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Understanding the Microbiome-gut-brain axis in Alzheimers disease and its Role

Award Number: R01AG067483
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/15/2020
PERIOD OF PERFORMANCE END DATE: 12/31/2030

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Understanding the Microbiome-gut-brain axis in Alzheimers disease and its Role - ABSTRACT The gut microbiome is emerging as a possible causative trigger for disease progression in Alzheimer's disease (AD) via systemic immune dysfunction. While full progression to clinical disease is complex and multifactorial, our ongoing work points to a novel microbiome-gut-brain axis associated risk and possible mechanism, which may be targeted for prevention and therapies. We established the Gut-brain Alzheimer's disease Inflammation and Neurocognitive Study (GAINS) cohort in 2020 and have followed older adults with AD, mild cognitive impairment (MCI), and healthy controls every 3 months. By systematically collecting robust clinical and cognitive information alongside gut microbiome and immune profiles, we have begun to shed light on possible causative mechanisms for the increased risk of AD progression. We have discovered a unique microbiome profile characterized by increased production of methionine and methionine related metabolites around the time of cognitive decline. This provokes a novel hypothesis that known immune senescence in AD patients may originate from overproduction of methionine by gut microbes leading to cognitive decline. In this proposal we will: 1) longitudinally assess cognition and neurocognitive decline alongside changes in the microbiome's methionine pathway and peripheral immune senescence; 2) expand our longitudinal cohort to include more MCI and mild AD patients; and 3) determine how the gut microbiome can induce immunopathology that potentiates AD and cognitive decline in transgenic AD mouse models. Our central hypothesis is that the gut microbiome is a driver of gut/immune/brain dysfunction in AD and that methionine is the critical trigger that potentiates neurological and immune dysfunction. We further hypothesize that this methionine process triggers early decline among MCI and mild AD patients. Our collaborative group of AD researchers are poised to contribute to a deeper understanding of how peripheral-to-central, adaptive immune-mediated mechanisms lead to AD cognitive decline. Specifically, in Aim 1 we will define the longitudinal changes in gut microbiome methionine production and its role in immune senescence driving AD cognitive decline by leveraging already collected cognitive scores, blood, and stool samples from AD patients. This will further define the role of methionine in AD progression by evaluating the gut microbiome production and systemic absorption of methionine and its related metabolites via metabolomics and provide deeper understanding of the immune states that change with higher methionine levels and investigation of a senescence-associated secretory phenotype. In Aim 2 we will examine how microbiome- produced methionine leads to systemic and neural immune dysfunction in transgenic AD mouse mode. In Aim 3 we will determine methionine and parallel dysbiotic microbiome related risk to early cognitive changes in mild AD and MCI patients in an expanded cohort. Successful completion of these aims will lead to a novel mechanistic understanding for cognitive decline in AD patients based on microbiome-immune interactions. Additionally, our mechanistic discoveries will guide future studies into microbiome-based interventions for 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 = $703,171 )
2026	2026	UNIVERSITY OF MASSACHUSETTS MEDICAL SCHOOL	55 LAKE AVE N	WORCESTER	MA	01655	WORCESTER	USA	Aging Research	001	3	1/30/2026	COMPETING CONTINUATION	$703,465
2026	2024	UNIVERSITY OF MASSACHUSETTS MEDICAL SCHOOL	55 LAKE AVE N	WORCESTER	MA	01655	WORCESTER	USA	Aging Research	000	2	1/21/2026	EXTENSION WITH OR WITHOUT FUNDS	-$294
														Subtotal = $703,171

Issue Date FY: 2024 ( Subtotal = $1,103,900 )
2024	2024	UNIVERSITY OF MASSACHUSETTS MEDICAL SCHOOL	55 LAKE AVE N	WORCESTER	MA	01655	WORCESTER	USA	Aging Research	002	2	8/23/2024	SUPPLEMENT FOR EXPANSION	$375,004
2024	2024	UNIVERSITY OF MASSACHUSETTS MEDICAL SCHOOL	55 LAKE AVE N	WORCESTER	MA	01655	WORCESTER	USA	Aging Research	001	2	8/22/2024	EXTENSION WITH OR WITHOUT FUNDS	$0
2024	2024	UNIVERSITY OF MASSACHUSETTS MEDICAL SCHOOL	55 LAKE AVE N	WORCESTER	MA	01655	WORCESTER	USA	Aging Research	000	2	8/13/2024	EXTENSION WITH OR WITHOUT FUNDS	$728,896
														Subtotal = $1,103,900

Grand Total All Awards = $1,807,071

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Understanding the Microbiome-gut-brain axis in Alzheimers disease and its Role

Award Number: R01AG067483

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/15/2020

PERIOD OF PERFORMANCE END DATE: 12/31/2030

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