Structural brain alterations associated with brain age may link to social dysfunction in male adults with autism spectrum disorder.

Neurodegenerative diseases (NDDs) encompass a diverse group of disorders marked by progressive neuronal dysfunction and cell death, resulting in cognitive decline, motor deficits, and ultimately death []. Alzheimer’s disease (AD) is the most prevalent neurodegenerative condition, currently affecting over 55 million individuals worldwide, with estimates projecting this figure to triple by 2050 []. The underlying pathophysiology of NDDs involves complex mechanisms including protein misfolding and aggregation, oxidative stress (OS), mitochondrial dysfunction, neuroinflammation and excitotoxicity []. This multifactorial nature has complicated drug development, with numerous single-target approaches failing to demonstrate disease-modifying effects in clinical trials. Among these mechanisms implicated in AD progression, OS has emerged as a central contributor to neuronal death []. Elevated levels of reactive oxygen species (ROS) trigger lipid peroxidation, protein oxidation, and DNA damage, ultimately leading to neuronal death and synaptic dysfunction, the hallmarks of AD pathology [,]. Importantly, oxidative injury in AD is not merely a downstream consequence but may serve as an early pathogenic event that amplifies amyloid-beta (Aβ) toxicity []. The oligomeric Aβ species can insert into membrane systems, promoting OS that damages key cellular components involved in energy metabolism, signaling, neurotransmission, and protein degradation pathways []. This oxidative environment exacerbates protein aggregation, impairs synaptic function, and accelerates neurodegeneration. Thus, small molecules capable of reducing OS while preserving mitochondrial function represent promising candidates for disease-modifying intervention in AD. In parallel with OS-centered therapeutic strategies, the cholinergic hypothesis continues to provide a major framework for anti-Alzheimer drug discovery []. Acetylcholinesterase (AChE), beyond its classical role in hydrolyzing acetylcholine and regulating cholinergic neurotransmission, has been implicated in broader pathological processes relevant to neurodegeneration, including neuroinflammation, apoptosis, oxidative injury, and Aβ aggregation []. Particularly notable is the role of AChE in accelerating amyloid fibrillogenesis through interactions at its peripheral anionic site, linking cholinergic dysfunction with amyloid pathology [,]. This multifunctional role has made AChE an enduring therapeutic target, as reflected by clinically used inhibitors such as Donepezil, Rivastigmine, and Galantamine, which provide symptomatic benefit through enhanced cholinergic transmission [,,].