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Mitochondrial Energetic Failures in Men and Women Across Trajectories of Alzheimer Disease

Award Number: U01AG095419
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: COOPERATIVE AGREEMENT
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/01/2026
PERIOD OF PERFORMANCE END DATE: 08/31/2031

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Mitochondrial Energetic Failures in Men and Women Across Trajectories of Alzheimer Disease - Although genetic predisposition plays a crucial role in Alzheimer’s disease (AD) and related dementias (ADRD), the Lancet Commission on dementia estimated modifiable factors such as environmental exposures, lifestyle, and socioeconomic status to contribute up to 45% of dementia risk. Our AD Metabolomics Consortium (ADMC), as part of the Accelerating Medicines Partnership for AD (AMP-AD) and in partnership with the AD Neuroimaging Initiative (ADNI), generated and utilized state-of-the-art metabolomics data as sensitive readout for influences of both the genome and exposome on disease pathogenesis. Combined with genomic, clinical, and imaging data, our studies confirmed that peripheral metabolic changes link to biomarker, cognitive, and brain changes across the ATN spectrum, suggesting a connection between peripheral and central changes through the metabolome. These studies identified mitochondrial energetic failures linked to cognitive and brain imaging changes as crucial, with significant differences noted between males and females. Multi-omics data from AMP-AD added strong support for a central, sex-specific role of mitochondrial metabolism, highlighting beta oxidation, the TCA cycle, and mitochondrial transport processes as being implicated with key metabolites, transporters, and enzymes potentially involved. Developing a first index for bioenergetic capacity to stratify patients and identify individuals who may benefit from personalized approaches to improve mitochondrial function, we demonstrate that interventions tailored to enhance energetic health and slow bioenergetic aging could mitigate the risk of symptomatic AD, especially in individuals with specific mitochondrial genotypes. However, the significant sex differences observed for mitochondrial bioenergetics necessitate a more detailed mapping of energetic failures and their trajectories in men and women to develop more personalized therapeutic approaches for each sex. We employ a cross-disciplinary team-science approach to address this need through the following aims: 1) Establish sex-specific metabolomics signatures in blood that represent proxies for mitochondrial function and identify impairments of mitochondrial bioenergetics relevant to AD at the single individual level; 2) Demonstrate the relevance of these molecular proxies for mitochondrial function to disease progression through longitudinal analyses and investigate sex differences in their evolution over time. Evaluate if changes peripherally also manifest in brains of AD patients and determine genetic and lifestyle influences on these metabolic failures; 3) Use chemical and genetic functional screening approaches to define mechanistic links and sex differences between mitochondrial dysfunction and AD pathology. Leverage large lifestyle intervention studies to define non- pharmacological interventions that may complement pharmacological interventions in correcting energetic failures in AD. Our approach will enable us for the first time to define genetic and potentially modifiable factors that contribute to sex-specific energetic failures in AD and to develop more tailored approaches for interventions based on these metabolic failures. All data will be made publicly available through the AD Knowledge Portal.


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 = $2,261,339 )
2026	2026	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT HOUSTON	7000 FANNIN ST FL 9	HOUSTON	TX	77030	HARRIS	USA	Aging Research	000	1	8/19/2026	NEW	$2,261,339
														Subtotal = $2,261,339

Grand Total All Awards = $2,261,339

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Mitochondrial Energetic Failures in Men and Women Across Trajectories of Alzheimer Disease

Award Number: U01AG095419

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: COOPERATIVE AGREEMENT

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

PERIOD OF PERFORMANCE START DATE: 09/01/2026

PERIOD OF PERFORMANCE END DATE: 08/31/2031

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