TABLE 1.

Monoclonal Antibodies (MABs) Developed to Target Amyloid Plaques. Abbreviations: ARIA-E − Amyloid-Related Imaging Abnormalities with Edema; ARIA-H microhaemorrhages, or small hemorrhages and hemosiderosis; Clinical Dementia Rating Sum of Boxes (CDR-SB), is a scale that assesses both function and cognition; Institute for Clinical and Economical Review–ICER; IV–intravenous administration; SC–subcutaneous administration.

MAB	Status	Results	Negative effects	Controversies	Key references
Aducanumab	2 trials of patients with MCI and confirmed amyloid pathology aged 50–85: 1638 subjects in EMERGE and 647 in ENGAGE.	Primary objective met in EMERGE but not in ENGAGE–based on Clinical Dementia Rating Sum of Boxes (CDR-SB)	i. ARIAs, were experienced by more than 40% of patients taking aducanumab and dose-dependent, of whom 7.5% were symptomatic (Sevigny et al., 2016). ARIASs were more frequent in patients carrying the ApoE4 allele, and most frequent for those who carry the ApoE4 4/4 versus 4/3 or 3/3 alleles (Kwan et al., 2020)	i. Three FDA resigned alleging absence of evidence of effectiveness	Mahase 2021a, b, c
IV (human MAB derived from a blood lymphocyte library of elderly people without any evidence of cognitive impairment)Biogen	FDA approved June 2021		ii. Conflicting evidence from 2 trials presented at the November 2020 meeting of the FDA’s Peripheral and CNS Drug Advisory Committee meeting with some data favouring the placebo (Dr. Krudys)	ii, 2021 not approved in Europe	Budd Haeberlein et al. (2022)
Has strong avidity for epitope-rich insoluble amyloid plaques and oligomers rather than amyloid monomers. spares amyloid monomers, which have putative protective actions half-life of approximately 25 days (Beshir et al., 2022)	July 2021 use restricted to MCI.			iii. June 2022 Biogen withdraws review from Health Canada	Arndt et al. (2018)
	In early 2024 Biomega announces availability of aducanumab will end in late 2024				Tolar et al. (2020)
					Decourt et al., 2021; Haddad et al., 2022
					Whitehouse and Saini (2022)
					Rahman et al. (2023)
					Wojtunik-Kulesza et al. (2023)
					Ackley et al., 2021
					Richard et al. (2022)
Bapineuzumab (humanized MAB)	2012: Failed two Phase III trials	Failed to produce significant cognitive improvements; despite lowering Aβ, and also phosphorylate tau in CSF.	First MAB to be associated with ARIA-E		Miles et al. (2013)
Pfizer and Johnson and Johnson	Discontinued 2013		6% developed aseptic meningitis		Abushouk et al., 2017
SC
Binds to the N-terminal of Aβ residues 1–5
Donanemab (humanized)	TRAILBLAZER-ALZ Phase III trials	Significant improvement noted at 76 weeks			Mintun et al., 2021
Eli-Lilly					Sims et al. (2023)
IV
Selectively targets amyloid plaques. See also Table 2
Gantenerumab (human)	2017 Failed in Phase III	Reduced Aβ plaques but did not slow cognitive decline at 116 weeks			Ostrowitzki et al., 2017
Hoffman-La-Roche	2023 GRADUATE I and II trials				Bateman et al. (2023)
SC
Targets insoluble plaques
Lecanemab (human)	approved by the FDA in July 2023	CLARITY AD trial with 1795 participants for 18 months. Moderately less decline based on CDR-SB scale	ARIA-E and	April 2023 ICER report raised concerns about cost-effectiveness of lecanemab for AD.	Van Dyck et al. (2023)
IV			ARIA-H and concerns over neuroinflammation and brain shrinkage, edema and some deaths	Longer trials also recommended	Couzin-Frankel & Piller (2022)
Biogen and Eisai			ARIA higher in ApoE4 patients		Piller (2022)
Targets both oligomers and plaques					Couzin-Frankel, (2023)
See also Table 2
Solanezumab (humanized from mouse)	Phase III EXPEDITION 1, EXPEDITION 2. showed + ve results, but failed in EXPEDITION 3. Also failed in The Anti-Amyloid Treatment in Asymptomatic Alzheimer’s (A4) study	After 240 weeks there was no slowing of cognitive decline in preclinical Alzheimer’s disease	ARIA-E >1% in each group. ARIA-H in ∼30% and similar in placebo group	Hoffman La Roche withdraws support in 2019 for continuation of trials with crenezumab	Sperling et al. (2023)
Eli-Lilly		Similarly, the 2014 phase II studies BLAZE and ABBY failed to show significant improvement with crenezumab	In 2022 NIH stated that crenezumab failed for treatment of early onset AD.		Cummings et al. (2018)
High affinity (picomolar) binding to monomeric aβ (amino acid sequence KLVFFAED)
Highly homologous to crenezumab
Genentech
IV