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Glial-Associated Immune Dysregulation and Alzheimer's Disease Pathology: Pathways for Neuritic Microstructural Changes, Synaptic Dysfunction, and Cognitive Decline

Award Number: R01AG101783
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/01/2026
PERIOD OF PERFORMANCE END DATE: 05/31/2030

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Glial-Associated Immune Dysregulation and Alzheimer's Disease Pathology: Pathways for Neuritic Microstructural Changes, Synaptic Dysfunction, and Cognitive Decline - PROJECT SUMMARY/ABSTRACT The overarching hypothesis of this proposal is that immune dysfunction occurs early in the Alzheimer’s disease (AD) pathological course and is characterized by astrogliosis-driven immune dysregulation that alters dendritic arbors in the brain, leading to synaptic dysfunction and accelerated cognitive decline. Astrocytes are central nervous system (CNS) glia that play integral roles in immune regulation, synaptic pruning, and stabilization of presynaptic terminals with dendritic spines; however, in response to pathology, astrocytes assume reactive phenotypes, which have been linked with inflammation, retraction of dendritic spines, and synaptic engulfment, leading to cognitive impairment in animals. Neuritic (e.g., dendritic) changes in the AD vulnerable brain network may offer key insights into areas of astrocyte-associated change. Autopsy studies have shown that AD is characterized by a retraction of dendritic trees and have reported co-localization of astrocytes with dystrophic neurites and inflammation-associated damage to dendritic spines. There is limited understanding, however, of temporal biological pathways and neuroanatomical mechanisms that underlie relationships between astrocyte reactivity, immune dysregulation, AD pathology, and cognitive decline in aging adults. It is also unclear whether astrocyte reactivity catalyzes downstream blood immune dysfunction, which would yield more accessible immune biomarkers for tracking AD pathological cascades. We will address the following Aims: Aim 1: Delineate astrocyte-related molecular alterations in the blood immune milieu longitudinally and appraise whether age and amyloid pathology differentially impact these networks. Aim 2: Evaluate whether astrocyte-related blood immune networks herald changes in neuritic brain structure and cognitive decline. Aim 3: Appraise potential mechanistic role(s) of astrocyte-associated blood immune dysregulation and neuritic alterations on synaptic dysfunction and cognitive decline. We will leverage an existing dataset of asymptomatic adults (i.e., n=200; 84 amyloid+ and 116 amyloid-) to analyze longitudinal neurite orientation dispersion and density imaging (NODDI) and cognitive outcomes. We will conduct new immune proteomics with NULISAseq (3 time points; 600 samples) to assess alterations in the blood immune milieu. For a subset (n=145), we will leverage existing cross-sectional CSF synaptic markers (neurogranin, NPTX2, SNAP-25) to test mechanistic pathways by which astrocyte-associated blood immune dysregulation impacts clinical outcomes. We will also conduct a validation of the proteomics results using an existing cross-sectional dataset (n=100). Understanding molecular bases of astrocyte- associated immune dysregulation and pathways by which they relate to AD pathology and clinical outcomes is integral to developing: a) accurate neurobiological models that explicate why age is the greatest risk factor for AD, b) accessible, blood-based immune biomarker panels that help predict and track early pathological processes in AD, and c) biological, druggable targets for large-scale therapeutic trials.


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 = $654,506 )
2026	2026	THE REGENTS OF THE UNIVERSITY OF COLORADO	13001 E 17TH PL STE F428	AURORA	CO	80045	ADAMS	USA	Aging Research	000	1	8/18/2026	NEW	$654,506
														Subtotal = $654,506

Grand Total All Awards = $654,506

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Glial-Associated Immune Dysregulation and Alzheimer's Disease Pathology: Pathways for Neuritic Microstructural Changes, Synaptic Dysfunction, and Cognitive Decline

Award Number: R01AG101783

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/01/2026

PERIOD OF PERFORMANCE END DATE: 05/31/2030

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