SUPPLEMENT – SUMMARY Tau contributes to Alzheimer’s disease (AD) and many other brain diseases. However, it is uncertain how tau causes neuronal dysfunction and degeneration, in part because experimental models are not optimized to compare the relative pathogenicity of different tau species in disease-relevant contexts. Mutations in MAPT, the gene encoding tau, cause frontotemporal lobar degeneration (FTLD) instead of AD. In contrast, the rare A152T variant of tau increases risk for both types of diseases. These associations merit further exploration, especially as models expressing FTLD-mutant tau are widely used to study tau in AD and to develop novel AD treatments. Clinical AD onset is preceded by abnormal accumulations of amyloid-b (Ab) peptides in brain, and many AD patients have at least one apolipoprotein (apo) E4 allele, the most important genetic risk factor for AD. Therefore, Project 3 will generate new mouse models combining human Ab and apoE4 expression with near-physiological levels of human tau that is wildtype, as in most AD patients, or carries the A152T substitution, which increases AD risk. Comprehensive functional, pathological, and transcriptomic analyses of the new models, to be carried out in collaboration with Projects 1, 2, and 4 and Core B, should yield new insights into differential effects of these tau species and their roles in the pathogenesis of dementia. Project 3 will also investigate whether tau species that increase AD risk or cause FTLD differ in their effects on the integrity and functions of neurons and neural networks. Until we know which forms of tau are most pathogenic in different conditions, the most pragmatic therapeutic approach to tau in our view is partial reduction of overall tau levels, which is well tolerated and has benefits in more conventional models. We will therefore use tau-targeting antisense oligonucleotides to reduce human tau levels in models co-expressing human Ab and apoE4. Single-nucleus/single-cell transcriptomic analyses will be used to identify cell-type-specific gene expression changes as well as novel molecular and cellular mechanisms that may mediate pathogenic effects of tau or beneficial effects of tau reduction. These analyses will help Projects 1 and 2 distinguish between pathogenic mechanisms of apoE4 and Ab that do or do not depend on tau. They could also identify novel molecular and cellular mechanisms that mediate tau sequence-specific effects. The requested supplement will allow a postdoctoral scholar from a background that is underrepresented in the health-related sciences to contribute to the experiments proposed in Project 3 and, at the same time, to benefit from training within the larger context of this AD-focused interdisciplinary program.