# Nextgen AD Models, Endotypes, and Screening > **NIH NIH RF1** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2024 · $2,319,456 ## Abstract PROJECT SUMMARY Alzheimer's Disease (AD) is a complex, multifactorial, slowly progressive, neurodegenerative disorder that causes dementia and cognitive decline. It is common to delineate AD into familial AD (FAD) and late-onset AD (LOAD), with the former with an early age of onset, having defined genetic origins (mutations in PSEN1, PSEN2, and APP genes), while the latter has no specific gene mutations and the genetic background determinants are unknown. Both AD forms manifest similar phenotypes, including memory loss and cognitive decline, the formation of plaques and tangles in the brain and death. There is no known effective cure for AD. The major barriers to our inability to identify drugs that will address this neurodegenerative disorder include (a) the absence of reliable and accurate AD models that can faithfully recapitulate human AD, (b) a lack of incisive and comprehensive understanding of the mechanisms (endotypes) underlying the onset and progression of the disease, and (c) absence of screening strategies in the model systems to assess the efficacy of drugs that will address all aberrant endotypes. Solutions to these barriers form the leitmotif of our proposal. Our first objective is the development of brain organoids which are realistic models of the human brain from human induced pluripotent cells (hiPSC). In aim 1 of the proposal, we plan to derive six isogenic mutant hiPSC lines (4 PSEN1, 1 PSEN2 and 1 APP) from a young, healthy individual. Similarly, derive isogenic mutation-corrected control hiPSC lines from three FAD patients (each PSEN1, PSEN2 and APP mutations). Develop brain organoids from these hiPSC cell lines and characterize them using biophysical and omics methods. In addition, we plan to develop brain organoids from two aged non-demented control subjects. These brain organoids will be developed with and without microglia additions and characterized using a repertoire of biophysical and omics methods as a function of their development. We plan to investigate them at 1, 3, 6, and 10 months of organoid development. These models will help us understand the role of genetic background in the disease process apart from the deterministic FAD mutations. They will also help us understand AD disease evolution mechanisms (Aim 2) and be a better tool for validating therapeutics screening (Aim 3). In Aim 2, We will use the multiome sequencing methods to profile these organoids' molecular and cellular functional states. The multiomics measurements will be analyzed using extant and innovative systems biology methods to identify "endotypes" that are disease- causing and those that are distinct across the mutations and across time. We will relate these endotypes to the biophysical and phenotypical measurements to develop causal mechanistic models that can help identify potential disease mechanisms to target therapeutically. In Aim 3, we plan to validate the endotypes that are disease causing using genetic perturbation strategies. Furth... ## Key facts - **NIH application ID:** 10885611 - **Project number:** 1RF1AG084030-01A1 - **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO - **Principal Investigator:** Alysson R. Muotri - **Activity code:** RF1 (R01, R21, SBIR, etc.) - **Funding institute:** NIH - **Fiscal year:** 2024 - **Award amount:** $2,319,456 - **Award type:** 1 - **Project period:** 2024-06-01 → 2027-05-31 ## Primary source NIH RePORTER: https://reporter.nih.gov/project-details/10885611 ## Citation > US National Institutes of Health, RePORTER application 10885611, Nextgen AD Models, Endotypes, and Screening (1RF1AG084030-01A1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10885611. Licensed CC0. --- *[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*