Why have so many trials failed over the past two decades?  What are the obstacles?  What are the challenges?  Can Alzheimer’s Disease be Cured?  Can Alzheimer’s Disease be Prevented and/or Delayed?  What is realism and hope?  These are all questions that have sensitivity associated with them and realistic expectations may be view as being negative. 

Trial Failures

            “Evidence suggests that Alzheimer’s pathophysiology process begins many years before the onset of cognitive symptoms.  So why keep testing drugs beneficial at the initial stage of the disease process in patients who are past these stages? 

Three hypotheses can explain these AD trial failures: (i) Targeting the wrong pathophysiology mechanisms (proteins, peptides, etc.); (ii) The drugs do not engage the intended targets; and (iii) The drugs are hitting the right targets but are doing so at the wrong stage of the disease”.  (Reisa A Sperling et. al. Nov. 2011).  Bruce adds that the FDA’s requirement to show meaningful cognitive benefits is not possible due to Entorhinal Cortex damage (lost neuron) when symptomatic AD begins.   

What are the obstacles?

  1. à Show “meaningful cognitive benefit for market approval
  2. A 30% loss fo neurons in level 2 of the EC at very mild AD.  (Teresa Gomez-Isla et. al. 1996)   The EC is like a computer server that processes data from a person’s five senses to store as memory)

What are the challenges?

Curing Alzheimer’s Disease

            Alzheimer’s disease cannot be cured today.  Cure means correcting damage and returning to a normal state.  At the cognitive symptomatic stage of AD there is to much neuron damage to return to a normal state.  However, it may be possible in the future with new knowledge and new technology that a metabolic bypass implants could be developed and replace damaged portions of the brain, such as the Entorhinal Cortex.  Such knowledge and technology may take a century.

Alzheimer’s Disease be Prevented and Delayed

            Alzheimer’s disease may possibly be prevented and delayed.  Prevention takes intervening before neuron damage occurs in the Entorhinal Cortex (EC), believed to be the initial point of neuron lost.  Bruce’s Blog Prevent Alzheimer’s Disease proposes one concept.  Delaying AD is more of a challenge, as delay means to slow or stop disease progression after the disease has started and neurons have been lost.  This optimally would be in the presymptomatic Prodromal AD stage, and possibly during the cognitive symptomatic Mild Cognitive Impairment stagee (MCI).  Either period has formable obstacles and challenges, such as, metabolic biomarker development. Therefore, the issues are:

  1. What is the amount of damage?
  2. What are the efficacy criteria for an intervention?
  3.  What is the insurance coverage (pre and post Medicare eligibility)?

What constitutes market approval for the presymptomatic intervention?

What is Realism and Hope

            Realism is that the Entorhinal Cortex is already damaged when symptoms are diagnosed, as well as neuron loss during aging.  This should guide senior expectations to pursue an active lifestyle along with planning for care options and future quality dementia care.

            Hope is in the “eye of the beholder”.  For diagnosed with mild and moderate AD, hope is loving care.  For those diagnosed with MCI, hope is for a delay intervention to be found and approved.  For those in the Prodromal AD period without cognitive symptoms but with an indeterminate amount of neuron loss in the Entorhinal cortex, hope is for a delay intervention to be found and approved, along with a method to determine amount of neuron loss.  For those with the identification of Beta Amyloid Plaque but without the start of tau fibrils and tangle that cause neuron loss in the entorhinal cortex, hope is that Bruce’s hypothesis (Article 56) is correct and current interventions (Crenezumab, Aducanumab, Gantenerumab, BIO2401, and Solanezumab) receive market approved to dissolve plaque, along with appropriate insurance coverage.

Conclusion

            Realism is that once AD is symptomatically diagnosed, the disease and aging promote a probable dementia outcome.  Therefore, priorities should be to PREVENT AD through accelerated approval of current clinical trials interventions for candidates who could benefit from dissolving the Beta Amyloid Plaque before an accumulated load triggers Tau fibrils and tangles that cause neuron loss in the Entorhinal Cortex,  To achieve this, establish Beta Amyloid Plaque as a disease (BAPD) with a criteria for market approval being AB42  detection (Blood and/or CSF) and efficacy for as dissolving AB42, preventing Tau fibrils and tangles, and confirming no EC neuron loss.  Execute market authorization to allow BAPD candidates to demonstrate prevention while pursuing parallel long-term confirmation trials. 

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