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Fighting Alzheimer’s Disease with Antibodies

One hypothesis of Alzheimer’s disease (AD) is the amyloid hypothesis. It proposes that amyloid-β (Aβ) plaques cause impairment in synaptic function and eventually neurodegeneration. The talk given by Dr. Sangram Sisodia was based on his research and the empirical article, The amyloid aducanumab reduces Aβ plaques in Alzheimer’s disease. It all provided support for the hypothesis as well as developed and tested an antibody-based immunotherapeutic approach to clear the plaques in prodromal and mild AD patients. The antibody, aducanumad, was derived from human memory B cells after screening for their ability to bind to Aβ aggregates. Before clinical studies, an analogue of aducanumad was tested on transgenic mice with Aβ plaques to prove that aducanumad can cross the blood-brain barrier, attach to the Aβ plaques, and clear them.

           

            The results of preclinical studies lead to a randomized, 12 month, double-blind, placebo-controlled, multi-dose clinical study of aducanumab in 165 patients with prodromal or mild AD at 33 sites in the US. The clinical studies show similar amyloid reduction in aducanumab-treated patients with both prodromal and mild AD as well as both ApoE ε4 carriers and non-carriers. The reduction is dose- dependent and the greatest slowing of clinical progression is with 10 mgkg^-1 dose. More than 10 kgmg^-1 of aducanumab produced amyloid-related imaging abnormalities (ARIA) which may lead to haemorrhages and clinical symptoms. The reduction is in all brain regions except in pons and sub-cortical white matter, and the binding is more prominent in parenchymal Aβ versus cerebral amyloid angiopathy lesions within brain vessel walls. The binding is also found on Aβ oligomeric forms and not on monomers. In addition, the binding of microglia to antibodies demonstrated the mechanism of Aβ clearance through microglia’s phagocytic activities. The clearance was detected after 6 months of treatment but clinical effects were not apparent until one year of treatment. However, all cognitive tests showed improvement.

           

            Currently, one of the greatest AD studies performed is on the world’s largest family with inherited genetic mutation in Yarumal, Colombia. This family is of Basque ancestry which has been isolated and had large families with intermarriage. This led to the fast spread of the mutation in clan of 5,000 people. This family has mutation carriers with early-onset AD and devising an early attack before the symptoms arise (about five years before) will show if the treatment slowed or prevented the symptoms. The treatment could be a drug that prevents plaques or vaccine that encourages the production of antibodies. The results from this study might benefit this suffering family as well as provide crucial information about AD that could lead to a cure.

Work Cited

Sevigny, J., Chiao, P., Bussiere, T., Weinreb, P. H., Williams, L., Maier, M., Dunstan, R., Salloway, S., Chen, T., Ling, Y., O’Gorman, J., Qian, F., Arastu, M., Li, M., Chollate, S., Brennan, M. S., Quintero-Monzon, O., Scannevin, R. H., Arnold, H. M., Engber, T., Rhodes, K., Ferrero, J., Hang, Y., Mikulskis, A., Grimm, J., Hock, C., Nitsch, R. M., & Sandrock, A. (2016). The antibody aducanumab reduces Aβ plaques in Alzheimer’s disease. Nature, 537, 50-56. doi: 10.1038/nature19323

D. (2014, February 03). Colombian Family Plagued With Early-Onset Alzheimer's. Retrieved May 03, 2017, from https://www.dementia.org/colombian-family-with-early-alzheimers-gene

Figure:

Kuwana, E. (2014, December 15). Alzheimer's Disease. Retrieved May 03, 2017, from https://faculty.washington.edu/chudler/alz.html