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Metabolic Regulation of Neural Oscillations in APOE4 Genetic Risk for Late Onset Alzheimer’s Disease

Award Number: R21AG101844
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/08/2026
PERIOD OF PERFORMANCE END DATE: 08/31/2028

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Metabolic Regulation of Neural Oscillations in APOE4 Genetic Risk for Late Onset Alzheimer’s Disease - Abstract: Currently, the average life expectancy exceeds the cognitive health span by several decades, and a majority of the 46 million Americans over the age of 65 will suffer cognitive decline and, in severe circumstances, dementia, which will interfere with quality of life and ability to maintain independence. To date, effective therapeutic options for slowing or halting cognitive decline associated with aging as well as Alzheimer’s disease and related dementias, are limited. Impaired glucose utilization and synaptic dysfunction are the strongest neurobiological predictors of cognitive decline in aging and Alzheimer's disease and related dementias (ADRD), yet we lack integrated methodological tools to quantify their interdependence in vivo with clinical translatability. This is particularly critical given recent failures of metabolism-based clinical trials and emerging evidence that therapeutic responses may depend on APOE genotype. The long-term goal of this research is to enhance cognitive resilience in older adults at risk for ADRD through metabolism-based therapies that improve brain function. The overall objective is to establish the first in vivo quantification of glucose-synaptic activity interactions across APOE genotype and metabolic state, paired with a non-invasive EEG biomarker suitable for clinical translation. Through innovative integration of fiber photometry for real-time intracellular glucose monitoring, simultaneous hippocampal local field potential (LFP) recordings, and surface EEG measurements in humanized APOE3 and APOE4 knock-in rats, we will test the central hypothesis that LFP and EEG dynamics are modulated by intracellular glucose availability in an APOE genotype-dependent manner, and that metabolic interventions can restore these relationships to improve cognition. We will test this hypothesis with two specific aims: Aim 1: Determine how cognitive load mediates coupling between hippocampal intracellular glucose and synaptic activity in young and aged APOE4 or E3 knock-in rats, using the clinically-relevant Paired Associates Learning task. Aim 2: Determine the impact of metabolic state (ketogenic diet or exogenous ketone supplementation) on hippocampal glucose-LFP interactions in middle-aged APOE3 and APOE4 rats, establishing whether bypassing glycolysis can restore synaptic dynamics detectable via surface EEG. This research is innovative in its technical integration of glucose photometry with invasive and non-invasive neurophysiology (modalities never previously combined in vivo) and its conceptual framework linking metabolism to circuit function across genotype. The significance lies in identifying mechanistic glucose metabolism-synapse relationships that can guide precision metabolic therapies while establishing translatable EEG biomarkers for treatment efficacy, advancing toward genotype-informed interventions to preserve cognitive function in populations at risk for late onset Alzheimer’s disease.


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 = $422,125 )
2026	2026	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Aging Research	000	1	9/7/2026	NEW	$422,125
														Subtotal = $422,125

Grand Total All Awards = $422,125

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Metabolic Regulation of Neural Oscillations in APOE4 Genetic Risk for Late Onset Alzheimer’s Disease

Award Number: R21AG101844

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/08/2026

PERIOD OF PERFORMANCE END DATE: 08/31/2028

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