Association of Excessive Daytime Sleepiness With Longitudinal β-Amyloid Accumulation in Elderly Persons Without Dementia

Abstract

Importance: Aging is associated with excessive daytime sleepiness (EDS), which has been linked to cognitive decline in the elderly. However, whether EDS is associated with the pathologic processes of Alzheimer disease remains unclear.

Objective: To investigate whether EDS at baseline is associated with a longitudinal increase in regional β-amyloid (Aβ) accumulation in a cohort of elderly individuals without dementia.

Design, setting, and participants: This prospective analysis included participants enrolled in the Mayo Clinic Study of Aging, a longitudinal population-based study in Olmsted County, Minnesota. Of 2900 participants, 2172 (74.9%) agreed to undergo carbon 11-labeled Pittsburgh compound B positron emission tomography (PiB-PET). We included 283 participants 70 years or older without dementia who completed surveys assessing sleepiness at baseline and had at least 2 consecutive PiB-PET scans from January 1, 2009, through July 31, 2016, after excluding 45 (13.7%) who had a comorbid neurologic disorder.

Main outcomes and measures: Excessive daytime sleepiness was defined as an Epworth Sleepiness Scale score of at least 10. The difference in Aβ levels between the 2 consecutive scans (ΔPiB) in Aβ-susceptible regions (prefrontal, anterior cingulate, posterior cingulate-precuneus, and parietal) was determined. Multiple linear regression models were fit to explore associations between baseline EDS and ΔPiB while adjusting for baseline age, sex, presence of the apolipoprotein E ε4 allele, educational level, baseline PiB uptake, global PiB positivity (standardized uptake value ratio ≥1.4), physical activity, cardiovascular comorbidities (obesity, hypertension, hyperlipidemia, and diabetes), reduced sleep duration, respiratory symptoms during sleep, depression, and interval between scans.

Results: Of the initial 283 participants, mean (SD) age was 77.1 (4.8) years; 204 (72.1%) were men and 79 (27.9%) were women. Sixty-three participants (22.3%) had EDS. Baseline EDS was significantly associated with increased regional Aβ accumulation in the anterior cingulate (B coefficient = 0.031; 95% CI, 0.001-0.061; P = .04), posterior cingulate-precuneus (B coefficient = 0.038; 95% CI, 0.006-0.069; P = .02), and parietal (B coefficient = 0.033; 95% CI, 0.001-0.065; P = .04) regions. Association of EDS with longitudinal Aβ accumulation was stronger in participants with baseline global PiB positivity in the anterior cingulate (B coefficient = 0.065; 95% CI, 0.010-0.118; P = .02) and cingulate-precuneus (B coefficient = 0.068; 95% CI, 0.009-0.126; P = .02) regions.

Conclusions and relevance: Baseline EDS was associated with increased longitudinal Aβ accumulation in elderly persons without dementia, suggesting that those with EDS may be more vulnerable to pathologic changes associated with Alzheimer disease. Further work is needed to elucidate whether EDS is a clinical marker of greater sleep instability, synaptic or network overload, or neurodegeneration of wakefulness-promoting centers. Early identification of patients with EDS and treatment of underlying sleep disorders could reduce Aβ accumulation in this vulnerable group.

Figure 1.. Distribution of Longitudinal β-amyloid (Aβ) Deposition Dichotomized by Excessive Daytime Sleepiness (EDS)

Deposition of Aβ is depicted as the unadjusted difference between the second and first Pittsburgh B compound (ΔPiB) standardized uptake value ratio (SUVR) for each region according to presence of EDS. Horizontal lines indicate median; boxes, first and third quartiles; and error bars, minimum and maximum. ^aP < .05.

Figure 2.. Regional Associations of Pittsburgh B Compound Uptake Changes (ΔPiB) With Excessive Daytime Sleepiness (EDS)

The prefrontal, anterior cingulate, posterior cingulate-precuneus and parietal regions are colored according to model estimates of regional difference between the second and first PiB scans (ΔPiB) by baseline EDS after controlling for multiple confounders in all participants (A) and participants who had global PiB positivity (standardized uptake value ratio [SUVR], ≥1.4) at baseline (B). The color scale indicates β-amyloid (Aβ) deposition increases in SUVR units as estimated by our models in every region of interest where EDS was significantly associated with ΔPiB. Regions of interest are demonstrated in a sagittal plane, from most lateral (left) to medial (right). An additional increase in Aβ accumulation is estimated in individuals with baseline global PiB positivity when compared with all individuals.