Basic Science and Pathogenesis.

Background: Adults with Down syndrome (DS) develop Alzheimer's disease (AD) brain pathology by their 40s due to triplication of the amyloid precursor protein (APP) gene on chromosome 21, and most develop clinical symptoms by age 50-60. Inheritance of the apolipoprotein E (apoE) ε4 allele (APOE4) is the strongest risk factor for AD besides age, whereas the ε3 allele (APOE3) does not change AD risk. The APOE4 genotype is associated with earlier and more rapid cognitive decline in both typical AD and DS-associated AD (DS-AD); however, understanding of the associated mechanisms is lacking.

Novel human iPSC models of neuroinflammation in neurodegenerative disease and regenerative medicine.

The importance of neuroinflammation in neurodegenerative diseases is becoming increasingly evident, and, in parallel, human induced pluripotent stem cell (hiPSC) models of physiology and pathology are emerging. Here, we review new advancements in the differentiation of hiPSCs into glial, neural, and blood-brain barrier (BBB) cell types, and the integration of these cells into complex organoids and chimeras. These advancements are relevant for modeling neuroinflammation in the context of prevalent neurodegenerative disorders, such as Alzheimer's disease (AD), Parkinson's disease (PD), and multiple sclerosis (MS).