From pathology to network failure: a Question-Model-Outcome framework for interpreting animal models of AD-related...

Animal studies remain indispensable for research on Alzheimer's disease (AD), vascular cognitive impairment, and other dementia-relevant mechanisms. Their value, however, is not that they reproduce human late-life dementia in miniature. A mouse line, vascular manipulation, or mixed-pathology preparation can make one aspect of the problem experimentally visible while not capturing the long preclinical course, clinical heterogeneity, and everyday functional consequences that define the human syndrome. This review therefore treats animal models as instruments for bounded inference. Drawing on translational, mechanistic, and methodological literature, we ask which biological question is posed, which outcome can legitimately answer it, and where the claim should be drawn back. The Question-Model-Outcome framework is developed around five recurrent problems: the loose relation between lesion burden and functional severity; vascular influences on proteinopathy and network injury; stage-dependent immune and glial responses; the narrow construct validity of many behavioral assays; and the interpretation of reported improvement after intervention. We argue that translational value arises when model biology, disease stage, and outcome level are aligned. In that role, animal studies can sharpen mechanistic reasoning and discipline clinical extrapolation without being treated as generic substitutes for human AD-related dementia.