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Gut microbiota-based biomarkers of Alzheimer's disease and its modulation by a ketogenic diet

Award Number: R56AG064075
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: 04/30/2024

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Gut microbiota-based biomarkers of Alzheimer's disease and its modulation by a ketogenic diet - Project Summary Cognitive decline and Alzheimer's disease (AD) are major causes of morbidity and mortality worldwide and are substantially burdensome to those affected, their caregivers, and society in general. There remain important and formidable challenges in diagnosis, prognosis and prevention of this disease. Mild cognition impairment (MCI) is characteristic of early stage AD, and interventions targeting MCI can prevent progression of AD. Currently, no effective treatments are available and highly reliable consensus-based prognostic criteria for mild cognitive impairment (MCI) are lacking. Moreover, there is insufficient evidence to support the use of pharmaceutical agents or dietary supplements to prevent/treat MCI/AD. However, emerging research demonstrates that gut microbiota influences gut-brain communication and pathology of AD. Others and our preliminary data show that AD and MCI patient's gut harbors a perturbed and unique microbiota (dysbiosis) compared to cognitively normal individuals, suggesting that the gut microbiota could be a source of new biomarkers for MCI/AD. Diet is the single most significant modulator of the gut microbiota. A ketogenic diet (KD) is a powerful modulator of brain function and improves AD pathology, along with modulating the gut microbiota. However, currently it is unknown whether a modified Mediterranean KD (MMKD) primarily acts on the brain or the gut microbiota to ameliorate AD. Our preliminary data show that in participants with MCI, MMKD improved the gut microbiota signature and markers of AD in cerebrospinal fluid (CSF). In addition, gut microbiota signatures were significantly different in individuals with and without MCI, with certain bacteria associated with MCI status. Overall, MMKD was effective to improve AD markers in CSF and microbiota. However, certain people responded better (responders) than others (non- responders) in improving markers of AD and changing unique microbiota signature. We thus hypothesize that (a) gut microbiota-based biomarkers can predict MCI and MMKD response, and (b) MMKD acts through the microbiota to reduce AD pathology. To test our hypotheses, we propose to use a cohort of participants with and without MCI already being recruited for ongoing studies at Wake Forest Alzheimer's Disease Research Center (ADRC) led by Dr. Craft. We will examine whether our new microbiota-based markers could strengthen MCI prognosis and predict MMKD response, and test whether a MMKD modulates gut microbiota and thereby improves AD pathology. Three specific aims are designed to: 1) establish if the gut microbiota signature can predict MCI in humans, 2) determine whether gut microbiota signature can predict MMKD responders and non- responders to ameliorate AD markers, and 3) assess whether gut microbiota mediates MMKD's beneficial effects to ameliorate AD pathology. Completion of these state-of-the-art studies by a highly interdisciplinary team will establish proof-of-concept that gut microbiota-based markers can strengthen prognosis of MCI and will open translational opportunities to explore the use of MMKD as a non-pharmacological approach to ameliorate AD pathology.


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: 2024 ( Subtotal = -$3 )
2024	2021	UNIVERSITY OF SOUTH FLORIDA	4202 E FOWLER AVE	TAMPA	FL	33620	HILLSBOROUGH	USA	Aging Research	000	3	9/9/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	-$3
														Subtotal = -$3

Issue Date FY: 2023 ( Subtotal = $0 )
2023	2021	UNIVERSITY OF SOUTH FLORIDA	4202 E FOWLER AVE	TAMPA	FL	33620	HILLSBOROUGH	USA	Aging Research	000	3	5/2/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $0 )
2022	2021	UNIVERSITY OF SOUTH FLORIDA	4202 E FOWLER AVE	TAMPA	FL	33620	HILLSBOROUGH	USA	Aging Research	001	3	11/30/2021	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$468,535
2022	2021	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BLVD	WINSTON SALEM	NC	27157	FORSYTH	USA	Aging Research	002	2	5/6/2022	NON-COMPETING CONTINUATION	$0
2022	2020	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BLVD	WINSTON SALEM	NC	27157	FORSYTH	USA	Aging Research	000	1	11/30/2021	NEW	-$468,535
														Subtotal = $0

Issue Date FY: 2021 ( Subtotal = $604,248 )
2021	2021	UNIVERSITY OF SOUTH FLORIDA	4202 E FOWLER AVE	TAMPA	FL	33620	HILLSBOROUGH	USA	Aging Research	002	3	8/31/2021	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$604,248
2021	2021	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BLVD	WINSTON SALEM	NC	27157	FORSYTH	USA	Aging Research	000	2	5/12/2021	NON-COMPETING CONTINUATION	$604,248
2021	2021	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BLVD	WINSTON SALEM	NC	27157	FORSYTH	USA	Aging Research	001	2	8/30/2021	NON-COMPETING CONTINUATION	-$604,248
														Subtotal = $604,248

Issue Date FY: 2020 ( Subtotal = $604,248 )
2020	2020	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BLVD	WINSTON SALEM	NC	27157	FORSYTH	USA	Aging Research	000	1	9/14/2020	NEW	$604,248
														Subtotal = $604,248

Grand Total All Awards = $1,208,493

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Gut microbiota-based biomarkers of Alzheimer's disease and its modulation by a ketogenic diet

Award Number: R56AG064075

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: 04/30/2024

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