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Author ORCID Identifier

https://orcid.org/0000-0003-1430-493X

Date Available

5-4-2026

Year of Publication

2026

Document Type

Doctoral Dissertation

Degree Name

Doctor of Philosophy (PhD)

College

Medicine

Department/School/Program

Neuroscience

Faculty

Shannon L Macauley

Faculty

Richard C. Grondin

Abstract

Metabolic flexibility is essential for maintaining normal physiological function, enabling an organism to sense, flux, utilize, and switch fuel sources in response to changing energetic availability, demand, and cellular needs. Energetic demands are state-dependent, with wake and sleep exhibiting distinct metabolic profiles. Sleep is highly sensitive to changes in metabolism and requires metabolic flexibility to both transition into and maintain sleep stability. Alzheimer’s disease (AD) is increasingly recognized as a disease of altered metabolism yet is often framed as a disease of energetic failure. We instead define AD as a disease of metabolic inflexibility, characterized not by insufficient energy availability, but by an impaired ability to appropriately adapt metabolic flux and fuel utilization to changing demands. The downstream consequences of this metabolic inflexibility are sleep loss, reduced sleep quality, cortical excitability, network dysfunction, and metabolic rigidity. Metabolic alterations emerge early in AD, during the presymptomatic phase of the disease, and coincide with the accumulation of amyloid plaques. This early stage is marked by cerebral glucose hypermetabolism, which precedes hypometabolism observed later in disease progression. We propose that this hypermetabolic state reflects a rigid, pro-glycolytic metabolic reprogramming that limits metabolic flexibility. Microglia contribute substantially to this process, favoring glycolysis over oxidative phosphorylation in response to amyloid pathology and increasing production of lactate, a metabolite associated with sleep-wake regulation, which stimulates cortical excitability resulting in sleep loss.

Using in vivo metabolic, electrophysiological, and behavioral approaches, we demonstrate that metabolism is tightly coupled to sleep-wake dynamics and cortical activity required for sleep stability. First, we identified a novel metabolic sensor that links cellular metabolism to cortical excitability and sleep: Kir6.2-KATP channels. Next, we described how the metabolite, lactate, acts as a sleep-wake switch, increasing during wake and decreasing during sleep. Loss of the metabolic sensor Kir6.2-KATP channels uncouples metabolism from neuronal activity, abolishing lactate dynamics associated with sleep-wake transitions and arousal. This metabolic uncoupling alters sleep-wake architecture and disrupts EEG activity critical for stable sleep and wake states, representing a form of metabolic inflexibility in which glucose availability is maintained but is improperly fluxed to support normal brain physiology. These principles extend to Alzheimer's disease. The emergence of amyloid plaques reduces sleep time, impairs sleep quality, and induces a rigid, hyperexcitable, desynchronized network state. Mechanistically, we demonstrated that microglia undergo metabolic reprogramming, increase lactate production, and disrupt sleep. In both normal aging and amyloid pathology, microglial expansion occurs in brain regions critical for sleep-wake regulation, including the thalamus, as well as white matter tracts connecting plaque-prone regions with sleep-promoting regions. Importantly, depleting microglia rescues up to two hours of sleep per day without altering amyloid plaque load, identifying a causal and reversible role for microglia in sleep disruption. Together, these findings highlight the exceptional sensitivity of sleep and quantitative EEG measurements for detecting early metabolic and pathological changes in AD, while dissociating distinct amyloid- and age-related changes. This shows that targeting metabolic pathways associated with disease reactive microglia can restore sleep in AD.

Digital Object Identifier (DOI)

https://doi.org/10.13023/etd.2026.112

Archival?

Archival

Funding Information

National institute of aging, (R01AG068330) 2021-2024

National institute of aging, (R01AG093847) 2025-2026

BrightFocus Foundation, (A20201775S)

 Coins for Alzheimer’s Research Trust Grant

National institute of aging, (P30AG072946)

Cure Alzheimer’s Fund

 National institute of neurological disorders and stroke, (T32NS115704) 2022-2023 This research was supported by an Institutional Development Award (IDeA) from the National institute of general medical sciences and National institute of health (P30GM127211) and the National institute of health Center of Biomedical Research Excellence (COBRE) in CNS Metabolism (CNS-Met; P20GM148326).

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