INTRODUCTION: Without disease-modifying interventions, Medicare and Medicaid spending on Alzheimer's disease (AD) management is expected to reach 637 billion USD annually by 2050. The recent advent of promising AD therapies after decades of a near-total failure rate in clinical trials suggests that more disease-modifying therapies are on the horizon. In this review, we assess the late-stage pipeline of disease-modifying candidates for AD and offer a novel classification of intervention candidates by treatment paradigms-groups of candidates that share an underlying biological mechanism of action and general disease target. METHODS: We extracted data from the National Library of Medicine clinical trials database regarding Phase 2 and 3 trials of disease-modifying AD therapies. We categorized trials into eight unique treatment paradigms, which we defined by combinations of therapy (biologic, small molecule, cell and gene therapy, other) and target (amyloid, tau, other). We analyzed primary endpoints, eligibility criteria including clinical ratings of cognition, trial phase and length, and funding sources. RESULTS: We identified 123 unique disease-modifying intervention candidates in 175 late-stage clinical trials. Biologic and small molecule drugs comprised 30% and 54% of trials, respectively. Eligibility criteria favored patients between the ages of 60 and 80 years with mild cognitive impairment. Including multi-phase trials, 81% of studies were engaged in Phase 2 and 27% in Phase 3. Notably, within the Biologic-Amyloid paradigm, 64% of trials were engaged in Phase 3. DISCUSSION: Current studies of disease-modifying therapies for AD comprise a diverse set of approaches to treating the disease. However, effort is largely concentrated in a few treatment paradigms and a narrow patient population, causing varying rates of progress among treatment paradigms in the late-stage clinical trial pipeline. Strategies may be warranted to accelerate successes in the most promising therapeutical paradigms and nurture growth within nascent areas lacking resources but not potential. HIGHLIGHTS: An analysis of Alzheimer's disease trial treatment paradigms was conducted.From April 2021 to March 2023, 175 trials of 123 unique candidates were reviewed.Biologic and small molecule drugs comprised 30% and 54% of trials, respectively.Eligibility criteria favored ages 60 through 80 with mild cognitive impairment.

Department of Neurology 2nd Faculty of Medicine and Motol University Hospital Charles University Prague Czech Republic

Health Economics Policy and Innovation Institute Faculty of Economics and Administration Masaryk University Brno Czech Republic

Leonard Davis School of Gerontology University of Southern California Los Angeles California USA

Sol Price School of Public Policy Leonard D Schaeffer Center for Health Policy and Economics University of Southern California Los Angeles California USA

Univeristy of California Irvine School of Medicine Irvine California USA

University of Arizona College of Medicine Phoenix Pheonix Arizona USA

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Alzheimer's Association . Costs of Alzheimer's to Medicare and Medicaid. Alzheimer's Impact Movement. Published 2024. Accessed November 25, 2024. https://portal‐legacy.alzimpact.org/media/serve/id/62509c7a54845

2023 Alzheimer's disease facts and figures 2023. Alzheimers Dementia. 2023;19:1598‐1695. doi:10.1002/alz.13016 PubMed DOI

Cummings JL, Goldman DP, Simmons‐Stern NR, Ponton E. The costs of developing treatments for Alzheimer's disease: a retrospective exploration. Alzheimers Dement. 2022;18:469‐477. doi:10.1002/alz.12450 PubMed DOI PMC

Biogen . Biogen to Realign Resources for Alzheimer's Disease Franchise. Published 2024. Accessed November 25, 2024. https://investors.biogen.com/news‐releases/news‐release‐details/biogen‐realign‐resources‐alzheimers‐disease‐franchise

van Dyck CH, Swanson CJ, Aisen P, et al. Lecanemab in early Alzheimer's disease. N Engl J Med. 2023;388:9‐21. doi:10.1056/NEJMoa2212948 PubMed DOI

Sims JR, Zimmer JA, Evans CD, et al. Donanemab in early symptomatic Alzheimer disease: the TRAILBLAZER‐ALZ 2 randomized clinical trial. JAMA. 2023;330:512‐527. doi:10.1001/jama.2023.13239 PubMed DOI PMC

Aisen PS, Bateman RJ, Carrillo M, et al. Platform trials to expedite drug development in Alzheimer's disease: a report from the EU/US CTAD task force. J Prev Alzheimers Dis. 2021;8:306‐312. doi:10.14283/jpad.2021.21 PubMed DOI PMC

National Library of Medicine . About ClinicalTrials.gov | ClinicalTrials.gov. Published 2024. Accessed November 25, 2024. https://www.clinicaltrials.gov/about‐site/about‐ctg

Food and Drug Administration . FDA Grants Accelerated Approval for Alzheimer's Drug. FDA; 2021. https://www.fda.gov/news‐events/press‐announcements/fda‐grants‐accelerated‐approval‐alzheimers‐drug

Food and Drug Administration . FDA Grants Accelerated Approval for Alzheimer's Disease Treatment. FDA; 2023. https://www.fda.gov/news‐events/press‐announcements/fda‐grants‐accelerated‐approval‐alzheimers‐disease‐treatment

Eli Lilly and Co . Lilly's donanemab significantly slowed cognitive and functional decline in phase 3 study of early Alzheimer's disease. Eli Lilly and Company; 2023. https://investor.lilly.com/news‐releases/news‐release‐details/lillys‐donanemab‐significantly‐slowed‐cognitive‐and‐functional

Alzforum . Trontinemab. Published 2023. Accessed November 25, 2024. https://www.alzforum.org/therapeutics/trontinemab

Hoffmann‐La Roche . A Phase III, multicenter, randomized, double‐blind, placebo‐controlled, parallel‐group, efficacy and safety study of Crenezumab in patients with prodromal to mild Alzheimer's disease. clinicaltrials.gov; 2020.

Filippi M, Cecchetti G, Spinelli EG, Vezzulli P, Falini A, Agosta F. Amyloid‐related imaging abnormalities and β‐amyloid‐targeting antibodies: a systematic review. JAMA Neurol. 2022;79:291‐304. doi:10.1001/jamaneurol.2021.5205 PubMed DOI

Cummings JL, Gonzalez MI, Pritchard MC, May PC, Toledo‐Sherman LM, Harris GA. The therapeutic landscape of tauopathies: challenges and prospects. Alzheimers Res Ther. 2023;15:168. doi:10.1186/s13195-023-01321-7 PubMed DOI PMC

Chakari‐Khiavi F, Dolati S, Chakari‐Khiavi A, et al. Prospects for the application of mesenchymal stem cells in Alzheimer's disease treatment. Life Sci. 2019;231:116564. doi:10.1016/j.lfs.2019.116564 PubMed DOI

Knight E, Geetha T, Broderick TL, Babu JR. The role of dietary antioxidants and their potential mechanisms in Alzheimer's disease treatment. Metabolites. 2023;13:438. doi:10.3390/metabo13030438 PubMed DOI PMC

Weiler M, Stieger KC, Long JM, Rapp PR. Transcranial magnetic stimulation in Alzheimer's disease: are we ready? eNeuro. 2020;7. doi:10.1523/ENEURO.0235-19.2019 PubMed DOI PMC

Arendash G, Cao C, Abulaban H, et al. A clinical trial of transcranial electromagnetic treatment in Alzheimer's disease: cognitive enhancement and associated changes in cerebrospinal fluid, blood, and brain imaging. J Alzheimers Dis. 2019;71(1):57‐82. doi:10.3233/JAD-190367 PubMed DOI PMC

Reich N, Hölscher C. The neuroprotective effects of glucagon‐like peptide 1 in Alzheimer's and Parkinson's disease: an in‐depth review. Front Neurosci. 2022;16:970925. doi:10.3389/fnins.2022.970925 PubMed DOI PMC

Yu JC, Hlávka JP, Joe E, Richmond FJ, Lakdawalla DN. Impact of non‐binding FDA guidances on primary endpoint selection in Alzheimer's disease trials. Alzheimers Dement. 2022;8:e12280. doi:10.1002/trc2.12280 PubMed DOI PMC

Food and Drug Administration . Early Alzheimer's disease: developing drugs for treatment, Draft guidance. FDA; 2024.

Cummings J, Lee G, Nahed P, et al. Alzheimer's disease drug development pipeline: 2022. Alzheimers Dement Transl Res Clin Interv. 2022;8:e12295. doi:10.1002/trc2.12295 PubMed DOI PMC

Huang LK, Kuan YC, Lin HW, Hu CJ. Clinical trials of new drugs for Alzheimer disease: a 2020‐2023 update. J Biomed Sci. 2023;30:83. doi:10.1186/s12929-023-00976-6 PubMed DOI PMC