Advances in modeling memory decline: A critical overview of current animal and human paradigms

Memory decline, particularly in neurodegenerative disorders such as Alzheimer's disease, represents a critical global public health challenge, with projections exceeding 150 million cases by 2050. Current therapeutic options remain limited: while drugs like donepezil and memantine offer symptomatic relief, and newer agents like lecanemab show modest effects on slowing progression, no disease-modifying cures exist. This underscores the urgent need to refine preclinical models bridging discovery and clinical translation. This review evaluates animal and human models of memory decline associated with aging, arguing that optimal model selection depends on aligning design with research phase objectives rather than pursuing a singular "best" model. For animal models, mechanism-focused approaches clarify individual pathways but often oversimplify multifactorial neurodegeneration; phenotypically integrative models mimic complex pathologies yet risk distorting natural disease courses via non-physiologically transgenic overexpressions; translation-enhanced models leverage human genetics or neuroanatomical homologies to improve validity, albeit with higher cost and ethical complexity, suiting late-stage validation. Human models (clinical cohorts, in vitro systems like 3D organoids, and computational tools) provide direct clinical relevance but require cross-system validation to address limitations like invasiveness or scalability. Given the marked heterogeneity of memory decline across individuals, future breakthroughs hinge on multisystem collaborative validation-iteratively cross-checking findings across cell, animal, and human models to bridge mechanistic insights and clinical applicability, thereby accelerating the development of personalized interventions. This review is based on a systematic literature search of PubMed, Web of Science, Google Scholar and Scopus databases for articles published between March 1951 to January 2026, focusing on animal and human models of memory decline and Alzheimer's disease.