable metabolic test markers, that are being pursued, are not approved.  Neither has a FDA requirement for market approval without cognitive impairment been provided.  In addition, the candidates for conducting research trials are probably below the age of 65 and with an uncertainty of insurance coverage if an intervention was approved for either prevention or treatment. 

            Recent research reports indicate that soluble amyloid oligomers become toxic producing inflammation whereby the immune system responds to control the inflammation with plaque, and supposedly removes the soluble toxic oligomers and plaque from the brain.  AD seems to occur if the removal process is ineffective to where the toxic oligomers along with plaque aggregate accumulate over time to trigger Tau fibrils and tangles and neurodegeneration (neuron loss).

            AD has identified amyloid peptide progressing to trigger fibrils and tangles of the Tau protein as two mechanisms that trigger neurodegeneration or Neuron loss.  Neuron loss is permanent and increases as the disease progresses.  Current view is that some form of amyloid aggregation accumulation produces an unknown trigger of Tau fibrils and tangles that then cause neuron death.  Evidence (AN-1792 trial) showed the disease continues without amyloid playing a role, once Tau neurodegeneration starts.

            Common sense might say stop the amyloid aggregate accumulation and you prevent AD.  A successful amyloid vaccine would achieve this.  Or a tau vaccine that stops the production of fibrils and tangles could also do the job.  Not so easy. 


            Recent research hypothesis suggest that amyloid oligomers produce a toxin that is confronted by the immune system in the form of inflation that forms a protective plaque around the toxic oligomers.  These oligomers aggregate if not protective by plaque and/or cleared from the brain.  At some unknown point, the aggregates accumulate to trigger Tau fibrils and tangles which lead to neurodegeneration (neuron loss).          

Because of age-linked immune decline, vaccines would be significantly more effective in preventing, rather than treating AD (D.J. Marciani -Oct. 2019).  However, vaccine trials have also failed. 


Selected clinical trial data of the monoclonal antibody Aducanumab indicated  slowing the progression of early AD.  This has created cautious optimism about its therapeutic use to neutralize cytotoxic soluble amyloid oligomers aggregates and remove them from the brain.  How this monoclonal antibody works with the immune system’s response has not been reported.

          This monoclonal antibody targeted amyloid aggregation and removal in patient 50 to 85 years of age who demonstrated cognitive symptoms in either MCI or Mild AD.       This means all patients were experiencing neurodegeneration and tauopathy.  MCI score inclusion was 30 to 24.  Mild AD inclusion was 24 – 20.  Trial duration was 18 months.  Normal MMSE yearly decline is 3 points.  Patients without cognitive symptoms were not included.  Biogen initial information stated the sub-element data was from a group that received a higher dose of Aducanumab. 

          Assuming the placebo group decline 15% in 18 months and the higher dose group experience a 40% slowing rate.  This would indicate that a 9% decline would have occurred in the high dose group over 18 months rather than a !5% decline in the placebo group.  Thus, a MMSE decline of approximately 2 rather than 3 points per year decline with Aducanumab.  Assuming the mean score of the high dose group began at a score of 27.  This would put them at a score of 24 rather than 21.5 at the end of the 18 months.  Is this Meaningful Cognitive Benefit for the patient or the pharmaceutical?  You be the judge. 

          However, if the pharmaceutical request to the FDA would include  approval to treat amyloidosis in asymptomatic patients before neurodegeneration occurs, then prevention may occur for future candidates and possibly be a major benefit outcome.

          The psychiatric syndrome of “Meaningful Cognitive Benefit” for market approval of an intervention has doomed clinical trials inclusion criteria.  Braak and Braak 1991 autopsy report and Teresa Gomez-Isle et. al. 1996 autopsy report of Entorhinal Cortex damage at the very mild stage of AD provided evidence and guidance that has apparently been ignored.

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