The brain obtains information from the body’s five senses which is passed through the brain’s transentorhinal cortex to the Entorhinal Cortex (EC).  The EC processes the information and transfers the information to the hippocampus for short term memory storage.  If long term memory storage is decided, the hippocampus transfers the information back to the EC which then processes it for long term memory storage and sends it to the neo-cortex.  The information is stored in the neo-cortex as knowledge to be used by its executive function for creative thinking, storytelling, decision making, and continual learning etc.

            When cognitive impairment is diagnosed due to Alzheimer’s Disease (AD), the EC has already lost thirty percent of  the EC’s level 2 that processes information to the hippocampus (Teresa Gomez-Isla, 1996).  Heiko and Eva Braak’s autopsy’s report in 1991 stated that EC damage was so great at the very mild stage of AD that the disease must have started many years earlier.  As the disease progresses, the EC continues to lose neurons and the executive function vanishes. 

            Braak and Braak’s 1991 report identified Dr. Alzheimer’s sticky substance as amyloid plaque and fibrils and tangles of the Tau protein.  In 2018 Clifford R Jack Jr. reported that a diagnosis of AD required evidence of amyloid aggregation and Tau fibrils and tangles.  Neurodegeneration or neuron loss, and Tau pathology continue undetected prior to cognitive impairment.      

            The picture above identifies five stages of AD.  In 2011, AD was classified into a presymptomatic, symptomatic, and a dementia periods.  The presymptomatic (symptoms uncertain) period has two stages.  An asymptomatic stage is where amyloid aggregates accumulate to trigger (unknown) fibrils and tangles that start the death of neurons that  produce the Tau protein.  The aggregation of amyloid is estimated to take up to ten years (center figure – age 45- 55) to accumulate and trigger Tau fibrils and tangles.  Prodromal AD  (AD-P) is the other stage (above Figure – age 55 – 65).  Neuron loss in the EC begins AD and the EC continues to lose neurons during the AD-P stage for an estimated ten years when cognitive impairment is discovered and classified as Mild Cognitive Impairment (MCI). 

            Since 2001, clinical trials have failed for patients with mild and moderate AD.  My opinion is that neuron loss is too great at these stages for any intervention to achieve the FDA efficacy requirement of “meaningful cognitive benefits”.  Even if an intervention stopped the disease that caused neuron death (unlikely), neuron loss would continue during the trial due to patient aging. 

            I believe the target needs to be prevention of amyloid aggregation and accummulation before fibrils and tangles are triggered.  Interventions from failed trials demonstrated removing amyloid plaque along with preventing amyloid aggregation. This was after the triggering Tau fibrils and tangles that caused (unknown)  neurodegeneration (loss of neurons) in the EC.  Neurodegeneration introduces uncertainties due to insufficient current level of  knowledge of the brain’s immune system and its response,  inflammation role, and rate of neurodegeneration progression.

            In 2016, Reisa Sterling, et. al. proposed a clinical trial to the National Institute of Aging (NIA) to prevent amyloid aggregation in the Asymptomatic stage (picture – age 45 – 55).   In 2019, with no NIA action, Paul Aisen re-proposed the concept.  Meanwhile, baby boomers are now candidates for the Asymptomatic and Prodromal AD stages.

            My perspective (without evidence) is that cure lacks in-depth knowledge of the brain.  Delay lacks sufficient knowledge along with many uncertainties needing resolution.  These should justify basic research funding.  Government leadership, however, should provide the public realistic transparency that such conditions are decades to centuries away.   A rule of thumb provided me in 2004 was it took 16 years to go from basic research to market.  Solanezumab is the intervention in the on-going A-4 clinical trial.  It was in basic research in 2002.

            It would be encouraging if government leaders would find a way to initiate the proposed recommendation by Reisa Sterling et. al. to prevent the start of Tau fibrils and tangles in the EC.   Such a trial could demonstrate prevention of amyloid aggregation efficacy and attract qualify baby boomer candidates in the Asymptomatic stage.  This would not only provide hope for baby boomers and future generations but possibly satisfy the 2025 national goal “Effectively treat and prevent Alzheimer’s Disease and Related Dementia (ADRD) by 2025”.  The ideal solution would be an active vaccine prior to loss of EC neurons.

            This article is by the Author of the book “ABC’S OF ALZHEIMER’S DISEASE: A SHARED REALITY BY ME AND MY SHADOW”  where more information is provided from the author’s experience as a caregiver, along with providing a mental exercise challenge in learning and understanding Alzheimer’s Disease.  Appendix D of the book provides a case study of the AN-1792 Alzheimer’s vaccine failed trial.  Author’s website –

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