Alzheimer's disease (AD) is a chronic neurodegenerative condition and the most common cause of dementia worldwide, affecting an estimated 50 million people today (Breijyeh and Karaman, 2020). This figure is projected to rise to 150 million by 2050 due to increased life expectancy and an aging population (Kumar et al., 2024)The primary signs of the disease, including loss of long-term memory, cognitive impairment, and reduced activity, are severely debilitating to patients' quality of life and place a heavy burden on caregivers Singh et al., 2023; Safiri et al., 2024). The clinical pathological features characterizing AD's multifactorial pathology influences the disease course (Thal et al., 2013). AD results from a multifactorial etiology, incorporating lifestyle, environmental, and genetic factors (Suresh and Singh, 2023). Mutations of the PSEN1 (presenilin 1), TSEN2 (tRNA splicing endonuclease subunit Sen2), and APP (Amyloid Precursor Protein) genes can cause early-onset familial AD (Lanoiselée et al., 2017; Qin et al., 2020; Wu et al., 2012). The primary genetic predisposition risk for late-onset (sporadic) AD is associated with the APOE-ε4 allele, which is considered the largest identified risk factor related to AD (M. Di Battista et al., 2016; Troutwine et al., 2022). Head trauma, comorbid vascular conditions, and lifestyle factors (such as smoking, diet, and lack of physical activity) are modifiable risk factors for AD (Behl et al., 2024; Eisenmenger et al., 2022). While it is true that many other risk factors exist, it is important to note that the largest factor is aging, as environmental stressors accumulate, leading to increased chronic inflammation and subsequent oxidative stress, which contribute to neurodegeneration (Dash et al., 2025; Liu et al., 2024; Xia et al., 2018). AD is caused by two abnormal conditions of brain proteins: amyloid-β plaques that accumulate in the extracellular environment, and intracellular neurofibrillary tangles formed from hyperphosphorylated tau protein (Murphy and Levine, 2010). While tau pathology inhibits intracellular transit and facilitates neuronal dysfunction, amyloid-β aggregation interferes with synaptic contact and evokes inflammatory responses. Oxidative stress, mitochondrial injury, and autophagic dysregulation contribute to these alterations, ultimately leading to massive synapse loss and neuronal death (Chen and Yu, 2023; Kamat et al., 2014; Rajmohan and Reddy, 2017). Despite progress, numerous uncertainties remain concerning the molecular basis of AD (Ewald and Li, 2009; Gooch and Stennett, 1996). The interaction between tau and amyloid-β in inducing neurodegeneration remains unclear (Iaccarino et al., 2018; Zhang et al., 2021). Targeted and innovative strategies are needed to address mitochondrial dysfunction and neuroinflammation (Edeas and Weissig, 2013; Onyango et al., 2021). Although understudied, biomarkers for individualized medicine and early detection have the potential to improve outcomes (Fortea, 2024; Rahmouni et al., 2023). The global challenge of addressing this complex condition has prompted ongoing AD research to seek advances in disease-modifying treatment options, improved diagnostics, and preventive strategies (Smith and Ownby, 2024; Yiannopoulou and Papageorgiou, 2020).

Autophagy is essential in the maintenance of metabolic equilibrium, the elimination of harmful general resistance, and the prevention of stress-evoked damage (Lahiri et al., 2019; Levine and Kroemer, 2008). Autophagy is the process of autophagosome formation, double-membraned vesicles that contain cellular wastes, and subsequent fusion with lysosomes, and degradation (Tanida, 2011). Autophagy is the major control mechanism of energy, protein quality, and cellular aging (He, 2022; Salminen and Kaarniranta, 2009). Autophagy is regulated by a mechanism in which the AMPK-mTOR mechanisms regulate autophagic flux based on cellular energy state (Kim et al., 2013). Autophagy is recruited upon starvation or stress to allow the cellular degradation of non-essential cellular components to deliver necessary biomedicals (Chen et al., 2019; Chun and Kim, 2018; He, 2022). Autophagy also plays a role in response to inflammation and mitochondrial control through mitochondria, which involves the recruitment and degradation of non-functioning mitochondria (Glick et al., 2010; Li et al., 2022). Because autophagy is at the heart of cellular survival, disturbance of autophagy results in many disease states and thus represents the best drug target to restore homeostasis and prevent disease (Gómez-Virgilio et al., 2022; Kocak et al., 2021).

Neuropeptide Y (NPY) is a 36-amino acid peptide produced by the central nervous system (CNS) and expressed in certain CNS areas related to cognition, such as the hippocampus and cortex (Larhammar, 1996; Shapovalova et al., 2024). NPY is involved in numerous physiological functions, including feeding, the stress response, and neuronal survival (Reichmann and Holzer, 2015). Due to its versatile mechanism of action, NPY presents a suitable treatment option for the complex pathology of AD. Currently, NPY is a leading regulator of autophagy in neurodegenerative diseases, including AD (Shapovalova et al., 2024). NPY regulates key signaling pathways, such as the AMPK-mTOR pathway, to enhance autophagic flux and cellular clearance (Ahmad et al., 2025; Oh et al., 2016). NPY-activated AMPK inhibits mTOR, a critical repressor of autophagy, thereby boosting autophagosome expression and lysosomal degradation pathways (Oh et al., 2016). This activity removes toxic protein aggregates, alleviating neuronal stress and neurotoxicity in AD, in addition to enhancing autophagy. NPY indirectly supports neuronal integrity by regulating mitochondrial health (Sousa et al., 2023). Since mitochondria are both a source and a target of oxidative stress in AD, maintaining their health is a top priority for neuroprotection (Misrani et al., 2021). NPY initiates mitophagy, the selective autophagic degradation of dysfunctional mitochondria, thereby addressing energy deficits and reducing the ROS burden. Additionally, NPY has anti-inflammatory effects by inhibiting the activation of microglia and reducing the levels of pro-inflammatory cytokines TNF-α and IL-1β, creating a neuroprotective environment against chronic neuroinflammation (Carniglia et al., 2017; Li et al., 2019). The NPY-autophagy interaction in AD is a crucial therapeutic target. NPY may halt the progression of protein aggregates, preserve mitochondrial function, and counteract neuroinflammatory responses by enhancing autophagic efficiency (Duarte-Neves et al., 2016). Given these multi-parametric benefits, NPY-based therapies, including targeted delivery methods and receptor-selective agonists, should be explored to advance AD treatment and slow disease progression (Spencer et al., 2016). Because of its diverse mechanisms, NPY represents a promising multi-target approach for managing AD. Table 1 summarizes how NPY counteracts major pathological hallmarks of AD.