Transfixed by transgenics: how pathology assumptions are slowing progress in Alzheimer's disease and related dementia research

Model organisms of human diseases are invaluable tools for unraveling pathogenic mechanisms, identifying potential targets for drug development, and evaluating the therapeutic efficacy of candidates in preclinical trials. The utility of model organisms hinges upon their ability to faithfully replicate the underlying pathogenic mechanisms of the human disease. For rodent models of Alzheimer's disease (AD) and AD‐related dementias (ADRD), the limited translatability to human disease raises concerns about their overall utility. What factors contribute to this limitation? Is AD inherently too complex to be accurately modeled in nonhumans? Is the divergence between rodent brains and the human brain so pronounced that rodents are unsuitable as model organisms for AD? Or is it plausible that the commonly used rodent models don't capture the genuine pathogenic mechanisms underlying these diseases? This editorial discusses the challenges associated with transgenic models of AD and ADRD and offers some alternative approaches.