Anti-Amyloid Therapies for Alzheimer’s Disease and the Amyloid Cascade Hypothesis

Abstract

Over the past 30 years, the majority of (pre)clinical efforts to find an effective therapy for Alzheimer’s disease (AD) focused on clearing the β-amyloid peptide (Aβ) from the brain since, according to the amyloid cascade hypothesis, the peptide was (and it is still considered by many) the pathogenic determinant of this neurodegenerative disorder. However, as reviewed in this article, results from the numerous clinical trials that have tested anti-Aβ therapies to date indicate that this peptide plays a minor role in the pathogenesis of AD. Indeed, even Aducanumab and Lecanemab, the two antibodies recently approved by the FDA for AD therapy, as well as Donanemab showed limited efficacy on cognitive parameters in phase III clinical trials, despite their capability of markedly lowering Aβ brain load. Furthermore, preclinical evidence demonstrates that Aβ possesses several physiological functions, including memory formation, suggesting that AD may in part be due to a loss of function of this peptide. Finally, it is generally accepted that AD could be the result of many molecular dysfunctions, and therefore, if we keep chasing only Aβ, it means that we cannot see the forest for the trees.

Ion transporter cascade, reactive astrogliosis and cerebrovascular diseases

“…Recently, FDA approved two anti-amyloid anti-bodies; Aducanumab (human monoclonal antibody) and Lecanemab (humanized IgG1 antibody), which markedly reduce Aβ deposition in brain ( Fedele, 2023 ). Aducanumab neutralizes oligomeric forms of Aβ in cerebral amyloid angiopathy (CAA) lesions.…”

“…Recently, FDA approved two anti-amyloid anti-bodies; Aducanumab (human monoclonal antibody) and Lecanemab (humanized IgG1 antibody), which markedly reduce Aβ deposition in brain (Fedele, 2023) recruiting Iba1-positive microglia and GFAP-positive astrocyte to Aβ plaques. Microglia and astrocytes clear pathological Aβ deposits through phagocytosis and degrades in CNS and moderately improves spatial working memory (Ries and Sastre, 2016;Sevigny et al, 2016;Kong et al, 2022).…”

Passive Anti-Amyloid Beta Immunotherapies in Alzheimer’s Disease: From Mechanisms to Therapeutic Impact

“…The amyloid cascade has been reviewed extensively in several studies [25,26], including the authors' previous works [17,27]. In normal conditions, the amyloid precursor protein (APP) undergoes two-phase processing via the non-amyloidogenic pathway.…”

The Protective Effects of Flavonoids from <i>Scutellaria Baicalensis</i> Georgi Stems and Leaves on Oligodendrocyte Damage Induced by A<i>β</i><sub>1-42</sub>

“…The formation of senile plaques via extracellular β-amyloid (Aβ), along with the formation of neurofibrillary tangles (NFTs) caused by hyperphosphorylation of intracellular tau proteins in neuronal cells, are defining pathologies of AD [2] [3] [4]. The amyloid cascade hypothesis proposes that the amyloid precursor protein (APP) is a transmembrane glycoprotein that produces Aβ in response to βand γ-secretase, and as the amount of Aβ increases, Aβ forms oligomers that eventually aggregate to form extracellular plaques [5] [6]. Aβ 42 is thought to have an important role in AD pathology and is the predominant form deposited in senile plaques, which is associated with its higher hydrophobicity and propensity to self-aggregation [7].…”