More Trouble in Alzheimer’s Research

Is the scientific establishment targeting the wrong potential cause(s)? Can we all take a deep breath and reconsider how science proceeds?

The cause(s) of Alzheimer’s Disease (AD) has been a subject of contention for some 30 years, although you wouldn’t know it from reading the lay press or even most scholarly articles on the subject.

AD is considered to be the most common form of neurodegenerative disease that results in dementia. Although every case is different, AD eventually causes increasingly severe problems with memory, reasoning, language, behavior and personality, and spatial understanding. It’s estimated that AD affects 24 million people worldwide. (1)

What causes this devastating disease? According to AD orthodoxy, it’s caused by an abnormal accumulation of two proteins named “amyloid” and “tau” in the brain.

“Amyloid protein sticks together in your brain cells, forming clumps called plaques,” according to the Cleveland Clinic. “Tau proteins twist together in fiber-like strands called tangles. The plaques and tangles prevent neurons from working as they should. They block neurons’ ability to send electrical and chemical signals back and forth.” (1)

There’s only one problem with that orthodoxy, but it’s a pretty big one: the drugs that have been designed to prevent the plaques and tangles seen in the brains of AD patients have neither reversed nor prevented its devastating cognitive symptoms.

So, if these plaques and tangles are causing AD, why doesn’t getting rid of them help the patients?

Which raises the question, are plaques and tangles really the causes of AD symptoms—or are they an effect of the disease process, or perhaps even relatively harmless artifacts?

In the May 22 issue of MedpageToday, Deputy Managing Editor Judy George examined the rift between “biological” and “clinical” staging of AD patients. There is no conclusive test to confirm AD except examining the brain at autopsy, which is rarely done. In the last decade or so, however, a number of blood and psychological tests have tried to fill that gap. (2)

“Older adults whose cognitive symptoms were more severe than their biological Alzheimer's disease stage often had additional pathologies, a cross-sectional study showed,” George reported.

So, the advanced cognitive impairment seen in these patients is apparently not caused by the plaques and tangles formed by the tau and amyloid proteins—detection of which comprises biological staging—identified by various blood tests and PET scans (specialized brain scans). The patients who exhibited this discrepancy had “additional pathologies,” according to George. (2)

As she explained: “Biological staging of Alzheimer's disease is distinct from clinical staging. Biological staging ranges from initial (amyloid-positive) to advanced (elevated amyloid and widespread tau) stages. Clinical staging is a continuum that includes no cognitive impairment in early stages, mild impairment in intermediate stages, and severe impairment in late stages.” (2)

If advanced cognitive impairment doesn’t correspond to the markers of advanced biological staging described above, doesn’t that create suspicion that the correct cause(s) of AD haven’t yet been discovered?

The “additional pathologies” found in AD patients with advanced cognitive decline weren’t explicitly defined by George. She reported that investigators evaluated “cross-sectional measures of neurodegeneration—cortical thickness, TDP-43 imaging signature, and NfL—plus alpha-synuclein cerebrospinal fluid status, plasma glial fibrillary acidic protein, white matter lesions, infarcts, microbleeds, comorbidities, and demographics.” [We’ll get into all of that when understanding it is shown to be crucial.] (2)

All of which sound like bad news—especially since none of them appears to be the result of the accepted causes of AD, the plaques and tangles formed by tau and amyloid proteins in the brains of patients.

However, it might explain why no successful drug has been developed to ameliorate the cognitive and behavioral decline of AD.

In fact, a number of AD drug trials have been halted because the treatments worsened patients’ symptoms. Two drug categories that were designed to rid the brain of AD’s plaques and tangles were found to make patients worse. “Secretase inhibitor” drugs “failed in clinical trials and worsened cognition,” and clinical trials of secretase inhibitor as well as monoclonal antibody drugs were, separately, abruptly discontinued. (3)

The Stage III clinical trial of an AD secretase inhibitor drug named verubecestat was ended abruptly in 2019 because the patients taking it were getting worse, showing measurable declines in cognition. Verubecestat was designed to stop the accumulation of amyloid protein plaques and tangles in the brain. (4)

Two monoclonal antibody drugs that were given accelerated FDA approvals, aducanumab (Aduhelm) and lecanemab (Leqembi), each targeted different forms of beta-amyloid plaques in the brain and suffered similar outcomes.

Unfortunately, both of these monoclonal antibody drugs caused “brain shrinkage” in treated patients, a hallmark symptom of AD. (5)

And then there’s the inexplicably high rate of scientific misconduct in AD research. Formerly highly respected researchers have been found to rig clinical trials, include fake data in scientific reports spanning decades of research, and manipulate data to improve the approval of questionably effective AD drugs. (6-8)

All of which cries out for more oversight of science and increased rigor at scientific journals, as well as encouragement of what has been called “disruptive research”—research that does not accept the status quo but instead creates new, conventional wisdom-busting ideas, studies, and publications. (9)

A Chinese research group—led by An Zeng at Beijing Normal University—recently examined a category they dubbed “persistently disruptive papers.” (10)

Science magazine associate news editor Jeffrey Brainard described Zeng and colleagues’ results as “add[ing] nuance to the narrative, advanced in several previous studies, that innovativeness has declined across many scientific fields because researchers are increasingly reliant on narrow existing knowledge within their subdisciplines.” (10)

Zeng and colleagues developed a new metric to measure how many “persistently disruptive” studies have been published in the recent past. Using their new method, they determined that persistently disruptive papers increased “about fivefold” between 2000 and 2019. (10)

So, what’s a persistently disruptive paper? In short, it plays a large role in changing an established scientific paradigm. According to the calculations performed by the Beijing researchers—starting with records from 1800, continuing through 2019—a truly “persistently disruptive” paper is not necessarily highly cited; it’s persistently disruptive, they determined, if none of the papers citing it overturn its paradigm-busting conclusions. (10)

Zeng et al. conceded that there’s “no formula for determining the optimal balance between disruptive research and work that builds incrementally on previous findings.” And Russell Funk, a sociologist at the University of Minnesota Twin Cities who has also studied scientific disruption, told Science that to solve complex problems that are both societal and scientific, “You might want much higher levels of disruption” than currently exist. (10)

The lack of original thinking and the plethora of shortcuts that accumulate in fraud, in addition to a lack of acknowledgements and rewards for scientists who question the common wisdom, are harming us all. Let’s declare a vendetta against lazy thinking and see what happens.

BIBLIOGRAPHY
1. “Alzheimer’s Disease.” myclevelandclinic.org. Last reviewed 2/19/2025. https://my.clevelandclinic.org/health/diseases/9164-alzheimers-disease
2. Judy George. “Mismatch Between Alzheimer’s Biomarkers and Symptoms May Signal Multiple Pathologies—Study helps identify underlying etiologies contributing to cognitive impairment.” MedpageToday. May 22, 2025.
3. Neenyah Ostrom. “BREAKING NEWS: Alzheimer’s Disease Drugs Make Patients' Brains Shrink. Brain shrinkage and worsening cognition found in response to several AD drugs.” The Real AIDS Epidemic, April 3, 2023.
4. Judy George. “BACE1 Inhibitor Worsens Cognition in Early Alzheimer's—Two trials spell doom for once-promising drug class”; MedpageToday, April 10, 2019. https://www.medpagetoday.com/neurology/alzheimersdisease/79143
5. Judy George. “Brains Shrink With Anti-Amyloid Alzheimer's Drugs—Treatments accelerate brain atrophy, but reasons why remain a mystery.” MedpageToday, March 31, 2023. https://www.medpagetoday.com/neurology/alzheimersdisease/103817
6. Charles Piller. “Top Alzheimer’s researcher goes ‘on leave’ amid misconduct concerns. Berislav Zlokovic no longer heads neuroscience institute, University of Southern California email reveals.” Science, November 8, 2024. https://www.science.org/content/article/top-alzheimer-s-researcher-goes-leave-amid-misconduct-concerns
7. Charles Piller. “BRAIN GAMES? Whistleblowers and former lab members suggest star neuroscientist Berislav Zlokovic may have manipulated data that support a major stroke trial and important Alzheimer’s research.” Science, November 13, 2023. https://www.science.org/content/article/misconduct-concerns-possible-drug-risks-should-stop-stroke-trial-whistleblowers-say
8. Neenyah Ostrom. “Fraud in Stroke and Alzheimer’s Disease Drug Trials—Again? Whistleblowers detect data and images in published papers that appear to have been manipulated, according to Science magazine.” November 16, 2023. The Real AIDS Epidemic SubStack.
9. Neenyah Ostrom. “Science Acknowledges the Current Lack of Innovation in Research, Nevertheless Forecasting a Bright Future: ‘Persistently disruptive’ publications resulting in paradigm shifts are on the rise—really?” The Real AIDS Epidemic SubStack, May 21, 2025.
10. Jeffrey Brainard. “Research may be increasingly incremental—but studies making lasting paradigm shifts are on the rise. New metric identifying ‘persistently disruptive’ papers offers a ‘bright spot’ amid signs of declining innovation.” Science, May 20, 2025. doi: 10.1126/science.zpuohvm