Sleep, pericyte subtypes and cognitive decline in adults with and without Alzheimer’s disease
Bibliographic record
Abstract
Sleep fragmentation is common in older adults and is associated with cognitive impairment and dementia, as well as key histopathological correlates of dementia, including small vessel disease and cerebral infarcts. Vascular and blood-brain barrier dysfunction are thought to contribute to cognitive decline and dementia. Pericytes, a key vascular cell type, may play a key role. In model organisms, sleep disruption is associated with pericyte dysfunction and blood-brain barrier breakdown. Recent advances in single-nucleus RNA sequencing (snRNAseq) technology have identified two transcriptionally distinct subtypes of pericytes: extracellular matrix protein-expressing M-pericytes and solute carrier-expressing T-pericytes. However, the relationship between sleep, pericyte biology and cognition in humans remains unclear. We tested the hypothesis that differences in the composition of brain pericyte subpopulations, as inferred from marker gene expression, may link sleep fragmentation and cognitive decline. We leveraged two published human brain snRNAseq datasets to identify specific marker genes for M- and T-type pericytes. We then used post-mortem bulk RNAseq data from the dorsolateral prefrontal cortex (n = 1092) and lateral orbitofrontal cortex (n = 495) to quantify expression of these marker genes in older adults in two longitudinal cohort studies: the Religious Orders Study and Rush Memory and Aging Project. We derived trajectories of global cognitive function from participants' ante-mortem annual cognitive assessments, while sleep fragmentation was derived from ante-mortem wrist-actigraphy recordings from a subset of 572 participants. We used multivariate linear regression to relate pericyte marker gene expression to sleep fragmentation and cognitive decline in the decade preceding death. In the dorsolateral prefrontal cortex, greater average sleep fragmentation was associated with greater expression of M-pericyte marker genes [estimate = +3.65 × 10-1, standard error (SE) = 1.61 × 10-1, P = 0.024] but not T-pericyte marker genes. Dorsolateral prefrontal cortex expression of M-pericyte (estimate = -8.30 × 10-3, SE = 3.37 × 10-3, P = 0.014) but not T-pericyte marker genes was associated with more rapid cognitive decline in the 10 years prior to death. In the lateral orbitofrontal cortex, greater sleep fragmentation was also associated with greater composite M-pericyte gene expression (estimate = + 4.48 × 10-1, SE = 1.92 × 10-1, P = 0.02), which in turn was associated with faster cognitive decline in the decade preceding death (estimate = -1.30 × 10-2, SE = 4.55 × 10-3, P = 0.0044). These findings identify a potential role of M-pericytes in linking sleep fragmentation and cognitive trajectories in older adults. Additionally, our findings highlight the importance of vascular mechanisms in linking disrupted sleep to dementia.
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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".