Decoding Alzheimer’s: The amyloid hypothesis and its impact on future therapies

Posted byimperialbiosciencereviewPosted inPharmaceuticals

By Soumya Jonnalagadda

In 1992, Sir Professor John Hardy introduced the amyloid cascade hypothesis, detailing that amyloid-β deposition in the brain acts as a crucial step for the progression of Alzheimer’s disease.1 This hypothesis has since become the cornerstone of Alzheimer’s disease research and therapeutic development, propelling the scientific community towards the exploration of potential curative treatments. The hypothesis has since been modified and updated with further research, but there remains a critical problem: why have most amyloid-β centred approaches failed Phase III clinical trials, and what are the next steps in Alzheimer’s research?

Most notable of failed Phase III trials were that of the γ-secretase inhibitor semagacestat.2 Semagacestat works by inhibiting the γ-secretase enzyme which is responsible for the formation of amyloid-β peptides. The intention was that by reducing the production of these peptides, the accumulation of amyloid-β plaques would be prevented, thus halting the progression of Alzheimer’s disease. In reality, semagacestat did not improve cognitive status, and those receiving a higher dose found themselves with worsening functional ability.3 Employing the drug at high concentrations of the amyloid precursor protein led to the desired effect being observed, with a definite decrease in the formation of amyloid plaques. On the other hand, low amyloid precursor protein concentrations led to the stimulation of γ-secretase activity, rather than inhibition.4 The discontinuation of semagacestat underscores the paradoxical behaviour of the drug, which in turn illuminates the intricate nature of γ-secretase inhibitors and their two-fold mode of action.

The lessons we can draw from this are significant. Firstly, the failed semagacestat trials highlight the importance of dose optimisation for neurodegenerative diseases. The complexity and sensitivity of the brain’s biochemical environment is well-known, and this causes the treatment window of diseases like Alzheimer’s to be particularly narrow. Whilst dose optimisation trials bring about ethical concerns, it may be vital to take advantage of physiologically based pharmacokinetic models such as Certara’s Simcyp Simulator, though their efficacy is currently unknown.5

Another approach to Alzheimer’s treatment which takes from the amyloid hypothesis involves the use of anti-amyloid-β monoclonal antibodies (Aβ MABs), which are described as the first disease-modifying therapy for Alzheimer’s disease.6 Notably, lecanemab, which employs Aβ MABs, has been approved for use by the FDA for early Alzheimer’s disease. While semagacestat was trialled on individuals with more advanced stages of the disease where significant neuronal damage had already occurred, lecanemab trials were focused on those with early-stage Alzheimer’s. It may be the case that the most effective kind of dementia treatment is one that tackles the disease using an early intervention strategy. The success of lecanemab in clinical trials can be attributed to the updated amyloid hypothesis. The amyloid PET biomarker was crucial in these trials.7 It confirmed the presence of the therapeutic target and measured the response to the anti-amyloid monoclonal antibody treatment – ultimately, providing evidence of disease modification.8

However, it is important to acknowledge that while lecanemab’s success is promising, it is not a definitive cure for Alzheimer’s disease. The mixed outcomes of various anti-amyloid trials suggest that amyloid-β is not the only factor driving the disease. While cognitive decline in patients has been linked to amyloid-β, tau protein tangles are another hallmark of Alzheimer’s disease that have been extensively researched. Tau-containing neurofibrillary tangles are twisted fibres that form inside nerve cells, contributing to the degeneration of brain cells. In fact, a study from the Memory and Aging Centre at the University of California San Francisco noted that tau protein tangles more reliably predict future brain cell death than amyloid-β.9 The abnormal hyperphosphorylation of these tau proteins leads to the formation of insoluble clumps which impair the structural stability and function of nerve cells.10 Similar to amyloid-targeted therapies, current research on tau-related therapeutics employs various strategies. These include inhibiting the formation of tau aggregates and regulating tau activity through kinases.11

Currently, there are several tau-related therapies in clinical trial, showing varying degrees of promise. JNJ-63733657, a humanised monoclonal antibody, works by binding onto the tau protein and inhibiting the pathological spread of tau within the brain.12 As of 2024, JNJ-63733657 and other monoclonal antibodies remain in Phase II clinical trials,13 but there continue to be major tau-related breakthroughs that bring hope to those who want to find a treatment that either halts or reverses the progression of Alzheimer’s.

For now, the pursuit of effective Alzheimer’s treatments continues with promising developments not only with both amyloid-β and tau-targeted therapies, but also with treatments targeting neurofilaments, beta-secretase 1 (BACE1), and other pathways14. The scientific community remains committed to overcoming the challenges posed by this complex disease. With ongoing research and clinical trials, there is renewed hope for finding a treatment that can halt or even reverse the progression of Alzheimer’s, bringing us closer to a future where this devastating disease can be effectively managed and cured.

References:

  1. Hardy J, Higgins G. Alzheimer’s disease: the amyloid cascade hypothesis. Science. 1992 Apr 10;256(5054):184–5.
  2. Bateman RJ, Siemers ER, Mawuenyega KG, Wen G, Browning KR, Sigurdson WC, et al. A gamma-secretase inhibitor decreases amyloid-beta production in the central nervous system. Annals of neurology [Internet]. 2009 Jul 1;66(1):48–54. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2730994/
  3. Doody RS, Raman R, Farlow M, Iwatsubo T, Vellas B, Joffe S, et al. A Phase 3 Trial of Semagacestat for Treatment of Alzheimer’s Disease. New England Journal of Medicine. 2013 Jul 25;369(4):341–50.
  4. ‌Karran E, Mercken M, Strooper BD. The Amyloid Cascade Hypothesis for Alzheimer’s disease: an Appraisal for the Development of Therapeutics. Nature Reviews Drug Discovery. 2011 Aug 19;10(9):698–712.
  5. Zhang T, Tyson JJ. Understanding virtual patients efficiently and rigorously by combining machine learning with dynamical modelling. Journal of pharmacokinetics and pharmacodynamics. 2022 Jan 5;49(1):117–31.
  6. van Dyck CH, Swanson CJ, Aisen P, Bateman RJ, Chen C, Gee M, et al. Lecanemab in Early Alzheimer’s Disease. New England Journal of Medicine. 2022 Nov 29;388(1):9–21.
  7. Cummings JL. Anti-Amyloid Monoclonal Antibodies are Transformative Treatments that Redefine Alzheimer’s Disease Therapeutics. Drugs [Internet]. 2023 Apr 15;83(7):569–76. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10195708/
  8. Alzheimer’s Association. Lecanemab Approved for Treatment of Early Alzheimer’s Disease [Internet]. Alzheimer’s Association. 2022. Available from: https://www.alz.org/alzheimers-dementia/treatments/lecanemab-leqembi
  9. Alzheimer “tau” protein far surpasses amyloid in predicting toll on brain tissue: Tau PET brain imaging could launch precision medicine era for Alzheimer’s disease [Internet]. ScienceDaily. [cited 2022 Jul 28]. Available from: https://www.sciencedaily.com/releases/2020/01/200101144012.htm
  10.  Calcul L, Zhang B, Jinwal UK, Dickey CA, Baker BJ. Natural products as a rich source of tau-targeting drugs for Alzheimer’s disease. Future Medicinal Chemistry [Internet]. 2012 Sep;4(13):1751–61. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3575183/
  11. Elmaleh DR, Farlow MR, Conti PS, Tompkins RG, Kundakovic L, Tanzi RE. Developing Effective Alzheimer’s Disease Therapies: Clinical Experience and Future Directions. Abraham C, editor. Journal of Alzheimer’s Disease. 2019 Oct 1;71(3):715–32.
  12. JNJ-63733657 | ALZFORUM [Internet]. http://www.alzforum.org. Available from: https://www.alzforum.org/therapeutics/jnj-63733657
  13. Janssen Research & Development, LLC. A Randomized, Double-blind, Placebo-controlled, Parallel-group, Multicenter Study With a Long-Term Extension Treatment Period to Assess the Efficacy and Safety of JNJ-63733657, an Anti-tau Monoclonal Antibody, in Participants With Early Alzheimer’s Disease [Internet]. clinicaltrials.gov. 2024 [cited 2024 Jun 24]. Available from: https://clinicaltrials.gov/study/NCT04619420?intr=JNJ-63733657&rank=3
  14. Accelerating development of next-generation drugs for Alzheimer’s and related dementias [Internet]. National Institute on Aging. 2023 [cited 2024 Jun 24]. Available from: https://www.nia.nih.gov/research/blog/2023/11/accelerating-development-next-generation-drugs-alzheimers-and-related

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