Meenakshi Dara

Background: Alzheimer’s disease (AD) is the leading cause of dementia worldwide and affects over 50 million people globally.¹ This neurodegenerative disorder is characterized by cognitive decline, memory loss, and behavioral changes that ultimately lead to a loss of independence in patients.¹ Pathologically, AD is characterized by the initial extracellular accumulation of amyloid-beta (Aβ) plaques, followed by the later formation of hyperphosphorylated tau aggregates called neurofibrillary tangles (NFTs) within neurons.² The mechanism linking these two pathologies has remained unclear. However, recent evidence suggests that Aβ, along with co-pathologies such as alpha-synuclein (α-syn), may enhance tau aggregation, promote its spread across connected brain regions, and activate molecular signaling pathways that contribute to neurodegeneration.^3,4,5,6 Current therapies for AD primarily focus on clearing Aβ plaque accumulation.⁷ A better understanding of the mechanisms that connect Aβ and tau pathology could reveal new therapeutic targets and support the development of more effective treatments for AD.

Objective: The purpose of this review is to discuss the mechanisms linking Aβ accumulation to tau aggregation in AD and their potential implications for therapeutic strategies.

Search Methods: An online PubMed search was conducted from 2017 to 2025 using the following keywords: “amyloid-β,” “amyloid-beta,” “amyloid-beta accumulation,” “tau,” “tau aggregation,” “Alzheimer’s disease,” “Alzheimer’s treatment,” and “clinical trials Alzheimer’s disease.”

Results: Studies have shown that Aβ caused tau aggregation and spread in AD mouse models through seeding events.³ Aβ initially caused tau to accumulate near dystrophic axons and form neuritic plaque (NP) tau.³ This NP tau spreads to other parts of the neuron, forming NFTs and neuropil threads (NTs) through secondary seeding events.³ The NFTs and NTs then spread to connected brain regions, disrupting neuronal circuits and causing behavioral deficits in mice.³ Additionally, research shows that the plexin-A4 receptor is required for Aβ to phosphorylate tau.⁴ Aβ binds plexin-A4 with its co-receptor neuropilin-2 and initiates a signaling cascade that activates cyclin-dependent kinase 5 (CDK5).⁴ CDK5 phosphorylates tau and causes the formation of NFTs.⁴ Furthermore, Aβ promotes tau spread by increasing neural connectivity.⁵ Aβ was associated with increased functional connectivity between tau epicenters and other brain regions even before widespread tau deposition.⁵ Patients with stronger connectivity had faster spread and accumulation of tau.⁵ Additionally, α-syn was found to enhance Aβ’s effects on tau aggregation in AD individuals.⁶ Individuals who were positive for α-syn pathology had faster Aβ-related tau accumulation, higher levels of phosphorylated tau, and greater tau aggregation.⁶ Clinical trials for treatments targeting Aβ support these findings. A recent trial for Donanemab, an antibody designed to target Aβ, showed that individuals with early symptomatic AD had reduced Aβ plaques and a 34% slowing of tau accumulation following treatment.⁷

Conclusions: The studies discussed above suggest that Aβ drives tau pathology through several mechanisms, including triggering early tau aggregation, promoting tau phosphorylation via the plexin-A4 receptor, and increasing tau spread through enhanced brain connectivity.^3,4,5 Additionally, α-syn exacerbates Aβ’s effects on tau aggregation.⁶ Clinical trial results from Donanemab show that Aβ plaque reduction slows tau accumulation, supporting preclinical findings.⁷ These mechanisms highlight potential targets for therapies aimed at disrupting Aβ-mediated tau pathology in AD.

Works Cited:

1. Breijyeh Z, Karaman R. Comprehensive Review on Alzheimer’s Disease: Causes and Treatment. Molecules. 2020;25(24):5789. Published 2020 Dec 8. doi:10.3390/molecules25245789
2. Zhang Y, Chen H, Li R, Sterling K, Song W. Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future. Signal Transduct Target Ther. 2023;8(1):248. Published 2023 Jun 30. doi:10.1038/s41392-023-01484-7
3. He Z, Guo JL, McBride JD, et al. Amyloid-β plaques enhance Alzheimer’s brain tau-seeded pathologies by facilitating neuritic plaque tau aggregation. Nat Med. 2018;24(1):29-38. doi:10.1038/nm.4443
4. Chung S, Yang J, Kim HJ, et al. Plexin-A4 mediates amyloid-β-induced tau pathology in Alzheimer’s disease animal model. Prog Neurobiol.2021;20 3:102075. doi:10.1016/j.pneurobio.2021.102075
5. Roemer-Cassiano SN, Wagner F, Evangelista L, et al. Amyloid-associated hyperconnectivity drives tau spread across connected brain regions in Alzheimer’s disease. Sci Transl Med. 2025;17(782):eadp2564. doi:10.1126/scitranslmed.adp2564
6. Franzmeier N, Roemer-Cassiano SN, Bernhardt AM, et al. Alpha synuclein copathology is associated with accelerated amyloid-driven tau accumulation in Alzheimer’s disease. Mol Neurodegener. 2025;20(1):31. Published 2025 Mar 18. doi:10.1186/s13024-025-00822-3
7. Shcherbinin S, Evans CD, Lu M, et al. Association of Amyloid Reduction After Donanemab Treatment With Tau Pathology and Clinical Outcomes:  -ALZ Randomized Clinical Trial. JAMA Neurol. 2022;79(10):10151024. doi:10.1001/jamaneurol.2022.2793