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Influence of microglial cell depletion and repopulation on aducanumab induced ARIA and vascular lesions in APOE4 carriers with AD

Award Number: R21AG089503
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/01/2024
PERIOD OF PERFORMANCE END DATE: 05/31/2027

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Influence of microglial cell depletion and repopulation on aducanumab induced ARIA and vascular lesions in APOE4 carriers with AD - After many failed clinical trials, the FDA recently approved new breakthrough antibody therapy for use in early AD. But these therapies have been revealed to increase the frequency of amyloid-related imaging abnormalities (ARIAs). Importantly, ARIA occurs more frequently in APOE4 carriers. Although the mechanism is unclear, ARIA is thought to occur after removal of amyloid from blood vessels with cerebral amyloid antipathy (CAA). APOE4 allele is one of the strongest risk factors for AD and has been shown to promote cerebrovascular lesions such as CAA and microhemorrhages. Because CAA is universally observed in AD, further investigation of APOE4-dependent mechanisms driving CAA and ARIA-events is needed. Activated microglia have been shown to drive the outcome and pace of APOE-mediated neurodegeneration. Importantly, microglia can modulate cerebrovascular integrity and cerebral blood flow, and release factors which contribute to BBB breakdown, cerebrovascular cell damage and neurovascular injury. In our studies, we revealed an increase in inflammatory pathways in AD vs control human cerebrovessels, and this was more prominent in APOE4 carriers, who also had higher CAA scores. Anti-Aβ antibody related ARIA has also been associated with reactive microgliosis in a primate model of CAA. In humans, in vivo PET imaging of microglial activation has been associated with the magnitude and severity of ARIA. No preclinical models have evaluated this association between activated microglia response and ARIA-events, particularly in the context of APOE4 genotype. In this proposal, we will address these unknowns by utilizing microglial ablation and repopulation techniques in a previously described chronic anti-Aβ treated EFAD mouse model of AD expressing human APOE isoforms and AD mutations (i.e., aducanumab treated E3FAD and E4FAD mice). From these studies, we will generate a detailed time-course of cognitive function, cerebral blood flow and cerebrovascular reactivity, and characterize the histopathological and biochemical level changes to the cerebrovasculature. No studies have characterized the cerebrovascular cell phenotypes in ARIA patients. We will thus employ a single cell transcriptomic approach to characterize the phenotypic brain vascular cell type response(s) in our EFAD models following aducanumab treatment with/without macrophage depletion and repopulation, and reveal key upstream regulators driving these unique vascular cell responses at the single cell level. From this proposal, our goal is to reveal whether activated microglia mediated cerebrovascular inflammation contributes to APOE4 mediated ARIA events following aducanumab treatment, and ii) identify novel targets through which APOE4 confers these vascular-specific abnormalities, to reveal new opportunities for improved antibodies and adjunct therapies that can one day minimize these complications in APOE4 patients with 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 = $0 )
2026	2025	THE ROSKAMP INSTITUTE, INC.	2040 WHITFIELD AVE	SARASOTA	FL	34243	MANATEE	USA	Aging Research	000	2	3/2/2026	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2025 ( Subtotal = $255,750 )
2025	2025	THE ROSKAMP INSTITUTE, INC.	2040 WHITFIELD AVE	SARASOTA	FL	34243	MANATEE	USA	Aging Research	000	2	5/2/2025	NON-COMPETING CONTINUATION	$255,750
														Subtotal = $255,750

Issue Date FY: 2024 ( Subtotal = $213,125 )
2024	2024	THE ROSKAMP INSTITUTE, INC.	2040 WHITFIELD AVE	SARASOTA	FL	34243	MANATEE	USA	Aging Research	000	1	8/27/2024	NEW	$213,125
														Subtotal = $213,125

Grand Total All Awards = $468,875

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Influence of microglial cell depletion and repopulation on aducanumab induced ARIA and vascular lesions in APOE4 carriers with AD

Award Number: R21AG089503

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/01/2024

PERIOD OF PERFORMANCE END DATE: 05/31/2027

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