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

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.

Graphical Abstract

Figure 1.

Topographic plots of associations between age and fast sleep spindle measures, including (a) absolute power in the fast sigma frequency range [13–<16 Hz], (b) fast sleep spindle density, and (c) mean fast sleep spindle duration during nonrapid eye movement (NREM) sleep across electroencephalography (EEG) derivations. Cooler colors represent more negative associations, while warmer colors reflect more positive associations. Cyan dots indicate EEG derivations exhibiting significant associations (p < .05 uncorrected), while white asterisks denote significant associations following correction for multiple comparisons across the entire EEG array (p < .05 threshold-free cluster enhancement [TFCE] corrected [72–74]).

Figure 2.

Topographic plots of associations between cerebrospinal fluid (CSF) (a) glial fibrillary acidic protein (GFAP), (b) calcium binding protein B (S100B), (c) chitinase-3-like protein (YKL-40), and (d) log soluble triggering receptor expressed on myeloid cell 2 (sTREM2) levels and absolute power in the fast sigma frequency range [13 to <16 Hz] (top panel), fast sleep spindle density (middle panel), and mean fast sleep spindle duration (bottom panel) during nonrapid eye movement (NREM) sleep across electroencephalography (EEG) derivations. In the top and middle panels, green asterisks denote EEG derivations where threshold-free cluster enhancement (TFCE) corrected significant associations were detected across assessed markers of glial fibrillary acidic protein [GFAP], calcium binding protein B [S100B], chitinase-3-like protein [YKL-40], log soluble triggering receptor expressed on myeloid cell 2 [sTREM2], log total tau [t-tau], log phosphorylated tau [p-tau], 1/α-synuclein, log neurogranin, and log neurofilament light chain protein [NfL] (11 derivations for fast sigma activity and 3 derivations for fast sleep spindle density). In the bottom panel, green asterisks denote EEG derivations where TFCE-corrected significant associations were detected across assessed markers of GFAP, YKL-40, log sTREM2, log t-tau, log p-tau, 1/α-synuclein, log neurogranin, and log neurofilament light chain protein [NfL] (13 derivations).

Figure 3.

Topographic plots of associations between cerebrospinal fluid (CSF) (a) ratio of β-amyloid 42 to β-amyloid 40 (Aβ _42/40), (b) log Aβ40, (c) log Aβ42, (d) log total tau (t-tau), and (e) log phosphorylated tau (p-tau) and absolute power in the fast sigma frequency range [13 to <16 Hz] (top panel), fast sleep spindle density (middle panel), and mean fast sleep spindle duration (bottom panel) during NREM sleep across electroencephalography (EEG) derivations.

Figure 4.

Topographic plots of associations between cerebrospinal fluid (CSF) (a) 1/α-synuclein, (b) log neurogranin, and (c) log neurofilament light-chain protein (NfL) and absolute power in the fast sigma frequency range [13 to <16 Hz] (top panel), fast sleep spindle density (middle panel), and mean fast sleep spindle duration (bottom panel) during NREM sleep across electroencephalography (EEG) derivations.

Figure 5.

(a) Schematic representation of SPSS Process Macro v3.5 model 80 [76] implemented to examine combined parallel and serial mediation linking age to fast sigma activity through cerebrospinal fluid (CSF) glial fibrillary acidic protein (GFAP), calcium binding protein B (S100B), chitinase-3-like protein (YKL-40), and log soluble triggering receptor expressed on myeloid cell 2 (sTREM2) levels, respectively, and then through CSF log total tau (t-tau), log phosphorylated tau (p-tau), 1/α-synuclein, log neurogranin, and log neurofilament light chain protein (NfL) levels, comprising five separate serial mediation models. Lowercase letters a–d reflect regression coefficients corresponding to each path within the mediation model, with a₁—a₄ indicating the effect of age on inflammation markers, a₅ indicating the effect of age on markers of Alzheimer’s disease (AD)-related proteins or synaptic integrity, b₁—b₄ indicating the effect of inflammation markers on sleep spindle measures in the cluster of 11 overlapping electrodes, b₅ indicating the effect of AD-related proteins or synaptic integrity on fast sigma activity, c₁ and c_1′ reflecting the total effect and direct effect of age on fast sigma activity after adjusting for mediators, and d₁—d₄ reflecting the effect of inflammation markers on AD-related proteins or synaptic integrity. (b) Schematic representation of all significant serial mediation paths linking age to sleep spindle measures (fast sigma activity [13 to <16 Hz], fast sigma oscillatory activity, fast sleep spindle density, mean fast sleep spindle duration, total sleep spindle density, and total mean sleep spindle duration) during nonrapid eye movement (NREM) sleep (Supplementary Tables S6—S35). No paths are shown for GFAP or S100B because no significant paths through these inflammation markers were detected. Significant paths through YKL-40 and log p-tau, log t-tau, and 1/α-synuclein are denoted in red, and significant paths through log sTREM2 and log p-tau and 1/α-synuclein are denoted in blue.

Figure 6.

Topographic plots of associations between cube root of proportion (top panel) overnight memory change [(post-sleep memory—pre-sleep memory)/pre-sleep memory] and absolute (bottom panel) overnight memory change [post-sleep memory—pre-sleep memory] on the word pairs task and (a) absolute power in the fast sigma frequency range [13 to <16 Hz], (b) sleep spindle density for total spindles, fast spindles, and slow spindles, and (c) mean sleep spindle duration for total spindles, fast spindles, and slow spindles during NREM sleep across electroencephalography (EEG) derivations.