Inflammation, tau pathology, and synaptic integrity associated with sleep spindles and memory prior to β-amyloid positivity

Bryce A Mander; Abhishek Dave; Kitty K Lui; Katherine E Sprecher; Destiny Berisha; Miranda G Chappel-Farley; Ivy Y Chen; Brady A Riedner; Margo Heston; Ivonne Suridjan; Gwendlyn Kollmorgen; Henrik Zetterberg; Kaj Blennow; Cynthia M Carlsson; Ozioma C Okonkwo; Sanjay Asthana; Sterling C Johnson; Barbara B Bendlin; Ruth M Benca

doi:10.1093/sleep/zsac135

Inflammation, tau pathology, and synaptic integrity associated with sleep spindles and memory prior to β-amyloid positivity

Sleep. 2022 Sep 8;45(9):zsac135. doi: 10.1093/sleep/zsac135.

Authors

Bryce A Mander^{1

2

3}, Abhishek Dave^{1

3}, Kitty K Lui^{1

4}, Katherine E Sprecher^{5

6

7}, Destiny Berisha⁸, Miranda G Chappel-Farley^{2

8}, Ivy Y Chen¹, Brady A Riedner⁹, Margo Heston^{6

7}, Ivonne Suridjan¹⁰, Gwendlyn Kollmorgen¹¹, Henrik Zetterberg^{12

13

14

15}, Kaj Blennow^{12

13}, Cynthia M Carlsson^{7

16

17}, Ozioma C Okonkwo^{7

16

17}, Sanjay Asthana^{7

16

17}, Sterling C Johnson^{7

16

17}, Barbara B Bendlin^{7

16

17}, Ruth M Benca^{1

2

5

8

9

18}

Affiliations

¹ Department of Psychiatry and Human Behavior, University of California, Irvine, CA, USA.
² Center for the Neurobiology of Learning and Memory, University of California, Irvine, CA, USA.
³ Department of Cognitive Sciences, University of California, Irvine, CA, USA.
⁴ San Diego State University/University of California San Diego, Joint Doctoral Program in Clinical Psychology, San Diego, CA, USA.
⁵ Neuroscience Training Program, University of Wisconsin-Madison, Madison, WI, USA.
⁶ Department of Medicine, University of Wisconsin-Madison, Madison, WI, USA.
⁷ Wisconsin Alzheimer's Disease Research Center, University of Wisconsin-Madison, Madison, WI, USA.
⁸ Department of Neurobiology and Behavior, University of California, Irvine, CA, USA.
⁹ Department of Psychiatry, University of Wisconsin-Madison, Madison, WI, USA.
¹⁰ Roche Diagnostics International Ltd, Rotkreuz, Switzerland.
¹¹ Roche Diagnostics GmbH, Penzberg, Germany.
¹² Institute of Neuroscience and Physiology, University of Gothenburg, Gothenburg, Sweden.
¹³ Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital , Mölndal, Sweden.
¹⁴ Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London, UK.
¹⁵ UK Dementia Research Institute at UCL, London, UK.
¹⁶ Wisconsin Alzheimer's Institute, Madison, WI, USA.
¹⁷ Geriatric Research Education and Clinical Center, Wm. S. Middleton Veterans Hospital, Madison, WI, USA.
¹⁸ Department of Psychiatry and Behavioral Medicine, Wake Forest University, Winston-Salem, NC, USA.

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 remain 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 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 to <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, 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.

Keywords: Alzheimer’s disease; inflammation; memory; neurodegeneration; sleep spindles; tau phosphorylation.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Aged
Alzheimer Disease* / pathology
Amyloid beta-Peptides / cerebrospinal fluid
Apolipoprotein E4 / genetics
Biomarkers / cerebrospinal fluid
Cognitive Dysfunction* / cerebrospinal fluid
Female
Humans
Inflammation
Male
Middle Aged
Peptide Fragments / cerebrospinal fluid
Sleep / physiology
tau Proteins* / cerebrospinal fluid

Substances

Amyloid beta-Peptides
Apolipoprotein E4
Biomarkers
Peptide Fragments
tau Proteins

Abstract

Publication types

MeSH terms

Substances

Grants and funding