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

Realism and Hope

  • Bruce’s realism: –> Alzheimer’s Disease (AD) causes the death of neurons in the brain. With an overproduction of the Amyloid Precursor Protein (APP), amyloid peptides along with fragments are produced. Amyloid plaques is formed in responses to inflammation. Aggregates accumulate over many years (assume 10)to an unknown level where an unknown mechanism triggers fibrils and tangles in the Tau Protein. Fibrils and tangles are followed by the death of neurons, thereby beginning Alzheimer’s Disease. Bruce’s Hope:—> Implement Bruce’s Prevention Hypothesis by approving Solanezumab, Aducanumab, and Gantenerumab to treat amyloid accumulation during the assume 10 years of accumulation. In parallel perform basic research to identify an effective intervention to delay and/or halt neuron loss through preventing the amyloid trigger mechanism (currently unknown) of Tau Pathology.

Can Alzheimer’s Disease be Cured

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

Can Alzheimer’s Disease be Prevented or Delayed?

Alzheimer’s disease may possibly be prevented and delayed.  Prevention takes intervening before neuron damage occurs in the Entorhinal Cortex (EC). Neuron loss is believed to start possibly 10 years before cognitive impairment is diagnosed as Mild Cognitive Impairment (MCI). Neuron loss is belief to start in theTtransentorhinal and Entorinal cortices.

Delaying AD is more of a challenge, as delay means to slow or stop disease progression, either before or 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 MCI stage.  Either period has challenging obstacles that involve the brain’s immune system along with the varied forms of the Tau protein.

Recent basic research have reported encouraging Tau protective findings involving the ApoE gene. First was two ApoE 2 allele prevented AD. Second was a single nucleotide change in the DNA also appears to have delayed the disease. However, both had negative consequences on Cholesterol and heart issues.

Therefore, the issues are: a) What is the amount of neuron damage? b) What is the presymptomatic efficacy requirement for an intervention? c) What is the insurance coverage (before & after Medicare eligibility)

Why have clinical trials failed?

Three hypothesize obstacles may 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’s reasons for Clinical Trial failure

  • 1. The wrong Stage of the Disease – Patients selection criteria of Mild & Moderate Alzheimer’s Disease (AD) had too much neuron damage to demonstrate the FDA efficacy requirement (Meaningful Cognitive Benefit) to attain market approval.
  • 2. Possible right drug & target, but wrong stage. Monoclonal Antibodies (MABs) demonstrated dissolving and removing amyloid but too late in the disease process. These drugs and the amyloid target has to be before neuron loss begins to be effective.
  • 3. FDA Market Requirement – Meaningful cognitive benefits requirement is not possible once amyloid aggregates accumulation triggers neurons loss via Tau fibrils & tangles. There is no existing evidence to indicate that new neurons can be created.

What are the obstacles?

Bruce views the obstacles as “Disease Oriented”, and “Stakeholder Oriented” as follows:

Disease Oriented Obstacles

a) Biological biomarkers: Non-invasive, cost effective biological biomarker (Blood, neurofilament protein) are needed for Asymptomatic Prevention and Prodromal AD delay stages.

  • b) ApoE Allele 2,3,and 4 role in Tau pathology along with possibility of genetic engineering changes to an allele currently lack basic research knowedge..
  • c) Brain’s immune system’s role: Additional knowledge and understanding needed for delaying or halting AD during Prodromal stage once Tau fibrils and tangles start.
  • d) Tau protein’s isoforms: Additional knowledge and understanding of their role relative to AD, Supranuclear Palsy, and Fronto-temporal Dementia.
  • e) Tau Hyper-phosphorylation: Additional knowledge and understanding is needed relative to fibrils and tangles.
  • f) Rate of neuron damage: needed for determining an efficacy criteria for delaying the disease process during the Prodromal AD stage
  • g) Rate of amyloid aggregate accumulation: Needed for Asymptomatic intervention efficacy., along with the trigger point causing Tau fibrils and tangles to begi
  1. h) The amyloid accumulation mechanism that trigger Tau fibrils and tangles would be a significant finding.

Stakeholder Oriented Obsticles

  • a) Awareness and understanding of AD by caregiver, patient & the general population.
  • b) Leadership, which appears driven by psychiatry educated medical personnel who guide research from their past experience of treating cognitive impairment symptoms as opposed to addressing Biological causes for neuron loss.
  • c) FDA market requirement – (Meaningful Cognitive Benefit) – is not appropriate for presymptomatic patient with no cognitive symptoms.

d) Government’s Health and Human Services Structure: A Separate Agency is needed like NASA. Centers and Research Laboratories outside of Washington should focus on a segment of the overall Alzheimer’s Disease and Related Dementia mental disorders. Patient Care should be a separate Center.

e) Pharmaceuticals incentives balanced to risks are needed.


Bruce’s strategic prioritization would be Asymptomatic stage to remove amyloid, prevent aggregate accumulation and initiate prevention for future candidates. Second would Prodromal AD and the many Tau protein issues. In parallel conduct basic research for Tau Protection and stopping Tauopathy. Finally, Symptomatic AD care needs realistic communication. Patient Care for symptomatic AD before the inability to sustain Activities of Daily Living (ADL) is a manageable lifestyle. The inability to sustain ADL is the trigger point to caregiver issue that need focus, support, and creative approaches.

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