A pair of neurologists have published a review in Cell discussing the current state of Alzheimer’s therapies, including drugs in early development, treatments in clinical trials, and therapies that are prescribed today.
The -mab drugs
Monoclonal antibodies, drugs whose names end in -mab, have become the go-to approach for pharma companies seeking to develop anti-Alzheimer’s drugs. These treatments are meant to attack and remove amyloid beta plaques in the brain. They were built around the amyloid cascade hypothesis: the idea that Alzheimer’s is driven by the accumulation of its well-known plaques [1].
While these treatments had succeeded in mice, they have largely failed in people until very recently. Aducanumab enjoyed accelerated approval in 2021, although much of the Alzheimer’s research community considers this approval to be controversial [2]. Lecenemab has had more clinical success in slowing the progression of Alzheimer’s, and it received accelerated FDA approval in January and full approval in June.
-mab drugs, being based around the immune system, have had their own unique challenges in development. One common side effect of many novel -mabs is a form of brain swelling known as ARIA, which is more likely to happen to people with the dreaded APOE4 allele: the same allele that is heavily associated with an increased risk of Alzheimer’s disease [3].
Additionally, the problem with even the best -mab drugs is that they merely slow the rate of decline by approximately 30%, even when given to people at earlier stages of Alzheimer’s progression [4]. While -mabs are still the only direct Alzheimer’s therapies to have passed the clinical trial process at all, different approaches are clearly needed.
Time for tau?
Misfolded, insoluble tau aggregates have long been known to herald Alzheimer’s, although the effects of targeting tau have remained unclear. First-generation tau therapies, which remove all forms of the protein, have been found to be ineffective [5]. After examining the results of Alzheimer’s -mabs and their variable effects on tau, these researchers hypothesize that directly targeting tau may not be effective at all.
However, a second generation of anti-tau therapies, which target only the toxic variants of the protein, are in early clinical trials [6]. One of these potential treatments has been found in one of these early trials to reduce tau in the human brain, although its clinical effects are not yet clear [7]. The National Institutes of Health intends to test tau-based therapies by combining them with anti-amyloid therapies in the upcoming Alzheimer’s Tau Platform trial.
Other targets
The amyloid beta plaques of Alzheimer’s disease are often accompanied by other biomarkers, including TDP-43 [8], which is itself part of frontotemporal dementia, and a-synuclein [9], the protein associated with Parkinson’s disease. The authors note that these elements impact Alzheimer’s progression and could be a reason why some therapies are less effective than they otherwise would be. They also note that Alzheimer’s is accompanied by a general loss of proteostasis.
In this vein, the authors point out that therapies that target proteostasis mechanisms may impact several related pathologies at once [10]. The protein maintenance protein ubiquitin and related compounds, such as the ligase TRIM11, have been noted as a potential target of such approaches. Many other protein-related neuropathies are particular to specific mutations, and other mutations are noted to be protective.
A problem with testing
The authors note a potential problem with -mabs becoming part of the standard of care. Combining amyloid and non-amyloid approaches would increase the risk of ARIA and other adverse events, and it would be difficult to get people to stop their existing Alzheimer’s medication to take part in a placebo-controlled study. Additionally, needing to test multiple combinations of drugs greatly increases the cost and time required for testing.
Umbrella approaches, which have multiple arms, along with basket approaches, which are used in cancer treatment, have also been suggested. In an umbrella trial, one arm can be stopped if it is not showing effectiveness. A basket trial would test multiple kinds of neurodegeneration with the same compound, potentially decreasing cost and increasing efficiency.
The authors are, ultimately, optimistic about the future of treatments for Alzheimer’s disease. If a combination therapy can wipe away the accumulations of amyloid beta and tau that are its hallmarks, restoring protein levels to normal and removing the amyloid aggregates both inside and outside cells, this would presumably stave off Alzheimer’s disease and prevent the associated creeping dementia that has taken so many people’s lives and selves.
Literature
[1] Hardy, J. A., & Higgins, G. A. (1992). Alzheimer’s disease: the amyloid cascade hypothesis. Science, 256(5054), 184-185.
[2] Rabinovici, G. D. (2021). Controversy and progress in Alzheimer’s disease—FDA approval of aducanumab. New England Journal of Medicine, 385(9), 771-774.
[3] Sperling, R. A., Jack Jr, C. R., Black, S. E., Frosch, M. P., Greenberg, S. M., Hyman, B. T., … & Schindler, R. J. (2011). Amyloid-related imaging abnormalities in amyloid-modifying therapeutic trials: recommendations from the Alzheimer’s Association Research Roundtable Workgroup. Alzheimer’s & Dementia, 7(4), 367-385.
[4] Sims, J. R., Zimmer, J. A., Evans, C. D., Lu, M., Ardayfio, P., Sparks, J., … & Kaul, S. (2023). Donanemab in early symptomatic Alzheimer disease: the TRAILBLAZER-ALZ 2 randomized clinical trial. Jama, 330(6), 512-527.
[5] Tsai, R. M., Miller, Z., Koestler, M., Rojas, J. C., Ljubenkov, P. A., Rosen, H. J., … & Boxer, A. L. (2020). Reactions to multiple ascending doses of the microtubule stabilizer TPI-287 in patients with Alzheimer disease, progressive supranuclear palsy, and corticobasal syndrome: a randomized clinical trial. JAMA neurology, 77(2), 215-224.
[6] Ji, C., & Sigurdsson, E. M. (2021). Current status of clinical trials on tau immunotherapies. Drugs, 81(10), 1135-1152.
[7] Mummery, C. J., Börjesson-Hanson, A., Blackburn, D. J., Vijverberg, E. G., De Deyn, P. P., Ducharme, S., … & Lane, R. M. (2023). Tau-targeting antisense oligonucleotide MAPTRx in mild Alzheimer’s disease: a phase 1b, randomized, placebo-controlled trial. Nature Medicine, 1-11.
[8] Nelson, P. T., Brayne, C., Flanagan, M. E., Abner, E. L., Agrawal, S., Attems, J., … & Schneider, J. A. (2022). Frequency of LATE neuropathologic change across the spectrum of Alzheimer’s disease neuropathology: Combined data from 13 community-based or population-based autopsy cohorts. Acta neuropathologica, 144(1), 27-44.
[9] Mehta, R. I., & Schneider, J. A. (2021). What is ‘Alzheimer’s disease’? The neuropathological heterogeneity of clinically defined Alzheimer’s dementia. Current opinion in neurology, 34(2), 237-245.
[10] Wilson, D. M., Cookson, M. R., Van Den Bosch, L., Zetterberg, H., Holtzman, D. M., & Dewachter, I. (2023). Hallmarks of neurodegenerative diseases. Cell, 186(4), 693-714.
