0415 Metabolic Dysfunction and Sleep Disruption in Models of Alzheimer’s Disease
Bibliographic record
Abstract
Abstract Introduction Metabolic perturbations and sleep disruptions are a cause and consequence of Alzheimer’s disease pathophysiology. A bidirectional relationship exists where impairments in sleep and metabolism contribute to the development of Alzheimer’s disease while the presence of Alzheimer’s disease pathology leads to decreased cerebral metabolism, peripheral glucose intolerance, and disrupted sleep. While the effects of type 2 diabetes (T2D) and Alzheimer’s disease on sleep have been explored separately, no previous studies have examined the effect of acute glycemic variability, a defining feature of T2D, on sleep in the context of Alzheimer’s disease. The goal of this study is to determine how glycemic variability drives sleep disruptions by modifying the relationship between cerebral glucose metabolism and neuronal activity. Methods Biosensors are implanted bilaterally into the hippocampus of APP/PS1, a model of amyloid-beta (Aβ) overexpression, and P301S, a model of tau deposition and neurodegeneration, mice to measure ISF glucose and lactate, markers of cerebral metabolism and neuronal activity, respectively. Simultaneous cortical EEG/EMG recordings are used for sleep/wake scoring and analysis. Results Glycemic fluctuations cause a decoupling of the typical relationships between cerebral metabolism and neuronal activity, while also increasing arousal in 3-month-old, wildtype mice. The presence of AD-like pathology results in a similar, albeit muted cerebral metabolic response to peripheral glycemic variability, but a diminished effect on wakefulness, likely due to age- and pathology-dependent increases in overall time spent awake. Conversely, in aged, P301S mice, cerebral metabolic responsiveness is lost and a ceiling effect on wakefulness emerges, suggesting differential effects on sleep with tau accumulation. Moreover, aged mice show progressive disruptions to overall sleep quality and quantity, highlighting the synergism existing between AD-like pathology and glucose intolerance in sleep dysfunction. Lactate seems to be a common driver of disruption in this synergistic cycle. Conclusion This study represents a novel approach to defining the dynamic interplay between risk factors for AD and T2D and suggests a feedforward loop of disease progression where disrupted sleep can alter the relationship between neuronal activity, metabolism, and pathology. Support NIH/NIA 1K01AG050719. Harold and Mary Eagle Fund for Alzheimer’s Research New Vision Award through Donors Cure Foundation
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".