Mander, Bryce A;
Dave, Abhishek;
Lui, Kitty K;
Sprecher, Katherine E;
Berisha, Destiny;
Chappel-Farley, Miranda G;
Chen, Ivy Y;
... Benca, Ruth M; + view all
(2022)
Inflammation, tau pathology, and synaptic integrity associated with sleep spindles and memory prior to β-amyloid positivity.
Sleep
, 45
(9)
, Article zsac135. 10.1093/sleep/zsac135.
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Abstract
STUDY OBJECTIVES: Fast frequency sleep spindles are reduced in aging and Alzheimer's disease (AD), but the mechanisms and functional relevance of these deficits remains unclear. The study objective was to identify AD biomarkers associated with fast sleep spindle deficits in cognitively unimpaired older adults at risk for AD. METHODS: Fifty-eight cognitively unimpaired, β-amyloid negative, older adults (mean±SD; 61.4±6.3 years, 38 female) enriched with parental history of AD (77.6%) and apolipoprotein E (APOE) ε4 positivity (25.9%) completed the study. Cerebrospinal fluid (CSF) biomarkers of central nervous system (CNS) inflammation, β-amyloid and tau proteins, and neurodegeneration were combined with polysomnography (PSG) using high density electroencephalography and assessment of overnight memory retention. Parallelized serial mediation models were used to assess indirect effects of age on fast frequency (13-<16Hz) sleep spindle measures through these AD biomarkers. RESULTS: Glial activation was associated with prefrontal fast frequency sleep spindle expression deficits. While adjusting for sex, APOE ε4 genotype, apnea-hypopnea index (AHI), and time between CSF sampling and sleep study, serial mediation models detected indirect effects of age on fast sleep spindle expression through microglial activation markers and then tau phosphorylation and synaptic degeneration markers. Sleep spindle expression at these electrodes was also associated with overnight memory retention in multiple regression models adjusting for covariates. CONCLUSIONS: These findings point toward microglia dysfunction as associated with tau phosphorylation, synaptic loss, sleep spindle deficits, and memory impairment even prior to β-amyloid positivity, thus offering a promising candidate therapeutic target to arrest cognitive decline associated with aging and AD.
| Type: | Article |
|---|---|
| Title: | Inflammation, tau pathology, and synaptic integrity associated with sleep spindles and memory prior to β-amyloid positivity |
| Location: | United States |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1093/sleep/zsac135 |
| Publisher version: | https://doi.org/10.1093/sleep/zsac135 |
| Language: | English |
| Additional information: | This version is the author accepted manuscript. For information on re-use, please refer to the publisher's terms and conditions. |
| Keywords: | Alzheimer’s disease, Inflammation, Memory, Neurodegeneration, Sleep spindles, Tau phosphorylation |
| UCL classification: | UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Neurodegenerative Diseases UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10150244 |
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