Obstructive sleep apnea (OSA) is a complex condition characterized by repeated episodes of upper airway collapse during sleep, leading to chronic intermittent hypoxia. Diffusion magnetic resonance imaging (dMRI) techniques offer sensitivity to white matter (WM) microstructure changes. 150 individuals from a community-based study underwent one-night nocturnal polysomnography (NPSG), cognitive assessments, and brain structural MRI. Gaussian and non-Gaussian diffusion signal changes in WM tracts were quantified with diffusion tensor metrics as (DTI) and Diffusion Kurtosis Imaging (DKI), respectively. While changes in WM microstructure were assessed in terms of Standard Model metrics. The genu of the corpus callosum (GCC) demonstrated negative correlations between AHI3A and FA (p < 0.01), AD (p < 0.05), f (SMI-based axonal water fraction) (p < 0.05), and p2 (p < 0.05) (SMI-based extra-axonal water), alongside positive correlations with RD (p < 0.05). The right cingulum showed negative associations with FA (p < 0.01), RK (p < 0.01), f (p < 0.01) and [Formula: see text](p < 0.01). Subjects without OSA showed higher values in FA (p = 0.001), AD (p = 0.01), f (p = 0.03), and [Formula: see text] (p = 0.0006) in the GCC and cingulum. The strongest differences between severity groups were observed between AHI3A(0–5/h) and AHI3A(> 30/h), particularly in the GCC FA (p = 0.001), RD (p = 0.008), and RK (p = 0.02), and the cingulum f (p ≤ 0.01). Decreases in AD, RK, and FA, and increased RD with increasing OSA severity suggest demyelination and axonal loss. This contrasts with f, a direct measurement for axonal density, which was lower in the OSA group, demonstrating that OSA affects the WM microstructure. Future studies should include longitudinal evaluations to assess the effects of disease duration, and the clinical significance of changes in dMRI metrics over time.

BACKGROUND:As individuals with Down syndrome age, they face high risks of Alzheimer's disease and epilepsy. With symptomatic Alzheimer's disease, late-onset myoclonic epilepsy in Down syndrome (LOMEDS) often emerges. We aimed to examine how epilepsy develops in Down syndrome, its timing relative to Alzheimer's disease symptom onset, and its effect on prognosis. METHODS:We conducted a multicentre, observational, longitudinal study across seven international cohorts with an aggregate observation window from Oct 24, 2012, to July 28, 2025. We included adults with Down syndrome aged at least 18 years and with at least one longitudinal clinical assessment. Alzheimer's disease staging was done by clinical consensus. Active epilepsy required an epilepsy diagnosis plus ongoing antiseizure medication or at least one seizure within the past 5 years. We analysed active epilepsy prevalence, incidence and cumulative incidence, its timing with respect to symptomatic Alzheimer's disease, and its effect on survival and cognitive trajectories as well as electroencephalogram (EEG) abnormalities. FINDINGS:We included 4804 adults with Down syndrome (mean age 43 years [SD 13]): 3238 (67·4%) were cognitively stable, 267 (5·6%) had non-degenerative cognitive decline, 321 (6·7%) had prodromal Alzheimer's disease, and 978 (20·3%) had Alzheimer's disease dementia. Intellectual disability was mild in 1020 (24·6%) participants, moderate in 2352 (56·7%), and severe to profound in 779 (18·8%). Active epilepsy prevalence was 145·2 per adults with Down syndrome overall but significantly increased with age, particularly with symptomatic Alzheimer's disease, when epilepsy manifested mostly as myoclonic or tonic-clonic seizures. Cumulative incidence of epilepsy increased linearly after symptomatic Alzheimer's disease, from 9·5% (95% CI 7·8-11·3) at diagnosis to 56·9% (51·7-61·7) after 9 years. Risk of epilepsy increased with time since Alzheimer's disease diagnosis (adjusted odds ratio 1·33 per year [95% CI 1·22-1·45]; p<0·0001), severe-to-profound intellectual disability (2·14 per year [1·25-3·70]; p=0·0057), and APOE ε4 carriership (1·61 per year [1·04-2·49]; p=0·034), independent of age. LOMEDS was associated with increased mortality (hazard ratio 2·10 [95% CI 1·57-2·82]; p<0·0001), and faster cognitive decline. Interictal EEG abnormalities showed little diagnostic utility. INTERPRETATION:Epilepsy increases sharply after symptomatic Alzheimer's disease onset in people with Down syndrome. The association of epilepsy with reduced survival and accelerated cognitive decline underscores the need for targeted preventive and therapeutic strategies against Alzheimer's disease-related epileptogenesis and hyperexcitability. FUNDING:See Acknowledgments for funders.

Abstract Introduction Associations between sleep architecture and change in plasma amyloid biomarkers have been only minimally evaluated, despite their advantages of high accessibility and safety when sampling. Here we examined the longitudinal effect of REM sleep on plasma beta-amyloid (Aβ) 42/40 ratio in cognitively normal older adults. Methods Sixty-four community-dwelling cognitively normal adults ages 55 to 90 were recruited at the NYU Alzheimer’s disease research center. All participants completed a baseline polysomnogram and had repeated plasma collections 3.2 ± 2.0 years apart. Plasma Aβ 42 and 40 were measured via mass spectrometry (Araclon Biotech, Spain). Amyloid positivity was calculated with the Youden Index (Aβ 42/40 ratio ≤0.0992). We evaluated associations between %REM sleep and annualized changes in the plasma biomarker divided by year interval (Δ Aβ42/40Post-Pre / year interval) using bivariate Spearman’s correlation and generalized linear models with annualized changes in the plasma biomarker divided by year interval (Δ Aβ42/40Post-Pre / year interval) as the dependent variable, after adjusting for age, sex, apolipoprotein ε4 (APOE4) status, presence of OSA (AHI4% ≥ 5/hour), and the use of SSRI/SNRI’s. Results Subjects were 66.7 ± 7.4 years old, 68.5% female, 57.4% Caucasian, 38.9 % APOE4 carriers, 18.5% amyloid positive, 46.3% with Apnea-Hypopnea Index 4% (AHI4%) ≥5, and 3.1% with SSRI/SNRI use. Total sleep time was 366.5 ± 83.3 minutes, REM sleep duration was 72.6 ± 31.1 minutes, and the percentage of REM sleep of total sleep time (REM%) was 19.4 ± 6.4%. Low REM% was significantly correlated with a high annual decline of plasma Aβ42/40 ratio (ρ=0.31, p=0.013), though to reflect increased intracranial amyloid, and was associated with an annual decline of plasma Aβ42/40 ratio, after adjusting for covariates (β=2.08, p=0.043). In a subgroup analysis, low REM% was significantly associated with a high annual decline of plasma Aβ42/40 ratio in the Aβ positive group (β=3.20, p=0.033), but more weakly so in the negative group (β=1.52, p=0.14). Conclusion A low percentage of REM sleep might be an indicator of a faster accumulation of intracranial amyloid in cognitively normal older adults. This relationship was more strongly observed once amyloid pathology initiates, even before cognitive symptom onset. Support (if any)

Obstructive sleep apnea (OSA) exerts pathogenic effects through a combination of sleep fragmentation (SF) and intermittent hypoxia (IH). The mechanisms through which sleep disruption impacts memory might arise by investigating disruption of specific sleep stages and, when such disruption occurs through OSA, by evaluating the individual contributions of SF and IH. Given that region-specific EEG slow activity during non-REM sleep has been associated with overnight declarative, motor, and spatial memory formation, we investigated the effects of disrupting slow wave sleep (SWS) on a virtual maze navigation task. Thirty-three participants (24 male, 56 years old [range 28-68 years] with OSA (baseline AHI4%>20/h) who were habitually well-treated and adherent to continuous positive airway pressure (CPAP) completed 3 timed trials on a 3D spatial maze before and after polysomnographically (PSG) recorded sleep. We restricted CPAP withdrawal to SWS through real-time monitoring of the PSG under three conditions: (1) stable SWS on therapeutic CPAP, (2) SWS-CPAP withdrawal containing SF and IH, and (3) SWS-CPAP withdrawal with supplemental oxygen containing SF with reduced IH. SWS-specific CPAP withdrawal (with or without supplemental oxygen) did not significantly impact EEG slow oscillation or spatial navigational memory despite effectively reducing %SWS and SWS bout length. Greater regional EEG slow oscillation (0.6-1 Hz), but not delta (1-4 Hz) activity, was associated with improvements in overnight memory during stable SWS in the CPAP condition. These observations suggest that slow oscillations may be important for overnight memory processing, and sleep disruptions of sufficient magnitude to reduce slow oscillations may be required to capture demonstrable change in spatial navigation performance.

Pre- and post-menopausal females have greater slow wave sleep (SWS) and delta power compared with males. However, the mechanisms underlying this sex difference remain unknown. Sleep and temperature regulation are highly interdependent. We explored whether sex differences in thermoregulation interact with sex differences in SWS as a potential mechanism. We also explored whether a prior history of shift work, known to disrupt circadian rhythms and sleep, moderated body temperature-SWS relationships. We compared measures of SWS and core body temperature (Tc) simultaneously recorded during a 60h laboratory study in males (n=36, mean age 68.85 yr) and females (n=37, mean age 68.02 yr). The 3-night protocol included one night of nocturnal PSG; one night of total sleep deprivation under constant routine conditions (36–40h) and one recovery PSG sleep night. The sample included 40 retired day workers (RDW) and 33 retired shift workers (RSW). Tc analysis focused on the sleep-associated Tc decline (Tdrop), known to correlate with SWS, during the recovery night. Compared to males, females had substantially higher recovery %SWS (13.8±10.75 vs 4.9±5.29 %, p< 0.001), SWS min (57.12±45.53 vs 18.26±20.77 min p < 0.001), mean delta power (109.01±44.91 vs 66.97±27.75, p < 0.001) and greater Tdrop (0.96±0.20 vs 0.82±0.28 °C, p < 0.05). Tdrop weakly correlated with %SWS in females (r=0.34, p = 0.07), but not in males. Tdrop was not significantly associated with SWS min and delta power in either sex. However, RDW females (n=17) showed moderate–strong and significant correlations: greater Tdrop correlated with greater %SWS (r=0.67, p< 0.01), SWS min (r=0.59, p < 0.05), and delta power (r=0.54, p< 0.05). These correlations were not significant in female RSW (despite similar SWS and Tdrop), or in male RSW or RDW (p > 0.10) all comparisons. The association between SWS and sleep-associated core body temperature decline varies by sex and a history of shift work. Further studies may determine whether sex differences in temperature and sleep regulation results from known sexual dimorphism in sleep-wake promoting and thermoregulatory nuclei, and how this pattern interacts with sex-differences in risk for sleep disorders or other health problems. R01AG047139; K01AG075151; R01AG070866

Sleep disturbance is bidirectionally associated with an increased risk of Alzheimer's disease and other tauopathies. While the sleep-wake cycle regulates interstitial and cerebrospinal fluid (CSF) tau levels, the underlying mechanisms remain unknown. Understanding these mechanisms is crucial, given the evidence that tau pathology spreads through neuron-to-neuron transfer, involving the secretion and internalization of pathological tau forms. Here, we combined in vitro, in vivo, and clinical methods to reveal a pathway by which changes in body temperature (BT) over the sleep-wake cycle modulate extracellular tau levels. In mice, a higher BT during wakefulness and sleep deprivation increased CSF and plasma tau levels, while also upregulating unconventional protein secretion pathway I (UPS-I) events including (a) intracellular tau dephosphorylation, (b) caspase 3-mediated cleavage of tau (TauC3), and (c) membrane translocation of tau through binding to phosphatidylinositol 4,5-bisphosphate (PIP2) and syndecan 3. In humans, the increase in CSF and plasma tau levels observed after wakefulness correlated with BT increases during wakefulness. By demonstrating that sleep-wake variation in BT regulates extracellular tau levels, our findings highlight the importance of thermoregulation in linking sleep disturbances to tau-mediated neurodegeneration and the preventative potential of thermal interventions.

INTRODUCTION:Alzheimer's disease (AD) dementia has near full penetrance in adults with Down syndrome (DS) and is strongly linked to late-onset myoclonic epilepsy in Down syndrome (LOMEDS). However, promising biomarkers of epileptogenicity, such as high-frequency oscillations (HFOs >250 Hz), have not been studied. This study is the first to use wideband polysomnography in DS to investigate if HFOs occurred and preceded AD dementia and LOMEDS. METHODS:Wideband (0.1 to 500 Hz, 2048 Hz) polysomnography was performed using the international 10-20 system. HFOs were automatically detected during slow-wave sleep, followed by manual review. RESULTS:Fourteen individuals with DS and five age-matched euploid controls were studied, with all DS cases showing HFOs. HFOs emerged before AD dementia and LOMEDS and showed hemispheric lateralization in asymptomatic but not symptomatic AD dementia cases. A trend toward increasing HFO rates with age in DS warrants further confirmation. DISCUSSION:HFOs are promising biomarkers that may predict symptomatic AD dementia in adults with DS. HIGHLIGHTS:Wideband polysomnography reveals a new electrical abnormality in DS. HFOs precede AD dementia in DS. The occurrence of HFOs in DS is independent of an epilepsy diagnosis. HFOs showed hemispheric lateralization in asymptomatic DS cases. A trend of increased HFO rate with advancing age warrants further investigation.

BACKGROUND:Comorbidity between alcohol use disorder (AUD) and post-traumatic stress disorder (PTSD) exacerbates symptom severity and worsens treatment outcomes. Limited clinical research suggests that cannabidiol (CBD) may have therapeutic effects on anxiety disorders and addictive behavior, but efficacy has not been established. METHODS:Two proof-of-concept trials of CBD were conducted simultaneously. In Study 1, 27 adults with moderate to severe AUD were randomized to CBD [600 mg/day for 4 weeks, then 1200 mg/day for 4 weeks] versus placebo. In Study 2, 30 adults with AUD plus DSM-5 PTSD or subthreshold post-traumatic stress disorder (PTSD) were randomized to CBD 600 mg/day vs. placebo for 6 weeks. The trials assessed CBD pharmacokinetics, safety and tolerability, alcohol consumption, craving, mood and anxiety symptoms, and, in Study 2, PTSD symptom severity. Efficacy analyses used mixed-effects models, and the primary drinking outcome was the average number of drinks per day during treatment. RESULTS:CBD was rapidly absorbed, achieving near-steady-state trough levels by week 1, with dose-dependent increases during weeks 5-8 in Study 1. Mean trough and estimated peak CBD levels at week 4 (n = 20) were 31.15 (SD: 21.22) ng/mL and 130.75 (SD: 152.57) ng/mL, respectively. Few safety concerns emerged, but 7/31 (22.6%) of participants assigned to CBD experienced dose-limiting side effects. In both studies, participants in both treatment groups showed large reductions in drinks per day and percentage heavy drinking days during treatment (Cohen's dz. > 0.9). Neither trial demonstrated superiority of CBD over placebo for drinking outcomes, craving, mood, anxiety, or PTSD symptoms. CONCLUSIONS:These findings support the feasibility and tolerability of twice-daily oral CBD up to 1200 mg/day in actively drinking individuals but do not demonstrate efficacy at the CBD levels that were achieved in this study. Further dose finding and larger, well-powered trials are needed to clarify CBD's therapeutic potential in AUD and comorbid PTSD.

There has been emerging evidence on the bidirectional relationship between sleep and Alzheimer’s disease (AD) pathology. However, there has been sparse data using plasma AD biomarkers despite its advantages of high accessibility and safety when sampling. This study aims to examine the longitudinal effect of slow wave sleep (SWS) on plasma beta-amyloid (Aβ) 42/40 ratio and phosphorylated-tau 217 (p-tau 217) in cognitively normal older adults. Sixty-three community-dwelling cognitively normal adults aged between 55 and 90, with Mini-Mental State Exam scores of 25 or more, were recruited at the New York University Brain Aging & Sleep Center. All participants completed a baseline polysomnogram and had repeated plasma collections at least 2 years apart. Plasma Aβ 42 and 40 were measured via mass spectrometry (Araclon Biotech, Spain). Plasma p-tau 217 was measured in a subset of 22 subjects by the single-molecule array technology (Quanterix Corp., USA). Spearman’s correlation analysis was performed. Multiple regression analyses were done with the dependent variable as log-transformed changes in plasma biomarkers divided by year interval (log [Δ Aβ42/40pre-post] or [Δ p-tau 217post-pre] / year interval), after adjusting for age, sex, and apolipoprotein ε4 (APOE4) status. Subjects were 66.3 ± 7.3 years old, 71.4 % female, and 41.5 % APOE4 positive. SWS duration was 73.6 ± 45.6 minutes (20.6 ± 13.1% of total sleep time). The mean follow-up interval was 3.3 ± 2.0 years. SWS duration and %SWS were associated with annualized log Δ Aβ42/40 (t = ─ 2.917, p = 0.005; t = ─ 3.026, p = 0.004). In 22 subjects who had repeated plasma p-tau 217, SWS duration and %SWS were correlated with annualized log Δ p-tau 217 (ρ = ─ 0.441, p = 0.040; ρ = ─ 0.457, p = 0.032), but not associated after adjusting for covariates (t = ─ 1.323, p = 0.210; t = ─ 1.901, p = 0.082). In cognitively normal older adults, short SWS duration and low SWS percentage may predict faster annualized plasma Aβ42/40 ratio decline and p-tau 217 increase longitudinally, reflective of increased cortical amyloid plaque and tau tangle load respectively, in the preclinical stage of Alzheimer’s disease.

Posttraumatic stress disorder (PTSD) is associated with cognitive deficits, particularly in executive functioning, which may be influenced by both past trauma and current symptom severity. We hypothesized that individuals with higher scores on the Childhood Trauma Questionnaire (CTQ) and the Clinician-Administered PTSD Scale for DSM-5 (CAPS-5) would show poorer performance on the Trail Making Test B, a measure of cognitive flexibility and executive function, and their interaction would compound these deficits. This study examined the relationship between childhood trauma, PTSD symptom severity, and executive functioning in a baseline sample of 60 individuals aged 18 to 70 across races and gender, enrolled in a clinical trial at an Academic Medical Center investigating the effects of cannabidiol (CBD) for PTSD. A factorial ANOVA was used to assess how CTQ and CAPS-5 scores, as well as their interaction, predicted performance on Trail B. Results:The overall model was significant, F(45, 14) = 3.77, p = .004, accounting for 91.7% of the variance in Trail B scores. Higher CTQ scores were associated with poorer performance, F(4, 14) = 5.30, p = .007, as were higher CAPS-5 scores, F(29, 14) = 3.34, p = .008. A significant CTQ by CAPS-5 interaction, F(11, 14) = 3.19, p = .020, revealed that individuals with both high childhood trauma exposure and elevated PTSD symptoms demonstrated the greatest impairments in executive function. These findings underscore the compounding effects of early-life adversity and current PTSD severity on cognitive functioning, highlighting neurocognitive vulnerabilities in PTSD and informing the potential cognitive implications of CBD treatment.

INTRODUCTION:Down syndrome (DS) is a genetic form of Alzheimer's disease (AD), with a high prevalence of sleep disorders, but data in adults with DS and dementia are lacking. We aim to assess sleep in adults with DS across the AD continuum. METHODS:We studied 78 healthy controls and 229 adults with DS (154 asymptomatic, 25 with prodromal AD, and 75 with AD) with subjective sleep measures and objective nocturnal polysomnography. RESULTS:Adults with DS presented worse sleep quality and higher prevalence of unnoticed obstructive sleep apnea (OSA) than controls. Sleep disruption and OSA severity increased across the AD continuum. Age-related decreases in slow-wave sleep and rapid eye movement sleep were more pronounced in the DS group. Subjective sleep measures did not capture sleep disorders. CONCLUSIONS:In DS, AD is linked to worse sleep disturbances and altered architecture. However, longitudinal studies are needed to clarify directionality and disease progression. HIGHLIGHTS:Down syndrome (DS) is associated with increased slow-wave sleep (SWS) and reduced rapid eye movement (REM) sleep. Obstructive sleep apnea prevalence increases along the Alzheimer's disease continuum in DS. Age-related decreases in SWS and REM sleep are accelerated in DS. Subjective sleep measures do not detect sleep disturbances in adults with DS.

The locus coeruleus (LC), an important sleep/wake regulating structure and site of early change in neurodegenerative disease, is best measured in humans with ultra-high field 7-Tesla MRI due to its small size. We hypothesized that obstructive sleep apnea (OSA) would negatively influence LC structural integrity and volume in cognitively normal elderly individuals. We examined the LC using 7T MRI with a computational LC localization and segmentation algorithm in 30 cognitively normal older subjects: 17 with a new OSA clinical diagnosis and 13 from the community without sleep complaints. Obstructive sleep apnea was assessed by WatchPAT home sleep study or in-lab polysomnography. We evaluated associations between OSA severity/hypoxic burden and LC structural metrics: absolute volume, volume normalized to brainstem or whole brain volume, and LC integrity, a relative measure of MRI contrast enhanced neuromelanin. Of the 30 subjects, mean age was 66 years and 53% were women. The cohort was dichotomized using an OSA cutoff of AHI4%>=5 (OSA+, n=22, OSA-, n = 8). Total sleep time was not significantly different between the OSA- and OSA+ groups. As expected, AHI4%, REM AHI4%, and min. oxygen saturation during sleep were all significantly different in the OSA- and OSA+ groups, though time below 90% oxygen saturation (T90) was not. We observed a significant negative association between LC integrity and T90 [R=-0.45, p=0.035] in the OSA+ group, but not the OSA- group [R=0.58, p=0.132]. We did not observe differences between the OSA+ and OSA- groups for the absolute LC volume [OSA-: 145± 63mm3, OSA+: 132± 74, p=0.44], LC volume normalized to brainstem volume [OSA-: 0.0052± 0.0032, OSA+: 0.0055± 0.0032, p=0.83], LC volume normalized to whole brain volume [OSA-: 8.0e-05± 4.8e-05, OSA+: 7.6-05± 4.7e-05, p=0.83], or LC integrity [OSA-: 1.60± 0.09, OSA+: 1.58± 0.14, =0.94]. This study presents some of the first evidence that greater hypoxic burden as assessed by T90 is associated with reduced LC integrity in older adults, potentially implicating a role for nocturnal hypoxemia in the pathological decline of the LC with aging. AASMF Bridge award, AARGD award, NIH

PURPOSE:The pathological hallmarks of Alzheimer's disease (AD), amyloid, tau, and associated neurodegeneration, are present in the cortical gray matter (GM) years before symptom onset, and at significantly greater levels in carriers of the apolipoprotein E4 (APOE4) allele. Their respective biomarkers, A/T/N, have been found to correlate with aspects of brain biochemistry, measured with magnetic resonance spectroscopy (MRS), indicating a potential for MRS to augment the A/T/N framework for staging and prediction of AD. Unfortunately, the relationships between MRS and A/T/N biomarkers are unclear, largely due to a lack of studies examining them in the context of the spatial and temporal model of T/N progression. Advanced MRS acquisition and post-processing approaches have enabled us to address this knowledge gap and test the hypotheses, that glutamate-plus-glutamine (Glx) and N-acetyl-aspartate (NAA), metabolites reflecting synaptic and neuronal health, respectively, measured from regions on the Braak stage continuum, correlate with: (i) cerebrospinal fluid (CSF) p-tau181 level (T), and (ii) hippocampal volume or cortical thickness of parietal lobe GM (N). We hypothesized that these correlations will be moderated by Braak stage and APOE4 genotype. METHODS:We conducted a retrospective imaging study of 34 cognitively unimpaired elderly individuals who received APOE4 genotyping and lumbar puncture from pre-existing prospective studies at the NYU Grossman School of Medicine between October 2014 and January 2019. Subjects returned for their imaging exam between April 2018 and February 2020. Metabolites were measured from the left hippocampus (Braak II) using a single-voxel semi-adiabatic localization by adiabatic selective refocusing sequence; and from the bilateral posterior cingulate cortex (PCC; Braak IV), bilateral precuneus (Braak V), and bilateral precentral gyrus (Braak VI) using a multi-voxel echo-planar spectroscopic imaging sequence. Pearson and Spearman correlations were used to examine the relationships between absolute levels of choline, creatine, myo-inositol, Glx, and NAA and CSF p-tau181, and between these metabolites and hippocampal volume or parietal cortical thicknesses. Covariates included age, sex, years of education, Fazekas score, and months between CSF collection and MRI exam. RESULTS:There was a direct correlation between hippocampal Glx and CSF p-tau181 in APOE4 carriers (Pearson's r = 0.76, p = 0.02), but not after adjusting for covariates. In the entire cohort, there was a direct correlation between hippocampal NAA and hippocampal volume (Spearman's r = 0.55, p = 0.001), even after adjusting for age and Fazekas score (Spearman's r = 0.48, p = 0.006). This relationship was observed only in APOE4 carriers (Pearson's r = 0.66, p = 0.017), and was also retained after adjustment (Pearson's r = 0.76, p = 0.008; metabolite-by-carrier interaction p = 0.03). There were no findings in the PCC, nor in the negative control (late Braak stage) regions of the precuneus and precentral gyrus. CONCLUSIONS:Our findings are in line with the spatially- and temporally-resolved Braak staging model of pathological severity in which the hippocampus is affected earlier than the PCC. The correlations, between MRS markers of synaptic and neuronal health and, respectively, T and N pathology, were found exclusively within APOE4 carriers, suggesting a connection with AD pathological change, rather than with normal aging. We therefore conclude that MRS has the potential to augment early A/T/N staging, with the hippocampus serving as a more sensitive MRS target compared to the PCC.

The sleep-wake cycle regulates interstitial fluid and cerebrospinal fluid (CSF) tau levels in both mouse and human by mechanisms that remain unestablished. Here, we reveal a novel pathway by which wakefulness increases extracellular tau levels in mouse and humans. In mice, higher body temperature (BT) associated with wakefulness and sleep deprivation increased CSF tau. In vitro, wakefulness temperatures upregulated tau secretion via a temperature-dependent increase in activity and expression of unconventional protein secretion pathway-1 components, namely caspase-3-mediated C-terminal cleavage of tau (TauC3), and membrane expression of PIP2 and syndecan-3. In humans, the increase in both CSF and plasma tau levels observed post-wakefulness correlated with BT increase during wakefulness. Our findings suggest sleep-wake variation in BT may contribute to regulating extracellular tau levels, highlighting the importance of thermoregulation in pathways linking sleep disturbance to neurodegeneration, and the potential for thermal intervention to prevent or delay tau-mediated neurodegeneration.

Background:An elevated neutrophil-lymphocyte ratio (NLR) in blood has been associated with Alzheimer's disease (AD). However, an elevated NLR has also been implicated in many other conditions that are risk factors for AD, prompting investigation into whether the NLR is directly linked with AD pathology or a result of underlying comorbidities. Herein, we explored the relationship between the NLR and AD biomarkers in the cerebrospinal fluid (CSF) of cognitively unimpaired (CU) subjects. Adjusting for sociodemographics, APOE4, and common comorbidities, we investigated these associations in two cohorts: the Alzheimer's Disease Neuroimaging Initiative (ADNI) and the M.J. de Leon CSF repository at NYU. Specifically, we examined associations between the NLR and cross-sectional measures of amyloid-β42 (Aβ42), total tau (t-tau), and phosphorylated tau181 (p-tau), as well as the trajectories of these CSF measures obtained longitudinally. Results:A total of 111 ADNI and 190 NYU participants classified as CU with available NLR, CSF, and covariate data were included. Compared to NYU, ADNI participants were older (73.79 vs. 61.53, p < 0.001), had a higher proportion of males (49.5% vs. 36.8%, p = 0.042), higher BMIs (27.94 vs. 25.79, p < 0.001), higher prevalence of hypertensive history (47.7% vs. 16.3%, p < 0.001), and a greater percentage of Aβ-positivity (34.2% vs. 20.0%, p = 0.009). In the ADNI cohort, we found cross-sectional associations between the NLR and CSF Aβ42 (β=-12.193, p = 0.021), but not t-tau or p-tau. In the NYU cohort, we found cross-sectional associations between the NLR and CSF t-tau (β = 26.812, p = 0.019) and p-tau (β = 3.441, p = 0.015), but not Aβ42. In the NYU cohort alone, subjects classified as Aβ+ (n = 38) displayed a stronger association between the NLR and t-tau (β = 100.476, p = 0.037) compared to Aβ- subjects or the non-stratified cohort. In both cohorts, the same associations observed in the cross-sectional analyses were observed after incorporating longitudinal CSF data. Conclusions:We report associations between the NLR and Aβ42 in the older ADNI cohort, and between the NLR and t-tau and p-tau181 in the younger NYU cohort. Associations persisted after adjusting for comorbidities, suggesting a direct link between the NLR and AD. However, changes in associations between the NLR and specific AD biomarkers may occur as part of immunosenescence.