Sleep Disturbances in Alzheimer Disease Tied to Loss of ‘Wakeful’ Neuron

Researchers sought to examine the association between the number of important subcortical wake-promoting neurons and clinical sleep phenotypes in patients with AD or PSP.

The proportion of subcortical wake-promoting neurons was associated with sleep phenotypes among patients with Alzheimer disease (AD) or progressive supranuclear palsy (PSP), according to study findings published in JAMA Neurology.

Sleep disturbance is a common symptom among patients with neurodegenerative diseases and generally precede disease-defining symptoms.

As sleep-related symptoms may be important for early prognosis, this study sought to evaluate sleep features among patients with neurodegenerative diseases. Patients with AD (n=33), PSP (n=20), and healthy control individuals (n=32) were recruited between 2008 and 2020 at the University of California, San Francisco. All study participants were evaluated by electroencephalographic and polysomnographic assessments. This study evaluated data among the subset of patients with AD (n=10) and PSP (n=9) who had a postmortem neuronal analysis of the brainstem.

The patients with neurodegenerative diseases were aged mean 70.53 (standard deviation [SD], 7.75) years at death, 52.6% were women, and 100% were White. Stratified by disease, the AD cohort were younger at death (P =.01) and had higher test lag times (P =.02).

Patients with PSP had shorter sleep time (mean, 285.39 vs 399.90 min; P =.04), lower sleep maintenance (mean, 61.20% vs 80.16%; P =.01), lower time in nonrapid eye movement (NREM) stage 2 (mean, 29.15% vs 43.04%; P =.006), and increased wake after sleep onset (mean, 183.72 vs 96.40 min; P =.03) compared with the AD group, respectively.

PSP was associated with higher percentage of tau+ lateral hypothalamic area (LHA) neurons (mean, 44.14% vs 24.78%; P =.03) and lower percentage of tau+ tuberomammillary nucleus (TMN) neurons (mean, 9.83% vs 24.23%; P =.03).

The proportion of LHA neurons correlated with total sleep time (r, -0.63; P =.009), sleep maintenance (r, -0.85; P <.001), wake after sleep onset (r, 0.85; P <.001), time in NREM stage 2 (r, -0.76; P <.001), and time in NREM stage 3 (r, -0.62; P =.01); TMN neurons correlated with total sleep time (r, -0.62; P =.008), sleep maintenance (r, -0.78; P <.001), wake after sleep onset (r, 0.78; P <.001), time in NREM stage 2 (r, -0.73; P <.001), and time in rapid eye movement (REM; r, -0.61; P =.01); tau+ TMN neurons correlated with total sleep time (r, 0.51; P =.04); and locus coeruleus neurons correlated with total sleep time (r, -0.68; P =.008) and REM latency (r, 0.71; P =.006).

In a clustering analysis, the AD-predominant group had higher total sleep time, sleep maintenance, lower wake after sleep onset, and more time in NREM stage 2 compared with PSP-dominant group.

Study limitations included not having access to data about sleep-promoting and circadian-regulating neuronal counterparts.

“In this cohort study, subcortical wake-promoting neurons were significantly correlated with sleep phenotypes in patients with AD and PSP, suggesting that the loss of wake-promoting neurons among patients with neurodegenerative conditions may disturb the control of sleep-wake homeostasis,” the researchers concluded.

Disclosure: Multiple authors declared affiliations with industry. Please refer to the original article for a full list of disclosures.


Oh JY, Walsh CM, Ranasinghe K, et al. Subcortical Neuronal Correlates of Sleep in Neurodegenerative Diseases. JAMA Neurol. Published online April 4, 2022. doi:10.1001/jamaneurol.2022.0429