- The Baby Boom generation is between age 55 to 73 as of 2019. Most are unaware that neuron loss has probably already started if they are future AD patients. Generation X is next at ages 40 – 54. Evidence indicates that neuron loss due to TAU fibrils and tangles begins during the Prodromal AD stage (Figure 1). What is the outlook? Author and Caregiver Bruce Bauer provides the following insight and possibilities.
|45 – 55||55 -65||65 – 70||70+||75+|
1980 – 1999
|Generation X |
1965 – 1979
1946 – 1964
| The Lucky Few Generation |
1929 – 1945
Figure 1 Stages & Generations of Late Onset Aheimer’s Disease
What is the Outlook
The outlook is far from rosy. The following provides insight of Presymptomatic AD, Current Research, Market Possibilities, Government Efforts, Realism for Patients, and Bruce’s Conclusion.
Presymptomatic Alzheimer’s Disease (AD)
In simple terms, amyloid plaque begins to aggregate during an assumed 10 year asymptomatic stage without awareness. It reaches a point where it triggers TAU fibrils and tangles beginning a Prodromal AD stage along with the start of neuron loos. The neuron loss continues (unaware) for an assumed 10-year period when memory signs and symptoms begin (diagnosed as Mild Cognitive Impairment – MCI)
Currently, there are three main types of interventions in trials for treatment and/or prevention of AD. The first are amyloid targets with symptomatic patients. These include Solanezumab A4 (mab = monoclonal antibody – an injection), a trial intervention with a primary outcome to demonstrate efficacy and a meaningful cognitive benefit. Others amyloid intervention include Aducanumab, Crenezumab, Gantenerumab, and beta secretase (BACE) inhibitors. The second, treatment trials, for the TAU fibrils and tangles are in early safety phases. The third, vaccine trials without success for both amyloid and Tau. Solanezumab, after failing efficacy at targets of mild and moderate AD) started the A4 efficacy trial Feb 2014 with a completion target of July 2022. Patients are from 65 – 85. The primary outcome measure is change in cognition from baseline (Solanezumab began in the laboratory in 2002). There are multiple TAU trials, some in Phase 1 and some in Phase 2, no Phase 3. All but one of the BACE inhibitor trials have terminated due to concerns to meet cognitive primary outcomes. The BACE trials were for patient with MCI and Mild AD. A guide for an intervention to reach market starts with basic research and progresses through clinical trials to a market approval in an expected 16 years if successful.
With a completion of July 2022 for Solanezumab, a 2024 market appearance could be possible if judge successful for cognitive efficacy. However, with the age of 65 – 85, cognitive efficacy is realistically uncertain, considering neuron loss for these ages. The probability is that even if some patients had no further disease decline from the baseline, aging decline continues. Ppatients with decline make efficacy unlikely. Without meaningful cognitive benefits, satisfying the primary outcome is unlikely, thus more failed trials. Watch and See. As for TAU, trials in Phase 2 will follow with a phase 3, it could be 2028 – 2030 for a market opportunity. TAU has uncertainties. Fibrils and tangles are known to cause both internal cell nucleus damage as well as external damage leading to neuron loss but with uncertainty as to which one or both influence AD pathology. Realistically there seems to be too many uncertainties for current patient hope. However, stopping Tau fibrils and tangles is needed for treatment of Prodromal AD where neuron loss starts. Basic research has recently identified six isoforms of the Tau protein and are now trying to determine each role. A lone remaining BACE inhibitor trial has uncertainty due to the termination of other BACE inhibitors. The remaining BACE trial is accepting patients of age 50 – 85 who have MCI or Mild AD and the trial is targeted for completion in November, 2023, which would make market introduction possibly in early 2026, if successful.
The FDA market requirement for an AD intervention is to demonstrate “MEANINGFUL COGNITIVE BENEFIT”. Since early presymptomatic AD has no cognitive symptoms, how can this be demonstrated? The FDA issued early presymptomatic AD guidance that indicated openness to consider recommendations. Could such a recommendation be: “treating Beta Amyloid” as a separate disease for the Asymptomatic stage? A primary outcome of dissolving plaque and removing it from the brain along with inhibiting plaque aggregation could be a primary outcome. Theoretically, this would prevent fibrils and tangles as well as neuron loss. Would this be like a heart disease statin?
An A3 Study notification was submitted in 2016 for support by NIH (Reisa A Sterling et. al.) and again in 2019 (Paul S. Aisen et. al.) for a Anti -Amyloid Prevention trial to treat amyloid plaque with an intervention’s primary outcome of inhibiting and eliminating plaque. With an accelerate market approval and a long-term confirmation trial to prove prevention, Asymptomatic candidates could demonstrate the beginning of a prevention methodology. Also, many monoclonal antibody trials have demonstrated eliminating and inhibiting plaque. What has happened to this patient hopeful idea?
Realism for Patients
Baby boomers are in range of Prodromal AD and MCI. Neuron loss has probably unknowingly started. The Prodromal AD stage has uncertainties of TAU fibrils and tangles and begins neuron loss in the transentorhinal cortex and entorhinal cortex, along with the hippocampus and eventually leads to memory symptoms. A treatment benefit for patients in this stage would be to stop neuron loss. Unfortunately, current basic research is exploring the uncertainties in processes, pathways, mechanisms, immune responses, and other unknowns while baby boomers increase their neuron loss each year. (Realism –> à basic research to market = 16 years)
Generation X is next. Unless the A3 Study moves into a trial, the group will follow the Baby Boomers path. Can Government (including the FDA) Research, and Pharmaceuticals as well as Activists focus on Anti-Amyloid Prevention for Asymptomic candidates without concerns for cognition? What has happened to the A3 Study notification for NIH support as well as hope for future Asymptomatic patients?
Bruce’s view is that once symptoms appear, neuron loss has been occurring in the Prodromal AD stage for 10 years where TAU uncertainties are plentiful, but being addressed in basic research and trials. Normal aging neuron loss compounds AD as patients age. Bruce believes the brain is too complex to hope for a near term intervention to halt neuron loss due to AD (what to do?). Bruce recommends education on AD, care-giving, research progress, and face reality. Learn your ABC’s of Alzheimer’s Disease with the knowledge Bruce shares in his book and this website. You can lead a horse to water, but you can’t make him drink. Comments are appreciated and helpful.