Faculty Bibliography

INTRODUCTION/BACKGROUND:Data on how sleep architecture relates to progression of plasma Alzheimer's disease biomarkers remains limited. METHODS:Sixty-four cognitively unimpaired older adults (ages 55-90) underwent plasma collection twice 2.6 years apart and polysomnography proximate to the first plasma collection. Plasma amyloid beta (Aβ) 42 and 40 were measured via mass spectrometry. RESULTS:Frontal slow-wave activity (SWA) was inversely associated with plasma Aβ42/40 at cross-section in bivariate analysis and in a covariate-adjusted model. In comparison, low rapid eye movement (REM) sleep percentage was associated with a large longitudinal decline in annualized blood-based Aβ42/40. In exploratory analyses, the association between low REM sleep percentage and faster decline in Aβ42/40 ratio was stronger in the amyloid-positive group. DISCUSSION/CONCLUSIONS:In cognitively unimpaired older adults, non-REM SWA correlates with cross-sectional amyloid load, whereas REM sleep may predict accelerated amyloid accumulation in preclinical stage, suggesting both may serve as early biomarkers and modifiable interventional targets.

INTRODUCTION/BACKGROUND:Data on how sleep architecture relates to progression of plasma Alzheimer's disease biomarkers remains limited. METHODS:Sixty-four cognitively unimpaired older adults (ages 55-90) underwent plasma collection twice 2.6 years apart and polysomnography proximate to the first plasma collection. Plasma amyloid beta (Aβ) 42 and 40 were measured via mass spectrometry. RESULTS:Frontal slow-wave activity (SWA) was inversely associated with plasma Aβ42/40 at cross-section in bivariate analysis and in a covariate-adjusted model. In comparison, low rapid eye movement (REM) sleep percentage was associated with a large longitudinal decline in annualized blood-based Aβ42/40. In exploratory analyses, the association between low REM sleep percentage and faster decline in Aβ42/40 ratio was stronger in the amyloid-positive group. DISCUSSION/CONCLUSIONS:In cognitively unimpaired older adults, non-REM SWA correlates with cross-sectional amyloid load, whereas REM sleep may predict accelerated amyloid accumulation in preclinical stage, suggesting both may serve as early biomarkers and modifiable interventional targets.

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/RESULTS: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/CONCLUSIONS: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/BACKGROUND:See Acknowledgments for funders.

INTRODUCTION/BACKGROUND:Sleep and circadian rest-activity rhythm (RAR) disruption may bidirectionally relate to Alzheimer's disease (AD). Down syndrome (DS), the most common genetic cause of AD, presents sleep disorders, yet RAR patterns across the DS-associated AD continuum remain uncharacterized. METHODS:We analyzed 7-day wrist actigraphy in 140 adults with DS (108 asymptomatic; 32 AD dementia) and 41 unimpaired controls. General linear models, adjusted for age, sex, sleep efficiency, and obstructive sleep apnea (OSA) severity, tested group differences, with interaction terms included to evaluate group-specific associations. RESULTS:DS showed lower relative amplitude and higher nocturnal activity, already in asymptomatic individuals. Rhythm strength declined further with AD progression, while regularity and phase timing remained preserved until dementia. Findings were independent of sleep duration and OSA. DISCUSSION/CONCLUSIONS:Adults with DS showed early RAR disturbance that progressed across the AD continuum, paralleling sporadic AD. Circadian RAR features may be scalable biomarkers of AD progression.

A recent case study reported a PSEN2 mutation carrier with high amyloid burden but unexpectedly restricted tau pathology and preserved cognition. While genetic and proteomic factors were explored, the patient's lifelong occupational heat exposure may represent an overlooked contributor to resilience. We highlight evidence from preclinical, clinical, and epidemiological studies suggesting that elevated body temperature promotes tau clearance via enhanced proteostasis. This observation invites deeper investigation into thermoregulation as a modifiable factor in tau homeostasis and Alzheimer's disease vulnerability, with implications for both biomarker interpretation and therapeutic strategies targeting tau-mediated neurodegeneration.

The locus coeruleus (LC) plays important roles in sleep/wake regulation and cognitive functions. LC neurons may be particularly sensitive to neural injury and serve as an early site of accumulation pathological tau in Alzheimer's disease. Obstructive sleep apnea (OSA) creates both chronic intermittent hypoxia and sleep fragmentation as potential insults to differentially sensitive neural populations including the locus coeruleus (LC). Using high field 7T imaging in cognitively normal older adults, we demonstrate that time spent with an oxygen saturation below 90% (T90), a measure of OSA's hypoxic burden, inversely correlates with LC structural integrity and explains significant variance in LC structural integrity after controlling for age, sex, and BMI. In contrast, other sleep variables such as the apnea-hypopnea index (AHI), total sleep time, and sleep efficiency did not contribute significant variance in LC structural integrity in this model. Thus, in the diagnosis of OSA, attention to hypoxic burden variables may be important in risk stratification for LC neural injury. This observation may inform future work determining whether mitigation of the hypoxemic burden from OSA can slow deterioration in LC integrity.

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.

INTRODUCTION/BACKGROUND: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/CONCLUSIONS:HFOs are promising biomarkers that may predict symptomatic AD dementia in adults with DS. HIGHLIGHTS/CONCLUSIONS: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.