Neurological conditions, such as Alzheimer’s disease (AD) and tau-related pathologies, represent a substantial worldwide health dilemma. This review explores recent advancements and challenges in single-domain antibody (VHH)-based strategies targeting beta-secretase 1 (BACE1) inhibition and tau-related therapeutics. The methodology adopted in this study involved a comprehensive search of databases (e.g., Scopus, PubMed, and Google Scholar), with recent articles cited to provide an up-to-date overview. The research examines the limitations of current AD treatments, emphasizing the need for innovative techniques. We, further, discuss potential gene transfer methods using adeno-associated virus-based vectors for central nervous system delivery of single-domain immunoglobins/antibodies (VHHs) to inhibit BACE1. In addition, insights into anti-tau therapeutics, including passive immunization and active vaccines, offer novel insights into research. These findings hold implications for the redesign of therapies for neurodegenerative disorders and the advancement of clinical understanding.

1. Alzheimer’s Association. Alzheimer’s disease facts and figures. Alzheimers Dement. 2022;18:700-789. doi: 10.1002/alz.12638

2. Panza F, Lozupone M, Seripa D, Imbimbo BP. Amyloid-β immunotherapy for Alzheimer disease: Is it now a long shot? Ann Neurol. 2019;85(2):303-315. doi: 10.1002/ana.25415

3. Kabir MT, Uddin MS, Mamun AA, et al. Combination drug therapy for the management of Alzheimer’s disease. Int J Mol Sci. 2020;21:3272. doi: 10.3390/ijms21093272

4. Wolfe MS. Probing mechanisms and therapeutic potential of γ-Secretase in Alzheimer’s disease. Molecules. 2021;26(2):388. doi: 10.3390/molecules26020388

5. Sagnou M, Mavroidi B, Kaminari A, Boukos N, Pelecanou M. Novel isatin thiosemicarbazone derivatives as potent inhibitors of β-Amyloid peptide aggregation and toxicity. ACS Chem Neurosci. 2020;11(16):2266-2276. doi: 10.1021/acschemneuro.0c00364

6. Knopman DS, Amieva H, Petersen RC, et al. Alzheimer disease. Nat Rev Dis Primers. 2021;7:33. doi: 10.1038/s41572-021-00304-9

7. Roda AR, Montoliu-Gaya L, Serra-Mir G, Villegas S. Both amyloid-β peptide and tau protein are affected by an anti-amyloid-β antibody fragment in elderly 3xtg-ad mice. Int J Mol Sci. 2020;21:6630. doi: 10.3390/ijms21010306

8. Busche MA, Hyman BT. The synergy between amyloid-β and tau in Alzheimer’s disease. Nat Neurosci. 2020;23:1183-1193. doi: 10.1038/s41593-020-00742-1

9. Tolar M, Abushakra S, Hey JA, Porsteinsson A, Sabbagh M. Aducanumab, gantenerumab, BAN2401, and ALZ-801 - the first wave of amyloid-targeting drugs for Alzheimer’s disease with potential for near-term approval. Alzheimers Res Ther. 2020;12:95. doi: 10.1186/s13195-020-00670-3

10. Singh Gautam A, Pandey SK, Lasure V, Dubey S, Singh RK. Monoclonal antibodies for the management of central nervous system diseases: Clinical success and future strategies. Expert Opin Biol Ther. 2023;23(7):603-618. doi: 10.1080/14712598.2023.2098875

11. Das B, Yan R. A close look at BACE1 inhibitors for Alzheimer’s disease treatment. CNS Drugs. 2019;33(3):251-263. doi: 10.1007/s40263-019-00623-4

12. Lu RM, Hwang YC, Liu IJ, et al. Development of therapeutic antibodies for the treatment of diseases. J Biomed Sci. 2020;27:1. doi: 10.1186/s12929-019-0602-2

13. Pothin E, Lesuisse D, Lafaye P. Brain delivery of single-domain antibodies: A focus on VHH and VNAR. Pharmaceutics. 2020;12:937. doi: 10.3390/pharmaceutics12100937

14. Marino M, Zhou L, Rincon MY, et al. AAV-mediated delivery of an anti-BACE1 VHH alleviates pathology in an Alzheimer’s disease model. EMBO Mol Med. 2022;14:e09824. doi: 10.15252/emmm.202009824

15. Yadav DB, Maloney JA, Wildsmith KR, et al. Widespread brain distribution and activity following i.c.v. infusion of anti-β-secretase (BACE1) in nonhuman primates. Br J Pharmacol. 2017;174(23):4173-4185. doi: 10.1111/bph.14055

16. Burns S, Selman A, Sehar U, Rawat P, Reddy AP, Reddy PH. Therapeutics of Alzheimer’s disease: Recent developments. Antioxidants (Basel). 2022;11(12):2402. doi: 10.3390/antiox11122402

17. Rawat P, Sehar U, Bisht J, Selman A, Culberson J, Hemachandra Reddy P. Phosphorylated Tau in Alzheimer’s disease and other tauopathies. Int J Mol Sci. 2022;23:12841. doi: 10.3390/ijms232112841

18. Sexton C, Snyder H, Beher D, et al. Current directions in tau research: Highlights from Tau 2020. Alzheimers Dement. 2022;18:988-1007. doi: 10.1002/alz.12452

19. Golde TE. Disease-modifying therapies for Alzheimer’s disease: More questions than answers. Neurotherapeutics. 2022;19:209-227. doi: 10.1007/s13311-022-01201-2

20. Brunello CA, Merezhko M, Uronen RL, Huttunen HJ. Mechanisms of secretion and spreading of pathological tau protein. Cell Mol Life Sci. 2020;77(9):1721-1744. doi: 10.1007/s00018-019-03349-1

21. Panza F, Lozupone M. The challenges of anti-tau therapeutics in Alzheimer’s disease. Nat Rev Neurol. 2022;18:577-578. doi: 10.1038/s41582-022-00702-0

22. Plotkin SS, Cashman NR. Passive immunotherapies targeting Aβ and tau in Alzheimer’s disease. Neurobiol Dis. 2020;144:105010. doi: 10.1016/j.nbd.2020.105010

23. Parrocha CMT, Nowick JS. Current peptide vaccine and immunotherapy approaches against Alzheimer’s disease. Pept Sci (Hoboken). 2023;115:e24289. doi: 10.1002/pep2.24289

24. Galpern WR, Mercken M, Van Kolen K, et al. A single ascending dose study to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of the anti-phospho-tau antibody JNJ-63733657 in healthy subjects. Alzheimers Dement. 2019;15(7S_Part_5):P252-P253. doi: 10.1016/j.jalz.2019.06.077

25. Guo X, Yan L, Zhang D, Zhao Y. Passive immunotherapy for Alzheimer’s disease. Ageing Res Rev. 2024;94:102192. doi: 10.1016/j.arr.2024.102192

26. Jurcau A, Nunkoo VS. Tau-targeted therapy in Alzheimer’s disease-history and current state. Front Clin Drug Res Dementia. 2021;2:56.

27. Novak P, Zilka N, Zilkova M, et al. AADvac1, an active immunotherapy for Alzheimer’s disease and non-Alzheimer tauopathies: An overview of preclinical and clinical development. J Prev Alzheimers Dis. 2019;6:63-69. doi: 10.14283/jpad.2018.45