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Study of Alzheimer's Disease Risk Genes Using Blood-Brain Barrier Assembloids

Award Number: R21AG100393
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/15/2026
PERIOD OF PERFORMANCE END DATE: 08/31/2028

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Study of Alzheimer's Disease Risk Genes Using Blood-Brain Barrier Assembloids - Abstract The blood-brain barrier (BBB) plays an essential role in maintaining central nervous system homeostasis by regulating molecular transport and immune surveillance. Emerging evidence indicates that BBB breakdown is an early event in Alzheimer’s disease (AD) pathogenesis and may precede cognitive decline. Genetic risk factors for AD—such as variants in APOE, TREM2, ACE, and CLU—have been implicated in vascular dysfunction, yet the mechanistic basis by which these variants contribute to BBB breakdown remains poorly defined. A key limitation in addressing this knowledge gap is the absence of physiologically relevant human BBB models that incorporate both AD-associated genetic risk and neurovascular complexity. To overcome this challenge, we propose to develop a novel 3D human BBB assembloid platform derived from human induced pluripotent stem cells (iPSC), engineered with isogenic knock-ins of AD risk variants. Our preliminary data demonstrate that BBB assembloids derived from iPSCs of AD patients carrying APOE4/4 alleles exhibit hallmark features of BBB dysfunction, including tight junction disruption and glucose transporter deficiency—mirroring clinical findings in AD. Furthermore, CRISPR-Cas9-mediated knock-in of APOE4 into healthy control iPSCs recapitulates these deficits, directly linking this variant to BBB pathology. Single-cell transcriptomic profiling of these assembloids reveals enrichment of AD risk gene expression in BBB-resident cell types and identifies impaired neurovascular crosstalk, characterized by diminished extracellular matrix ligand- receptor interactions and weakened Wnt signaling pathways. We hypothesize that engineering isogenic AD risk variants into human BBB assembloids will uncover the variant-specific contributions to BBB dysfunction and identify associated gene regulatory pathways and neurovascular interaction mechanisms driving BBB decline in AD. We propose two specific aims: Aim 1 will define the causal contributions of APOE, TREM2, ACE, and CLU risk variants to structural and functional breakdown of the BBB. Aim 2 integrates single-cell transcriptomics and spatial sequencing to map dysregulated gene regulatory networks and disrupted ligand-receptor signaling across spatially resolved neurovascular cell pairs affected by AD risk variants. This project will establish a high-fidelity human BBB platform for mechanistic interrogation of AD genetic risk, directly advancing NIH priorities in AD and vascular contributions to dementia. By integrating stem cell- derived assembloids, CRISPR editing, and multi-omics approaches, this work will provide foundational insights into AD-related BBB pathology, paving the way for future therapeutic strategies targeting the neurovascular interface. Deliverables will include open-access omics datasets, validated isogenic iPSC lines, and analytical pipelines to advance the field’s understanding of vascular contributions to AD.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $462,593 )
2026	2026	CHILDRENS HOSPITAL MEDICAL CENTER	3333 BURNET AVE	CINCINNATI	OH	45229	HAMILTON	USA	Aging Research	000	1	9/9/2026	NEW	$462,593
														Subtotal = $462,593

Grand Total All Awards = $462,593

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Study of Alzheimer's Disease Risk Genes Using Blood-Brain Barrier Assembloids

Award Number: R21AG100393

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 09/15/2026

PERIOD OF PERFORMANCE END DATE: 08/31/2028

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