BREAKING! Harvard Scientists Find That Alzheimer is Driven by a Hidden Protein Fragment and Not Amyloid Beta!
Nikhil Prasad Fact checked by:Thailand Medical News Team May 01, 2025 3 weeks, 2 days, 4 hours, 3 minutes ago
Medical News: A groundbreaking new theory is upending decades of beliefs about what causes Alzheimer’s disease, offering new hope and direction for treatment strategies that have long failed patients. According to researchers from the Department of Developmental Biology at Harvard School of Dental Medicine and the Division of Molecular Medicine at Boston Children’s Hospital—both institutions affiliated with Harvard Medical School—the real culprit behind Alzheimer’s might not be the well-known amyloid beta (Aβ) protein, but rather a lesser-known protein fragment called C99 that is produced through an alternative cellular mechanism.
Harvard Scientists Find That Alzheimer is Driven by a Hidden Protein Fragment and Not Amyloid Beta
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Medical News report delves into a bold new perspective proposed by Dr. Vladimir Volloch and Dr. Sophia Rits-Volloch, which traces the evolution of what is now called the Amyloid Cascade Hypothesis 2.0 (ACH2.0). This new version completely reimagines how Alzheimer’s develops and progresses.
How the Traditional View of Alzheimer’s Is Crumbling
For decades, Alzheimer’s research has revolved around the idea that the buildup of amyloid beta plaques in the brain was responsible for triggering the disease. This concept—known as the original Amyloid Cascade Hypothesis—led to massive investments in drug development to either clear these plaques or prevent their formation.
Yet, nearly all of these treatments have failed. Clinical trials involving drugs like verubecestat and others targeting amyloid beta have repeatedly shown that even when amyloid levels in the brain are drastically reduced, patients show no real improvement. This has raised serious questions about the amyloid theory’s validity.
The ACH2.0 framework introduced by the Harvard researchers offers a transformative explanation for these failures. Rather than focusing on extracellular amyloid beta plaques, the new theory centers on something called the "neuronal integrated stress response" or ISR—a process activated in brain cells under chronic stress.
A Shift in Blame from Amyloid Beta to C99
In the updated theory, Alzheimer’s disease begins with stress in neurons, which can be triggered by amyloid beta in some cases (called conventional Alzheimer’s), or by other stressors like brain trauma, infections, or inflammation (called unconventional Alzheimer’s). Once the ISR is activated, it shuts down the typical production of many proteins, including those that generate amyloid beta. At the same time, it enables a completely different route for the production of a toxic fragment called C99.
C99 is typically an intermediate fragment produced from a larger protein called amyloid precursor protein (AβPP), which is normally cut down to form amyloid beta. But under ISR conditions, cells appear to bypass AβPP entirely a
nd produce C99 directly through a novel RNA-based mechanism. This C99 buildup, not amyloid beta, is now thought to drive the progression of Alzheimer’s.
Why Current Mouse Models and Drug Approaches Are Failing
An important implication of this new theory is that most current mouse models used for Alzheimer’s research are inadequate. They are engineered to overproduce amyloid beta using human genes, but they lack the cellular machinery necessary for this alternative C99-producing pathway. As a result, they don’t develop the full range of Alzheimer’s pathology seen in humans.
This helps explain why drugs that work on these mouse models don’t translate to success in human patients. In real Alzheimer’s cases, it’s not the amyloid beta that needs to be stopped—it’s the C99 fragment that’s being generated in a completely different way.
New Directions for Treatment
The ACH2.0 theory proposes radically new ways to treat or even prevent Alzheimer’s:
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Depleting C99 and intraneuronal Aβ (iAβ): If the abnormal buildup of C99 and iAβ in neurons can be eliminated early enough, it may be possible to stop Alzheimer’s before symptoms begin—or even reverse early-stage disease.
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Inhibiting the ISR: Since the ISR is what enables the alternative C99 production, targeting it could block the disease at its source. There are already known ISR inhibitors that may be useful in this approach.
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Dual therapy strategies: A combination of C99/iAβ depletion with ISR suppression could be a one-time treatment that prevents Alzheimer’s for life in conventional cases, and with repeated treatments, manage unconventional cases as well.
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Gene editing or RNA-based therapies: The researchers also suggest novel RNA-targeted approaches to stop the alternative C99 production mechanism without affecting the normal function of the AβPP gene. These include shifting the gene's transcription start site, modifying untranslated regions, or using anti-antisense oligonucleotides.
Validations and Proof of Concept
The study doesn’t rely on theory alone—it builds upon multiple layers of evidence.
One pivotal point is the analysis of previous clinical trials with BACE1 inhibitors like verubecestat. These drugs should have worked if Aβ production was the problem. Instead, they performed excellently in reducing Aβ levels but failed to improve symptoms. This paradox fits perfectly with the new theory: the real driver—C99—was untouched.
Further, the researchers validated the biological feasibility of the new mechanism. They demonstrated how human neurons under ISR conditions can produce a 5’-truncated version of AβPP mRNA that starts at the Met671 codon. This produces C99 directly—no AβPP, no beta-secretase required. This was long suspected but finally confirmed by identifying RNA fragments in lab settings that support this alternative translation initiation.
Two Types of Alzheimer’s Disease
The ACH2.0 theory also makes a key distinction between two types of Alzheimer’s:
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Conventional AD: Triggered by amyloid beta-induced ISR in neurons, leading to C99 production.
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Unconventional AD: Triggered by other stressors like infections or brain trauma, yet following the same C99-driven pathway.
Importantly, the theory suggests that all cases of conventional AD also contain an unconventional component—meaning the disease is more complex and multifactorial than previously believed.
Powerful Implications and a Sobering Reality
One of the study's more unsettling conclusions is that conventional Alzheimer’s is not really “sporadic” or random, as it’s often described. Instead, it’s a predictable outcome of aging in a genetically susceptible subset of the population. Given enough time, the theory suggests, most people in this group will inevitably develop the disease—unless interventions based on this new understanding are developed.
Additionally, ACH2.0 debunks the idea that simply removing amyloid beta from the brain (as drugs like lecanemab and donanemab attempt to do) will stop the disease. These drugs might slightly delay early symptoms, but according to this theory, they offer no meaningful benefit once C99-driven pathology has begun.
A New Hope for Patients and Families
This revolutionary approach offers a desperately needed course correction for Alzheimer’s research and treatment. It provides a biological explanation for past failures, presents new and promising paths forward, and—most importantly—brings hope to patients and families who have watched for years as ineffective drugs failed to slow this devastating disease.
This new perspective suggests that with proper targeting of C99 and ISR pathways, it may one day be possible to not only prevent Alzheimer’s but also treat it successfully in its early stages. The research community now faces the urgent task of designing human trials around these concepts and creating accurate lab models to replace outdated ones.
The study findings were published in the peer reviewed International Journal of Molecular Sciences.
https://www.mdpi.com/1422-0067/26/9/4252
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