Critical Appraisal of Amyloid Lowering Agents in AD

Abstract

Purpose of Review According to the amyloid cascade hypothesis, removing amyloid beta (Aβ) should cure Alzheimer’s disease (AD). In the past three decades, many agents have been tested to try to lower Aβ production, prevent Aβ aggregation, and dissolve Aβ deposits. However, the paucity in definitive preventative or curative properties of these agents in clinical trials has resulted in more avant-garde approaches to therapeutic investigations. Immunotherapy has become an area of focus for research on disease-modifying therapies for neurodegenerative diseases. In this review, we highlight the current clinical development landscape of monoclonal antibody (mAb) therapies that target Aβ plaque formation and removal in AD. Recent Findings Multiple potential disease-modifying therapeutics for AD are in active development. Targeting Aβ with mAbs has the potential to treat various stages of AD: prodromal, prodromal to mild, mild, and mild to moderate. Monoclonal antibodies discussed here include aducanumab, lecanemab, solanezumab, crenezumab, donanemab, and gantenerumab. Summary The final decision by the FDA regarding the approval of aducanumab will offer valuable insight into the trajectory of drug development for mAbs in AD and other neurodegenerative diseases. Future directions for improving the treatment of AD will include more inquiry into the efficacy of mAbs as disease-modifying agents that specifically target Aβ peptides and/or multimers. In addition, a more robust trial design for AD immunotherapy agents should improve outcomes such that objective measures of clinical efficacy will eventually lead to higher chances of drug approval.

Oxidative Stress and Beta Amyloid in Alzheimer’s Disease. Which Comes First: The Chicken or the Egg?

“…In the last 30 years, many authors supported the hypothesis of the “amyloid cascade” that considers Aβ to possess a crucial role in the pathogenesis of the disease [ 26 , 27 , 28 , 29 , 30 ]. According to this theory, the accumulation and deposition of Aβ is responsible for Tau aggregation and, therefore, for the cognitive and mnemonic decline observed in AD patients [ 31 ].…”

Aducanumab: evidence from clinical trial data and controversies

“…In a critical appraisal of monoclonal antibody therapies that target Aβ plaque formation and removal in AD, Decourt et al indicate that lecanemab, solanezumab, crenezumab, donanemab, and ganterenumab are being studied in individuals with AD. 27 Although these drugs are relatively safe for use in humans, they have had limited positive outcomes in the clinical trials. Additional drug trials for AD that are currently under way include those of (1) a tau aggregation inhibitor (LMTX); (2) inflammation-targeting drugs (ALZT-OP1, a nasally inhaled cromolyn, a mast cell stabilizer + oral ibuprofen, a non-steroidal anti-inflammatory agent; COR388, which irreversibly inhibits gingipains; and masitinib, a selective tyrosine kinase inhibitor); (3) AGB101 (levetiracetam repurposed as a synaptic vesicle glycoprotein 2A (SV2A) modulator); (4) blarcamesine (ANAVEX2-73, a sigma-1 receptor agonist); (5) CAD106 (second-generation active Aβ vaccine); (6) icosapent ethyl; (7) the Plasma Exchange – Alzheimer’s Management by Albumin Replacement (AMBAR) trial; and (8) troriluzole (BHV-4157, a prodrug conjugate of riluzole).…”

Aducanumab, a Novel Anti-Amyloid Monoclonal Antibody, for the Treatment of Alzheimer’s Disease: A Comprehensive Review

“…The drug functions by selectively binding amyloid aggregates in both the oligomeric and fibrillar states rather than amyloid monomers. 37 This binding discrimination by the drug is what distinguishes aducanumab from its contemporary Aβ immunotherapeutic agents. The Aβ aggregates have been shown to exert neurotoxic effects while monomeric Aβ has exhibited beneficial neurological functions.…”