Intervention Issues for Presymptomatic AD are many. Consider questionable amyloid staging, lack of biological biomarkers, Tau uncertainties, and neuron loss accumulation. In addition, efficacy must be demonstrated for patients who do not have cognitive impairment, along with the current requirement by the FDA is that “meaningful cognitive benefits” be demonstrated in a clinical trial.  Therefore, a basic issue becomes: “how to overcome this FDA requirement”, when candidates display no cognitive impairment symptoms and Presymptomatic AD tools need to be developed and approved.

The Dilemma

Amyloid accumulation reaches a level to trigger Tau fibrils and tangles. At that point, Alzheimer’s Disease progression is through the Tau protein. Amyloid is no longer involved. Tau fibrils and tangles then cause neurodegeneration or neuron loss. This all occurs prior to any cognitive symptoms. Therefore, clinical trial interventions, that target amyloid in patients with cognitive symptoms, are aimed at the wrong target in the wrong stage of Alzheimer’s Disease.

As Tau fibrils and tangles cause neuron loss in the Entorhinal Cortex (EC), a level is reached whereby short-term memory is impacted in the hippocampus and cognitive symptoms appear. Timing for this progression is uncertain but assumed to take up to ten years. As neuron loss continues, the disease spreads via Tau pathways (Tauopathy) throughout the brain.

Therefore, interventions need to either target amyloid before it accunulates to trigger Tau fibrils and tangles or target Tau fibrils and tangles before neuron loss occurs, or discover how tauopathy begins and target that event to stop the spread. All of this has to occur before cognitive symptoms appear. This is the dilemma facing research as well as the complexity associated with the tau protein and its damage rate in the Entorhinal Cortex and the rest of the brain.

Based on the above dilemma, Amyloid Intervention should aim for Prevention https://alzheimersabcs.com/2019/01/04/510/ in the Asymptomatic Stage of Presymptomatic AD. Tau Interventions should target the Prodromal AD Stage https://alzheimersabcs.com/?p=2556 of Presymptomatic AD.

Current Tau Status

Research has focused on Tau and its complexity. Efforts are directed at progressive rates associated with fibrils and tangles. Disease locations are being investigated relative to early evidence and progression. Most Tau clinical trials indicate the serious lack of biological biomarkers whereby attempts to used more advanced cognitive tools are targeting the late portion of the Profromal AD Stage and including MCI patients, many in their seventies (not good).

Current Trial Tools

Available cognitive tools, such as, the Alzheimer’s Disease Assessment Scale–cognitive sub-scale (ADAS-cog), Mini-Mental State Examination (MMSE), and neuropsychological tests, have shown relatively little change over time in the Presymptomatic Prodromal AD (AD-P) stage or even Amnestic Mild Cognitive Impairment (aMCI) participants. This is primarily due a ceiling effect where everyone scores at the top level of the test. Scales that measure functional or global change are unable to capture subtle clinical decline due to the comparatively minimum functional deficits in AD-P/a MCI patients. These clinical tools, which have been widely used in symptomatic AD trials, apparently lack overall sensitivity to be responsive to clinical decline in aMCI/AD-P.

A two-year study that began in 2010, creatively developed a composite cognitive test for Prodromal AD (AD-P) candidate selection, that combined selected subsets from existing cognitive tests to demonstrate more sensitive measures of cognitive decline.  This composite cognitive test is described in a March 2016 report “ADCOMS: a composite clinical outcome for Prodromal Alzheimer’s Disease trials”, Jinning, Wang et. al.  The study claimed justification to use ADCOMS as an increase sensitivity tool for AD-P clinical trials.  ADCOMS is being used in the A4 clinical trial along with a concurrent clinical trial to obtain FDA approval of ADCOMS as an acceptable biomarker

Conclusion

The best hope is recognition to approved a drug targeting amyloid for candidates in the Asymptomatic Stage of Presymptomatic AD and demonstrate “PREVENTION” .

Then, accept the fact that a beneficial Tau intervention may take up to two decades. Biological biomarkers are needed to demonstrate beneficial results and address the early period of the Prodromal AD Stage.

Hopefully,current research will identify progression rates and locations of early Tau fibrils and tangles damage as well as neuron loss during this decade.

Other uncertainties needing increased knowledge include immune system responses, inflammation, toxins, ApoE-4, and Tau isoforms (Isoforms are different combinations of DNA instructions that are associated with mental disorders other than AD).

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