NIH grant: Integrating Multi-Omics to Uncover Microbial Aging Dynamics in Cognitive Health (1K99AG097920-01)

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NIH grant 1K99AG097920-01: Integrating Multi-Omics to Uncover Microbial Aging Dynamics in Cognitive Health
Institute: {'code': 'AG', 'abbreviation': 'NIA', 'name': 'National Institute on Aging', 'admin_org_id': '12500002', 'admin_funding_url': ''}. PI: Yuxi  Liu. Award: $135540.
Start: 2026-07-01T00:00:00.
PROJECT SUMMARY/ABSTRACT
Alzheimer’s disease and related dementias (AD/ADRD) are projected to affect nearly 13 million individuals in the
United States by 2050. Recent advancements, including monoclonal antibodies targeting amyloid-beta, have
shown potential in slowing cognitive decline. However, their benefits remain limited and do not fully address the
complex biological mechanisms underlying ADRD, underscoring the need to identify novel, modifiable risk factors
and therapeutic targets, particularly in early cognitive decline. The gut microbiome has emerged as a promising
contributor to cognitive health through the gut-brain axis, modulating immune responses, metabolic processes,
and neurotransmitter synthesis. Ample prior data from our group and others support this link. Genetic
predispositions, such as the apolipoprotein E-ε4 (APOE4) genotype, and aging are well-established ADRD risk
factors, but the joint and interactive influence of genetics, aging, and the microbiome on cognitive health remains
unclear. This K99/R00 proposal aims to leverage a multi-omics approach to investigate microbial aging dynamics
in cognitive health, with an emphasis on longitudinal changes in microbial functionality and the modulatory role
of host genetics. Aim 1 is to examine the interrelationships between genetic predispositions to AD/ADRD (e.g.,
APOE4, ABCA7, CR1, and polygenic risk scores), gut microbial taxonomic and functional profiles, and cognitive
outcomes in multiple large prospective cohorts. This aim tests the hypothesis that genetic predispositions
modulate microbial contributions to cognitive decline, for example, that protective associations of short-chain
fatty acid (SCFA)-producing bacterial abundances might be more pronounced among APOE4 carriers. Aim 2 is
to develop microbiome-based aging clocks using machine learning algorithms in an international microbiome
consortium, testing the hypothesis that microbial age acceleration is prospectively associated with cognitive
decline and MRI-measured brain aging, and that these associations vary by genetic predispositions to AD/ADRD.
Aim 3 employs a longitudinal design to investigate the functional roles of gut microbes and their dynamic changes
in relation to cognitive health, generating new and diverse functional data from stool samples and ATX(N)
biomarker data, which reflect early pathophysiologic changes in ADRD, from blood samples. This aim will explore
whether microbial functional activities, such as SCFA production and amyloid-like peptide synthesis, interact with
aging and genetics to influence cognitive decline and biomarker changes. This project will enhance
understanding of ADRD etiology and will enable the identification of actionable biomarkers for early prevention
and intervention. This study directly aligns with the NIA’s mission to prevent and treat ADRD and advance
knowledge of aging. The proposed training in ADRD, neuropsychology, cognitive aging, microbiome, and clinical
and translational research, supported by Brigham and Women’s Hospital, will establish a strong foundation for
an independent research career focused on multi-omics dissection of ADRD and cognitive aging.

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