Alzheimer disease: Amyloid peptide controversies and challenges of anti-Aβ immunotherapy.

Abstract

Alzheimer disease (AD) is a progressive neurodegenerative disease marked by the accumulation of extracellular β-amyloid (Aβ) plaques and intracellular neurofibrillary tangles containing tau protein. Given the relentless deterioration in AD, strategies to slow its progression often focus on inhibiting Aβ production or aggregation. However, numerous clinical trials targeting Aβ in later disease stages have shown limited success in reversing cognitive decline, potentially due to intervening too late in the disease course. Emerging evidence suggests that addressing Aβ pathology during the earliest phases of AD, before the occurrence of neuronal damage, may be beneficial for preserving cognitive function. Thus, therapeutic approaches aimed at reducing Aβ levels, such as anti-Aβ antibodies, are likely to yield greater benefits when implemented early in the disease trajectory. Such evidence underscores the rationale for prioritizing early-stage interventions in AD drug development. However, disrupting the physiological role of Aβ, which plays a role in normal brain function, might inadvertently worsen clinical outcomes, highlighting the need for nuanced therapeutic strategies. Therefore, this review aims to explore the dual aspects of Aβ biology: its natural role in the brain and the potential of anti-Aβ immunotherapy, particularly targeting amyloid plaques, as a promising avenue for modifying AD progression when timed appropriately. SIGNIFICANCE STATEMENT: This review highlights that β-amyloid (Aβ) has a dual role in both supporting synaptic plasticity and memory via nicotinic receptor activation and driving Alzheimer disease neuropathology, emphasizing that early-stage Aβ-targeted immunotherapy may prevent cognitive decline while preserving the neuroprotective functions of Aβ, thereby refining therapeutic strategies and advancing understanding of the complex role of Aβ in neural health and disease.