Immunotherapies for Alzheimer’s Disease—A Review

Abstract

Alzheimer’s disease (AD) is a chronic neurodegenerative disorder that falls under the umbrella of dementia and is characterised by the presence of highly neurotoxic amyloid-beta (Aβ) plaques and neurofibrillary tangles (NFTs) of tau protein within the brain. Historically, treatments for AD have consisted of medications that can slow the progression of symptoms but not halt or reverse them. The shortcomings of conventional drugs have led to a growing need for novel, effective approaches to the treatment of AD. In recent years, immunotherapies have been at the forefront of these efforts. Briefly, immunotherapies utilise the immune system of the patient to treat a condition, with common immunotherapies for AD consisting of the use of monoclonal antibodies or vaccines. Most of these treatments target the production and deposition of Aβ due to its neurotoxicity, but treatments specifically targeting tau protein are being researched as well. These treatments have had great variance in their efficacy and safety, leading to a constant need for the research and development of new safe and effective treatments.

Current Advances of Plant-Based Vaccines for Neurodegenerative Diseases

“…Active CD4+ T cells interplay with those B cells that share the same peptide-MHC II complex and stimulate them to undergo cell proliferation, Ig class-switching, differentiating into plasma cells that can secrete highly antigen-specific antibodies and produce memory B cells [ 71 , 76 ]. Lastly, the produced antibodies might reach and cross the blood-brain barrier through circulation and selectively bind to aberrant disease-associated proteins present in NDDs [ 50 , 77 ]. Once in the brain, the antibodies might mediate different processes to eliminate these proteins, such as blocking the formation of protein aggregates, disabling existing protein aggregates by changing their conformation, and/or acting as markers for microglial cells to phagocytose aberrant proteins and their aggregates [ 50 , 77 ].…”

“…Lastly, the produced antibodies might reach and cross the blood-brain barrier through circulation and selectively bind to aberrant disease-associated proteins present in NDDs [ 50 , 77 ]. Once in the brain, the antibodies might mediate different processes to eliminate these proteins, such as blocking the formation of protein aggregates, disabling existing protein aggregates by changing their conformation, and/or acting as markers for microglial cells to phagocytose aberrant proteins and their aggregates [ 50 , 77 ]. Furthermore, vaccines may be focused on inducing the production of antibodies targeting the enzymes responsible for the synthesis of aberrant proteins in order to block their activity [ 78 ].…”

AmyP53 Prevents the Formation of Neurotoxic β-Amyloid Oligomers through an Unprecedent Mechanism of Interaction with Gangliosides: Insights for Alzheimer’s Disease Therapy

“…Unfortunately, this approach has been unsuccessful because even if such treatments could actually decrease the burden of the amyloid plaques in the patients’ brains, they did not improve their cognitive status nor stop the evolution of the disease [ 8 ]. Thus, most immunotherapies with monoclonal antibodies targeting amyloid plaques have failed [ 9 , 10 ]. The only exception is Lecanemab, an antibody claimed to be more specific to Aβ protofibrils with limited cross-reaction with Aβ 1–42 monomers or amyloid plaques [ 11 ].…”

Could routine vaccinations prevent dementia?

“…5 For example, key risk factors in dementia pathogenesis including ageing, hypertension, alcohol intake, obesity, smoking, diabetes and depression, 2 are all associated with inflammation. [6][7][8][9][10][11] Novel treatment approaches have targeted the immune system aiming to destroy amyloid plaques, but are showing limited benefit thus far in clinical trials 12 : for example, aducanumab, which was recently approved in the USA 13 (though its marketing application in Europe was withdrawn due to concerns that benefits did not outweigh risks 14 ), and solanezumab. Other treatments such as Lecanemab, Gantenerumab, and Donanemab have followed similar rationales.…”