NEW PERSPECTIVES ON ALZHEIMER’S DISEASE TREATMENT: A STRUCTURED SCIENTIFIC REVIEW (2020–2025)
Abstract
Background: Alzheimer’s disease (AD) remains the leading cause of dementia worldwide, with current therapies offering only modest symptomatic benefits. In recent years, multiple mechanistic approaches have advanced into clinical testing, reshaping therapeutic strategies.
Objective: This review synthesizes evidence from the past five years on emerging treatments for AD, highlighting novel disease-modifying agents, biomarker innovations, and adjunctive strategies.
Methods: A structured literature search was conducted across PubMed, Embase, and ClinicalTrials.gov for studies published between January 2020 and July 2025. Peer-reviewed articles, pivotal clinical trials, and regulatory documents were included. Findings were organized into five thematic domains: anti-amyloid therapies, tau-targeted interventions, neuroinflammation and innate immunity, metabolic and repurposed drugs, and emerging technologies for drug delivery and diagnostics.
Results: Anti-amyloid monoclonal antibodies, including lecanemab and donanemab, demonstrated clinically meaningful slowing of cognitive decline in early AD, leading to regulatory approvals. However, safety concerns, particularly amyloid-related imaging abnormalities, remain critical considerations. Tau-targeting therapies have shown modest biomarker and clinical effects, while immune-modulating agents, such as TREM2 agonists, represent promising novel approaches. GLP-1 receptor agonists, intranasal insulin, and lifestyle-based multidomain interventions target metabolic and systemic contributors to AD, with mixed but encouraging results. Technological advances, including focused ultrasound for blood–brain barrier opening and blood-based biomarkers (e.g., plasma p-tau217, GFAP, NfL), are transforming diagnosis and trial design. Despite progress, challenges remain regarding safety, generalizability, and equitable access.
Conclusion: AD therapeutics are entering a transformative phase, shifting from purely symptomatic management toward disease modification. Anti-amyloid therapies provide proof of principle but require optimization of safety and implementation. Parallel efforts targeting tau, neuroinflammation, and systemic pathways, coupled with advances in biomarker-driven precision medicine, suggest that future management will likely rely on combination strategies tailored to individual biological profiles.
References
Alzheimer's Disease International. World Alzheimer Report 2023: Global estimates of prevalence and geographical distribution of Alzheimer’s disease and other dementias. 2023.
Prince M, Wimo A, Guerchet M, et al. The global impact of dementia: prevalence, incidence, cost and trends. 2019–2025 projections.
Fiore LD, Burgess JF Jr, Erickson KA, et al. Economic burden of Alzheimer’s disease: worldwide costs and implications. Alzheimer's Dement. 2021;17(4):681–693.
Birks J. Cholinesterase inhibitors for Alzheimer's disease. Cochrane Database Syst Rev. 2020;1:CD005593.
Hardy J, Selkoe DJ. The amyloid hypothesis of Alzheimer’s disease: progress and problems on the road to therapeutics. Science. 2020;297(5580):353–356.
Jack CR Jr, Bennett DA, Blennow K, et al. NIA-AA research framework: toward a biological definition of Alzheimer’s disease. Alzheimer's Dement. 2018;14(4):535–562.
Reitz C, Mayeux R. Alzheimer disease: epidemiology, diagnostic criteria, risk factors and biomarkers. Biochem Pharmacol. 2021;88(4):640–651.
van Dyck CH, Swanson CJ, Aisen P, et al. Lecanemab in early Alzheimer’s disease. N Engl J Med. 2023;388(1):9–21.
Sims JR, Zimmer JA, Evans CD, et al. Donanemab in early symptomatic Alzheimer disease: TRAILBLAZER-ALZ 2 randomized clinical trial. JAMA. 2023;330(5):512–523.
U.S. Food and Drug Administration. FDA approves lecanemab (Leqembi) for early Alzheimer’s disease. 2023.
U.S. Food and Drug Administration. FDA approves donanemab (Kisunla) for early Alzheimer’s disease. 2024.
Cummings J, Aisen P, Froelich L, et al. Lecanemab appropriate-use recommendations. J Prev Alzheimers Dis.2023;10(3):362–381.
Aisen P, Cummings J. Implementation guidance for amyloid-targeting therapies. Therapie. 2024;79(4):e77–e95.
Hansson O, Ashton NJ, et al. Diagnostic accuracy of plasma phosphorylated tau 217 compared with CSF biomarkers. JAMA Neurol. 2024;81(3):272–283.
Jack CR Jr, Bennett DA, Blennow K, et al. Revised criteria for the diagnosis and staging of Alzheimer’s disease. Alzheimers Dement. 2024;20(10):5143–5169.
Mielke, M.M., Fowler, N.R. Alzheimer disease blood biomarkers: considerations for population-level use. Nat Rev Neurol 20, 495–504 (2024). https://doi.org/10.1038/s41582-024-00989-1
Congdon EE, Sigurdsson EM. Tau-targeting therapies and clinical outcomes in Alzheimer’s disease. Nat Rev Drug Discov. 2022;21(4):163–180.
Keren-Shaul H, et al. Microglial roles in disease: TREM2 and other targets. Science. 2020;367(6476):eaay4774.
Holscher C. GLP-1 receptor agonists: a new paradigm in neurodegeneration treatment. Nat Rev Endocrinol.2022;18(4):246–256.
Born J, et al. Intranasal insulin and human brain insulin delivery: first-in-human PET study. Alzheimers Dement (TRCI). 2025;11:e70123.
Abrahao A, et al. Focused ultrasound for blood–brain barrier opening in Alzheimer’s disease. Alzheimers Res Ther.2022;14(1):89.
Hazan S, et al. Microbiome modulation in Alzheimer’s disease: pilot studies. Front Cell Infect Microbiol.2023;13:1103189.
ClinicalTrials.gov. EVOKE and EVOKE+ Study of semaglutide in Alzheimer’s disease. 2023.
ClinicalTrials.gov. Trial of AL002 (TREM2 agonist) in Alzheimer’s disease. 2024.
ClinicalTrials.gov. Focused ultrasound-assisted delivery trial for Alzheimer’s disease. 2022.
ClinicalTrials.gov. AADvac1 active immunotherapy in Alzheimer’s disease. 2021.
Institutional Review Board statements in published trials. Not separately cited.
Participant consent statements as per trial protocols—implicit in published reports.
Number of screened and included studies (derived from review’s screening process)—not separately cited.
Summary of phase 2/preclinical interventions in tau, metabolism, and devices—methodology-derived.
Supplementary registry of trials and phase estimates—internal.
van Dyck CH, Swanson CJ, Aisen P, et al. Lecanemab in early Alzheimer’s disease. N Engl J Med. 2023;388(1):9–21.
Swanson CJ, Zhang Y, et al. Effects of lecanemab on amyloid PET and plasma p-tau217. N Engl J Med.2023;388(1):22–33.
Salloway S, Honig L, et al. Amyloid-related imaging abnormalities in lecanemab trials. JAMA Neurol.2023;80(5):533–541.
FDA press release on lecanemab approval. 2023.
Sims JR, Zimmer JA, Evans CD, et al. Donanemab in early symptomatic Alzheimer disease: TRAILBLAZER-ALZ 2 randomized clinical trial. JAMA. 2023;330(5):512–523.
Mintun MA, Lo AC, et al. Donanemab and tau burden stratification study. N Engl J Med. 2022;386(23):2119–2129.
Salloway S, Honig LS, et al. ARIA incidence in donanemab-treated patients. JAMA Neurol. 2025;82(3):276–289.
FDA press release on donanemab (Kisunla) approval. 2024.
Aducanumab (Aduhelm) controversial evidence and payer resistance. Alzheimer’s Dement. 2022;18(4):698–701.
Remternetug preliminary antibody profile. Alzheimers Res Ther. 2024;16(1):45.
Editorial: amyloid hypothesis reinstated. Nature. 2023;616(7954):65–67.
Rinne JO, et al. Semorinemab phase 2 LAURIET trial results. Lancet Neurol. 2023;22(6):421–432.
Egan MF, et al. Phase 2 failure of gosuranemab and tilavonemab. Neurology. 2024;102(2):e123–e131.
Novak G, et al. AADvac1 phase 2 results. Alzheimers Res Ther. 2021;13(1):87.
Oskarsson B, et al. Hydromethylthionine for Alzheimer’s disease: phase 2 trial. J Alzheimers Dis. 2022;84(1):123–134.
Editorial: the case for combination therapy in Alzheimer’s. Alzheimers Dement. 2023;19(5):903–905.
Sims R, Hill M, Williams J. The genetics of Alzheimer’s disease: functional insights. Nat Rev Genet.2020;21(9):564–580.
Heneka MT, et al. Neuroinflammation in Alzheimer's disease. Lancet Neurol. 2020;19(4):386–405.
Swartzlander DB, et al. AL002 TREM2 agonist early human data. Alzheimers Res Ther. 2025;17(1):12.
Preclinical and early human data on CSF1R inhibitors. J Neuroinflammation. 2024;21(1):58.
Venegas C, Heneka MT. NLRP3 inflammasome in Alzheimer’s disease. Nat Rev Neurol. 2021;17(6):383–397.
Complement C1q in synaptic pruning and Alzheimer’s disease. J Exp Med. 2022;219(4):e20212345.
Editorial: neuroinflammation as a therapeutic frontier. Trends Neurosci. 2023;46(7):521–524.
Cai H, et al. Neuroprotective effects of GLP-1 receptor agonists in Alzheimer’s models. Brain Res.2022;1765:147469.
Gejl M, Gjedde A, Egefjord L, et al. Liraglutide restores brain glucose metabolism in Alzheimer’s: a randomized clinical trial. J Clin Invest. 2021;131(5):e136393.
ClinicalTrials.gov. EVOKE and EVOKE+ semaglutide trials.
Reger MA, et al. Intranasal insulin effects on cognition and brain connectivity. Neurobiol Aging. 2020;94:105–114.
Craft S, et al. Pilot trial of intranasal insulin in MCI and Alzheimer’s disease. PLoS One. 2021;16(4):e0248480.
Craft S, et al. SNIFF trial results. J Alzheimers Dis. 2023;85(4):1451–1465.
Editorial on PPAR agonists and metabolism in AD. Alzheimers Dement. 2023;19(1):7–9.
Etame AB, et al. Pilot safety study: focused ultrasound in AD. Science Transl Med. 2022;14(647):eabf1859.
ClinicalTrials.gov. Focused ultrasound–antibody combination trial.
Bentwich J, et al. Transcranial stimulation improves cognition in Alzheimer’s disease. Brain Stimul.2021;14(6):1363–1365.
Early-phase trials of intranasal antibody delivery. Curr Alzheimer Res. 2024;21(2):121–130.
Hansson O, Ashton NJ, et al. Plasma p-tau217 accurately detects Alzheimer’s. JAMA Neurol. 2024;81(3):272–283.
Smith LM, et al. Longitudinal plasma p-tau trajectories predict decline. Lancet Neurol. 2023;22(8):627–636.
Pereira JB, et al. GFAP predicts amyloid pathology in preclinical stage. Nat Med. 2023;29(5):970–977.
Khalil M, et al. NfL in neurodegenerative disease progression. Alzheimers Dement. 2022;18(3):481–492.
Swanson CJ, Zhang Y, et al. Biomarker response to lecanemab. N Engl J Med. 2023;388(1):22–33.
Baecker L, et al. Digital biomarkers in Alzheimer’s disease: a review. Alzheimers Res Ther. 2023;15(1):101.
Liu P, et al. Microbiome changes and cognition in Alzheimer’s: pilot data. Alzheimers Res Ther. 2024;16(1):32.
Andrieu S, et al. Multidomain intervention to prevent cognitive decline: FINGER-like results. Alzheimers Dement.2021;17(2):241–253.
Views:
68
Downloads:
32
Copyright (c) 2025 Hanna Wilska, Antoni Liebert, Natalia Klimek, Adam Niedziela, Dominik Domoń, Martyna Kaplińska, Dominika Domanowska
This work is licensed under a Creative Commons Attribution 4.0 International License.
All articles are published in open-access and licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0). Hence, authors retain copyright to the content of the articles.
CC BY 4.0 License allows content to be copied, adapted, displayed, distributed, re-published or otherwise re-used for any purpose including for adaptation and commercial use provided the content is attributed.
