Sleep and Temperature Disturbance as risk factors for Alzheimer's Disease in Down Syndrome: a Longitudinal Study

睡眠和体温紊乱是唐氏综合症中阿尔茨海默病的危险因素：一项纵向研究

• 批准号: 10591135
• 负责人: Esther Marian Blessing
• 金额: $ 187.12万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-02-01 至 2026-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10591135
• 关键词: Acceleration; Adult; Affect; Age; Age of Onset; Alzheimer' s Disease; Alzheimer' s disease pathology; Alzheimer' s disease risk; Alzheimer’s disease biomarker; Amyloid; Amyloid beta-42; Amyloid beta-Protein; Apnea; Biological Markers; Blood; Body Temperature; Brain; Brain region; Cause of Death; Cerebrospinal Fluid; Circadian Dysregulation; Circadian Rhythms; Clinical; Cognition; Cognitive; Collection; Data; Data Collection; Dementia; Disease Marker; Disease Progression; Down Syndrome; Early Onset Alzheimer Disease; Elderly; Evaluation; Functional disorder; Genetic; Genetic Diseases; Goals; Heterogeneity; High Prevalence; Hippocampus; Home; Hour; Impaired cognition; Individual; Intellectual functioning disability; Intervention; Lead; Life; Life Expectancy; Light; Literature; Longitudinal Studies; Longitudinal, observational study; Magnetic Resonance Imaging; Measurement; Measures; Medical; Modeling; Nerve Degeneration; Obstructive Sleep Apnea; Onset of illness; Outcome; Pathology; Persons; Physiologic Thermoregulation; Plasma; Polysomnography; Population; Positron-Emission Tomography; Research; Risk Factors; Severities; Sleep; Sleep disturbances; Slow-Wave Sleep; Structure; Study models; Telemetry; Temperature; Testing; Thick; Work; Wrist; actigraphy; age related; aged; apolipoprotein E-4; autosomal dominant Alzheimer' s disease; circadian; cognitive change; cognitive performance; cognitive testing; cohort; follow-up; high risk; indexing; lifetime risk; modifiable risk; neurofilament; neuroimaging; novel; pre-clinical; progression marker; rate of change; recruit; screening; sex; symptomatology; tau Proteins; tau-1; uptake

Project Summary Abstract Down syndrome (DS), the most frequent form of intellectual disability of genetic origin, involves a >95% cumulative risk of Alzheimer’s Disease (AD) by the seventh decade. Further, AD is now the most common cause of death in this population as life expectancy in DS individuals has increased. Importantly, while AD in DS individuals has a mean age of onset 20–30 years younger compared to euploid individuals, there is substantial heterogeneity in this age of onset (between 40 and 70 years old), emphasizing the urgent need to identify and treat modifiable causes of AD in DS. Our work in the Down Alzheimer Barcelona Neuroimaging Initiative (DABNI) Cohort has established that clinical and Amyloid/Tau/Neurodegeneration (ATN) related biomarker changes in DS have a similar temporal profile to that in sporadic and autosomal dominant AD, meaning these biomarkers may be used to identify modifiable causes of AD in DS individuals prior to AD dementia onset. Existing literature and our preliminary data suggest that potential causes of AD in euploid individuals, namely age-related sleep and body temperature (Tb) circadian rhythm disturbance, are more severely perturbed in DS compared to euploid older adults: specifically, results suggest that greater obstructive sleep apnea (OSA) severity and lower Tb are particularly important modifiable AD risk factors in DS. This project will test the hypotheses that greater baseline OSA severity and lower baseline Tb will longitudinally predict ATN AD biomarker increase and cognitive decline in initially cognitively stable DS adults. We will recruit 60 DS adults with normal cognition aged 40–60 years old and follow them longitudinally at three annual timepoints over 2 years. Baseline assessments will include screening; cognitive evaluation; at home and in lab polysomnographic assessments overlapping with 36 hours of telemetrically measured Tb data collection, and collection of ATN biomarkers including amyloid (flutemetamol PET SUVR, plasma Aβ), tau (PI-2620 PET SUVR, plasma T-tau and P-tau181) and neurodegeneration (hippocampal volume, cortical thickness, plasma neurofilament light) related biomarkers. Follow-up cognitive evaluations and collection of plasma-based biomarkers will occur annually at all three timepoints, and neuroimaging-based biomarkers at two timepoints (baseline and 2 years). The goals of this study are to test 1) Whether greater baseline OSA apnea hypopnea index (AHI3A) is associated with ATN biomarker severity (Aim 1), 2) Whether lower baseline Tb is associated with greater tau biomarker severity (Aim 2), and 3) Whether OSA severity and lower Tb longitudinally predict greater estimated rate of change in AD biomarkers (Aim 3). Predictors of cognitive decline and additional sleep and Tb parameters will be explored. This novel proposal will advance our understanding of how age-related sleep and thermoregulatory disturbances impact AD biomarker progression in people with DS—a population at high risk for all three AD, OSA, and temperature dysregulation—with the aim of identifying modifiable risk factors in both DS and euploid individuals.

项目摘要