Recent advances in model systems for interrogating diseases of brain aging and associated dementia: Toward human-relevant endophenotypes

Neurodegenerative diseases are characterized by key pathological hallmarks, progressive loss of neuronal structure and function, and synaptic loss. Often, mild behavioral changes including subjective cognitive decline and neuropsychiatric symptoms precede the diagnosis and may be a harbinger of disease inception and progression. Despite the success of new treatments that attenuate pathological burden, the ability to translate clinical benefit for cognitive impairment and dementia-related behavioral syndromes remains challenging. While model systems are essential, the appropriate model must be carefully chosen for the specific research question, with complementary model systems necessary to capture multiple aspects of disease. This review will cover the emergence of model systems that provide more translationally relevant trajectories of the progression of pathological changes throughout brain aging, and the advancement of model systems that are able to better capture the spectrum of behavioral and cognitive changes that signal the early prodromal period prior to diagnosis.