Dissecting the complexities of Alzheimer disease with in vitro models of the human brain

Alzheimer disease (AD) is the most prevalent type of dementia. It is marked by severe memory loss and cognitive decline, and currently has limited effective treatment options. Although individuals with AD have common neuropathological hallmarks, emerging data suggest that the disease has a complex polygenic aetiology, and more than 25 genetic loci have been linked to an elevated risk of AD and dementia. Nevertheless, our ability to decipher the cellular and molecular mechanisms that underlie genetic susceptibility to AD, and its progression and severity, remains limited. Here, we discuss ongoing efforts to leverage genomic data from patients using cellular reprogramming technologies to recapitulate complex brain systems and build in vitro discovery platforms. Much attention has already been given to methodologies to derive major brain cell types from pluripotent stem cells. We therefore focus on technologies that combine multiple cell types to recreate anatomical and physiological properties of human brain tissue in vitro. We discuss the advances in the field for modelling four domains that have come into view as key contributors to the pathogenesis of AD: the blood–brain barrier, myelination, neuroinflammation and neuronal circuits. We also highlight opportunities for the field to further interrogate the complex genetic and environmental factors of AD using in vitro models. In this Review, Li-Huei Tsai and colleagues discuss the ongoing work towards the generation of more physiological in vitro models of Alzheimer disease (AD), with a particular focus on the modelling of AD-related changes to the blood–brain barrier, myelination, neuroinflammation and neuronal circuits. Key points This Review discusses ongoing efforts to integrate genomic data from patients with cellular reprogramming technologies to build physiological models of the human brain in vitro. Multicellular in vitro models are beginning to replicate key aspects of human brain tissue and are increasingly complementing existing approaches to provide new molecular and cellular insights into the pathogenesis of Alzheimer disease (AD). Each section provides a summary of our current understanding as it relates to the pathogenesis of AD and discusses the latest advances in technology that are enabling modelling of the blood–brain barrier, myelination, neuroinflammation and neuronal circuits in vitro. The ultimate aim of these efforts is to combine multiple approaches into a single model to recreate t