01847nas a2200253   4500000000100000008004100001260001500042653000900057653001200066653000800078653001000086653002200096653002200118100002200140700001700162700002000179700002200199245011000221856004000331300001100371490000700382520119000389022001401579       2024                            d  c2024-09-2710aAPOE10aamyloid10atau10aaging10aNeurodegeneration10aneuroinflammation1 aAlberto Granzotto1 aBryce Vissel1 aStefano L Sensi1 aTimothy E Behrens00aLost in translation: Inconvenient truths on the utility of mouse models in Alzheimer’s disease research  uhttps://doi.org/10.7554/eLife.90633  ae906330 v133 aThe recent, controversial approval of antibody-based treatments for Alzheimer’s disease (AD) is fueling a heated debate on the molecular determinants of this condition. The discussion should also incorporate a critical revision of the limitations of preclinical mouse models in advancing our understanding of AD. We critically discuss the limitations of animal models, stressing the need for careful consideration of how experiments are designed and results interpreted. We identify the shortcomings of AD models to recapitulate the complexity of the human disease. We dissect these issues at the quantitative, qualitative, temporal, and context-dependent levels. We argue that these models are based on the oversimplistic assumptions proposed by the amyloid cascade hypothesis (ACH) of AD and fail to account for the multifactorial nature of the condition. By shedding light on the constraints of current experimental tools, this review aims to foster the development and implementation of more clinically relevant tools. While we do not rule out a role for preclinical models, we call for alternative approaches to be explored and, most importantly, for a re-evaluation of the ACH.  a2050-084X