With Alzheimer’s Disease and Related Dementia receiving nearly $2 billion for FY 2018 along with a FY 2019 budget of over $2.5 billion, research funding should no longer be the issue. Though basic research benefitted with increase knowledge and hopeful expectation, benefits for the general population remained for the future. Positive knowledge gains are overwhelmed by the brain’s complexity whereby the current general population and future patients, caregivers, and candidates remain yearning for results, while craving for miracle which appears not at hand.

Excerpts are from Alzforum – 2018 Year in Research. (Bruce’s comments are in italics)

1. The 2025 deadline for effective therapy was established by the National Alzheimer’s Plan based on Congress’s National Alzheimer’s Project Act (NAPA) and accepted by the World Dementia Council. 2018 brought no drug approvals or Phase 3 breakthroughs.  In order to meet its goal of a game-changing treatment by 2025, everything must go right from now on.  Unfortunately, two monoclonal antibody drugs (Crenezumab and Aducanumab) that clear amyloid plaque, AB42 from the brain had their Phase 3 trials terminated in March 2019 for lack of efficacy probability. Then, in October, 2019, Aducanumab was questionably determined acceptable for FDA approval. See Bruce’s Aducanumab Story https://wordpress.com/block-editor/post/alzheimersabcs.com/1679

2. Therapeutic antibodies massively reduce brain amyloid—will that help?   Only if Bruce’s hypothesis (https://wordpress.com/block-editor/post/alzheimersabcs.com/1458) for AD prevention becomes accepted.

3. Blood tests are coming—Feb. 1, 2019, the FDA has fast-tracked review of CZN’s blood test for amyloid pathology.  The goal is to develop an inexpensive and non-invasive test for Aβ pathology that can be used in clinical trial recruitment and in clinical diagnosis.  Further support for Bruce’s “Prevent AD Hypothesis

4. Imaging Dementia–Evidence for Amyloid Scanning (IDEAS) study.
   An effort to persuade the Centers for Medicare & Medicaid Services (CMS) to start reimbursing for amyloid PET Scans was to determine whether such scans make a difference in a person’s treatment.  Benefits were reported from 11,409 cognitively impaired people scanned.  However, a cheaper test of Aβ in Cerebral Spinal Fluid (CSF) agreed with amyloid PET Scan 90 percent of the time, as do up-and-coming blood tests. 
Meanwhile, brain imaging is becoming more able to track and distinguish one neurodegenerative disorder from another.  Also, scientists reported that accumulation of AB aggregation is a necessary precursor for the broad invasion of the cortex by tau aggregates (See Fig. 1 – the spot where BAPD changes to AD-P) and neurons begin to die becomes the start of Alzheimer’s disease.  Bruce’s hypothesis considers this the beginning of cognitive impairment in the Entorhinal Cortex (EC) of people with sporadic and familial AD.  A very tough CMS decision for PET Scan reimbursement is pending.

5.            Researchers are now probing a new framework in their longitudinal research cohorts, and early indications are that biomarkers for amyloid, tau, and neurodegeneration (ATN, when used in combination, do a good job of predicting a person’s progression. When a person shows no cognitive symptoms, three evidences are: A) there is biomarker evidence of amyloid, T) there is evidence of neurofibrillary tangles where , and N) there is evidence of neurodegeneration. These helps stage the disease.  Neurofilament light (Nft) protein has emerged as a strong contender for determining N of AT(N).                     Researchers are now assessing this new framework in their longitudinal research cohorts, and early indications are that biomarkers for amyloid, tau, and neurodegeneration, when used in combination, do a good job of predicting a person’s progression.

6. 2018 research increased studies of the immune system that deepened scientists understanding of how TREM2 protects the brain and broadened the appreciation of just how dynamic and complex microglial subtypes are.  Researchers reported that Aβ binds TREM2, activating microglia and setting off a signaling cascade that spurs the microglia to degrade the AB peptide. TREM2 makes microglia less inflammatory and more phagocytic (increases the possibility), reducing amyloid.   

BRUCE’S COMMENTS

Number 5 above is a major step in the right direction for research.  To put the ATN criteria in perspective with my hypothesis to prevent AD, consider it Is a presymptomatic focus.  With the mindset that “meaningful cognitive benefit” is needed for an intervention market approval, the need for biological evidence in the form of AB, Tau fibrils and tangles, and neurodegeneration is logical for the AD-P stage.  However, it is probably ineffective in the Asymptomatic stage that is Bruce’s BAPD stage, since the T evidence would not be present

  • Bruce summarizes Alzheimer’s disease status at the end of 2018, a) possible prevention if BAPD is recognized as a separate disease with treatment by the therapeutic antibodies indicated in number 2 above, b) delay in a decade or two may be possible, if biological biomarker’s criteria (ATN) is successful for AD-P.  c) Blood test would make insurance coverage possible for candidates in the BAPD and AD-P stages.  Will government leadership get past “meaningful cognitive benefit” and focus on possible prevention by a proposed BAPD disease, and thereby meet the 2025 goal?
FIGURE 1:  PROPOSED ALZHEIMER’S DISEASE STAGES
(ADL = Activity of Daily Living)

Bruce summarizes Alzheimer’s disease status at the end of 2018, a) possible prevention if BAPD is recognized as a separate disease with treatment by the therapeutic antibodies indicated in number 2 above, b) delay in a decade or two may be possible, if biological biomarker’s criteria (ATN) is successful for AD-P.  c) Blood test would make insurance coverage possible for candidates in the BAPD and AD-P stages.  Will government leadership get past “meaningful cognitive benefit” and focus on possible prevention by a proposed BAPD disease, and thereby meet the 2025 goal?

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