For decades, Alzheimer’s disease has challenged researchers and clinicians in their journey to find effective treatment strategies. The core hypothesis targeting amyloid beta plaques – aggregates that build up in patients’ brains and are considered a hallmark of Alzheimer’s disease – has been facing significant skepticism following numerous clinical trial failures. A Nature “Outlook” article by Simon Makin in April 2025 focuses on the long-requested shifts in perspective and new treatment possibilities in the near future.

Between 2004 and 2021, treatments targeting amyloid beta have been largely unsuccessful with few exceptions.

Lecanemab and donanemab:

These two drugs received approval from the FDA in 2023 and 2024, respectively, after demonstrating a slowing in cognitive decline by up to 30%. However, a closer look into the published phase 3 trial CLARITY AD of lecanemab revealed severe sex differences in clinical efficacy, as cognitive decline in female patients was only slowed by 12%. Additionally, the significant risk of ARIA, including brain swelling and bleeding, presents challenges that directly result from antibody treatment. The elevated genetically driven ARIA risk in homozygous APOE ε4 carriers therefore renders treatment in these cohorts inadvisable. Mitigating these risks, perhaps through innovations such as “brain shuttle” technologies that deliver drugs more precisely and efficiently through the blood brain barrier, is essential to reduce the amount of administered antibody, thereby enhancing the treatment ^{[1, 2, 3]}  .

Advances beyond immunologic clearance of amyloid beta have begun reshaping Alzheimer’s disease research and treatment:

• early intervention: The Ahead and Trailblazer-Alz 3 trials are exploring pre-symptomatic intervention, potentially reshaping current prevention efforts. Early detection through biomarker analysis could make Alzheimer’s disease preventable, shifting the therapeutic landscape dramatically. However, critical voices have mentioned the potential to over-diagnose asymptomatic individuals by biomarker diagnosis only, resulting in financial and psychological harm ^{[4, 5, 6]}.
• modulators instead of antibodies: Innovations such as γ-secretase modulators aim to control or prevent plaque formation. These could lead to simpler, cost-effective treatments widely accessible to broader populations without the need for clinical visits ^{[7, 8]}.

More than just amyloid beta: shaping a broader perspective

While amyloid beta remains an important factor, there’s growing consensus that the pathogenesis of Alzheimer’s involves multiple complex mechanisms that reach far beyond this specific protein:

• Tau proteins: Therapies targeting tau proteins, another long-known pathological feature of Alzheimer’s disease, are in early-stage trials, often combined with amyloid-targeting treatments for potentially greater effectiveness ^[9].
• Lysosomal dysfunction: A novel hypothesis proposed by Ralph A. Nixon emphasizes dysfunction in lysosomal pathways, especially cellular waste management, as an earlier driver of Alzheimer’s disease. Treatments correcting/restoring lysosomal acidification and function represent exciting new potential therapeutic avenues ^[10].
• Proteostasis and the unfolded protein response: Beyond lysosomal pathways, other proteostatic systems such as the ubiquitin-proteasome system and endoplasmic reticulum stress responses are being explored. Modulating these systems may help neurons clear or refold misfolded proteins more effectively ^[11].
• Neuroinflammation and microglial dysfunction: Chronic inflammation in the brain, often mediated by activated microglia, is increasingly seen as a critical contributor to neurodegeneration. Drugs targeting innate immune pathways (e.g., TREM2 modulation, CSF1R inhibitors) aim to rebalance microglial activity and reduce harmful neuroinflammatory cascades ^{[12, 13]}.
• Synaptic dysfunction and neurotransmitter imbalance: Long before plaques accumulate, Alzheimer’s may involve disrupted synaptic signaling. New therapies aim to protect synaptic integrity or restore neurotransmitter balance, such as glutamate regulation. For instance, modulators of mGluR5 are in preclinical testing ^[14].
• Mitochondrial dysfunction and metabolic failure: Defects in cellular energy conservation and mitochondrial function are being linked to early neuronal stress. Improvement of mitochondrial health, reduction in oxidative stress, and modulation of glucose metabolism (e.g., ketone-based interventions, insulin sensitizers) are under investigation ^{[15; 16; 17]}.
• Epigenetic and gene regulation therapies: Dysregulation of gene expression, including through microRNAs, histone modification, and DNA methylation, plays a role in Alzheimer’s progression. Drugs targeting epigenetic mechanisms (e.g., S-Adenosyl methionine) are still largely experimental but offer a potential way to modulate pathological gene expression ^[18].

While the recent success of amyloid beta-targeting therapies is seen as a breakthrough by supporters of the amyloid cascade hypothesis, the overall journey toward effective treatment remains incomplete. The complex nature of Alzheimer’s disease requires a multifaceted approach, addressing various pathological mechanisms simultaneously. Continued research, exploring early interventions and expanding beyond amyloid beta plaques, is essential for achieving more significant breakthroughs.

This article refers to:

Makin S (2025) The future of Alzheimer’s treatment. Nature 640, S4-S6. DOI: doi.org/10.1038/d41586-025-01102-2

Further references:

[1] FDA.gov (6 July 2023). FDA Converts Novel Alzheimer’s Disease Treatment to Traditional Approval. Retrieved 18 June 2025.

[2] Sperling RA, Jack CR, Black SE, Frosch MP, Greenberg SM, Hyman BT, Scheltens P, Carrillo MC, Thies W, Bednar MM, Black RS, Brashear HR, Grundman M, Siemers ER, Feldman HH, Schindler RJ (2011) Amyloid-related imaging abnormalities in amyloid-modifying therapeutic trials: recommendations from the Alzheimer’s Association Research Roundtable Workgroup. Alzheimers Dement 7:367–385. DOI: 10.1016/j.jalz.2011.05.2351

[3] Clinicaltrialsarena.com (4 April 2025). AD/PD 2025: Roche’s Brainshuttle technology promises next generation of amyloid beta mAbs. Retrieved 18 June 2025.

[4] Aheadstudy.org (2025). Retrieved 18 June 2025.

[5] Pugh MAM (2023) TRAILBLAZER‐ALZ 3 – A deeper dive into time‐to‐event trials. Alzheimer’s & Dementia 19. DOI: 10.1002/alz.070865

[6] American Geriatrics Society. (2023, November 16). American Geriatrics Society Response – Revised Criteria for Diagnosis and Staging of Alzheimer’s Disease: Alzheimer’s Association Workgroup. Retrieved July 18 June 2025.

[7] Yu HJ, Dickson SP, Wang P-N, Chiu M-J, Huang C-C, Chang C-C, Liu H, Hendrix SB, Dodart J-C, Verma A, Wang CY, Cummings J (2023) Safety, tolerability, immunogenicity, and efficacy of UB-311 in participants with mild Alzheimer’s disease: a randomised, double-blind, placebo-controlled, phase 2a study. EBioMedicine 94:104665. DOI: 10.1016/j.ebiom.2023.104665.

[8] Nordvall G, Lundkvist J, Sandin J (2023) Gamma-secretase modulators: a promising route for the treatment of Alzheimer’s disease. Front Mol Neurosci 16:1279740. DOI: 10.3389/fnmol.2023.1279740.

[9] Congdon EE, Ji C, Tetlow AM, Jiang Y, Sigurdsson EM (2023) Tau-targeting therapies for Alzheimer disease: current status and future directions. Nat Rev Neurol 19:715–736. DOI: 10.1038/s41582-023-00883-2.

[10] Nixon RA, Rubinsztein DC (2024) Mechanisms of autophagy-lysosome dysfunction in neurodegenerative diseases. Nat Rev Mol Cell Biol 25:926–946. DOI: 10.1038/s41580-024-00757-5.

[11] Scheper W, Nijholt DAT, Hoozemans JJM (2011) The unfolded protein response and proteostasis in Alzheimer disease: preferential activation of autophagy by endoplasmic reticulum stress. Autophagy 7:910–911. DOI: 10.4161/auto.7.8.15761.

[12] Long H, Simmons A, Mayorga A, Burgess B, Nguyen T, Budda B, Rychkova A, Rhinn H, Tassi I, Ward M, Yeh F, Schwabe T, Paul R, Kenkare-Mitra S, Rosenthal A (2024) Preclinical and first-in-human evaluation of AL002, a novel TREM2 agonistic antibody for Alzheimer’s disease. Alzheimers Res Ther 16:235. DOI: 10.1186/s13195-024-01599-1.

[13] Tamayanti WD, Lin JR, Ariyanti AD, Chang Y, Cheng HY, Huang CW, Ru WC, Wang CY, Hsieh TH, Lin UD, Pai CY, Tsai J-W, Chen H-K (2024) Safety of the CSF1R Inhibitor EI‐1071 in Human and Its Pharmacological Effects to Reduce Neuroinflammation and Improve Memory Function in a Mouse Model of Alzheimer’s Disease. Alzheimer’s & Dementia 20. DOI: 10.1002/alz.091161.

[14] Wang J, He Y, Chen X, Huang L, Li J, You Z, Huang Q, Ren S, He K, Schibli R, Mu L, Guan Y, Guo Q, Zhao J, Xie F (2024) Metabotropic glutamate receptor 5 (mGluR5) is associated with neurodegeneration and amyloid deposition in Alzheimer’s disease: A (18)FPSS232 PET/MRI study. Alzheimers Res Ther 16:9. DOI: 10.1186/s13195-024-01385-z.

[15] Carvalho C, Moreira PI (2023) Metabolic defects shared by Alzheimer’s disease and diabetes: A focus on mitochondria. Curr Opin Neurobiol 79:102694. DOI: 10.1016/j.conb.2023.102694.

[16] Ramezani M, Fernando M, Eslick S, Asih PR, Shadfar S, Bandara EMS, Hillebrandt H, Meghwar S, Shahriari M, Chatterjee P, Thota R, Dias CB, Garg ML, Martins RN (2023) Ketone bodies mediate alterations in brain energy metabolism and biomarkers of Alzheimer’s disease. Front Neurosci 17:1297984. DOI: 10.3389/fnins.2023.1297984.

[17] Koenig AM, Mechanic-Hamilton D, Xie SX, Combs MF, Cappola AR, Xie L, Detre JA, Wolk DA, Arnold SE (2017) Effects of the Insulin Sensitizer Metformin in Alzheimer Disease: Pilot Data From a Randomized Placebo-controlled Crossover Study. Alzheimer Dis Assoc Disord 31:107–113. DOI: 10.1097/WAD.0000000000000202.

[18] Gao X, Chen Q, Yao H, Tan J, Liu Z, Zhou Y, Zou Z (2022) Epigenetics in Alzheimer’s Disease. Front Aging Neurosci 14:911635. DOI: 10.3389/fnagi.2022.911635.