Research reveals how brain inflammation may link Alzheimer’s risk, sleep disturbance

Multisite team included UCI, University of Wisconsin-Madison, Wake Forest University

"Discovering these mechanisms is an important step in identifying at-risk individuals as early as possible and developing targeted interventions," says lead study author Bryce Mander, PhD, a UCI assistant professor of psychiatry and human behavior. Photo / UCI School of Medicine

Irvine, Calif. – A multisite research team from the University of California, Irvine, the University of Wisconsin-Madison and Wake Forest University has discovered that brain inflammation may link Alzheimer’s disease risk with sleep disturbance, which may aid early detection and prevention efforts by identifying novel treatment targets at preclinical stages.

Brain inflammation, sleep disturbance and disrupted brain waves have all been associated with Alzheimer’s disease, but the interactions among them have not been investigated until now. The study, published online in the journal Sleep, examined whether inflammation had any effect on specific brain waves called fast sleep spindles, which have been shown to promote long-term memory retention.

“Our findings indicate that age-related increases in brain inflammation have a downstream effect on Alzheimer’s disease-related tau proteins and neuronal synaptic integrity." said Bryce Mander, PhD, an assistant professor of psychiatry & human behavior at the UCI School of Medicine and the study’s lead and co-corresponding author.

"This results in deficits in the brain’s capacity to generate fast sleep spindles, which contribute to age-related memory impairment in older adults. Discovering these mechanisms is an important step in identifying at-risk individuals as early as possible and developing targeted interventions.”

Chronic activation of the brain’s immune cells, called “glial cells,” increases with age, elevating production of beta-amyloid and tau proteins, the hallmarks of Alzheimer’s disease. Independently, sleep disturbance has been linked to Alzheimer’s disease pathology in the brain, and studies have also indicated an association between sleep disturbance and inflammation. Selectively disrupted fast sleep spindles have been identified in normal aging as well as preclinical stages of Alzheimer’s disease, but it has not been clear what causes this and what it means for memory impairment in older at-risk adults.

For the study, 58 cognitively unimpaired adults in their 50s and 60s were examined at the University of Wisconsin–Madison. All had a parental history of Alzheimer’s or a genetic risk factor for it, but none of them had beta-amyloid plaques or neurofibrillary tau tangles. Sleep was recorded overnight using high-density electroencephalography to map brain wave expression during sleep, and overnight memory retention was assessed. Participants also underwent a lumbar puncture so that cerebrospinal fluid biomarkers of central nervous system inflammation, beta-amyloid and tau proteins, and neuronal integrity could be examined.

Statistical tests were used to evaluate whether the effect of age on fast sleep spindles was mediated by Alzheimer’s-related proteins. Researchers found that activation of two types of glial cells — microglia and astrocytes, which trigger brain inflammation — was associated with disrupted expression of fast sleep spindles. The fact that these relationships were identified in people without any accumulation of beta-amyloid plaques or neurofibrillary tangles indicates that sleep deficits and inflammation might be among the earliest warning signs of Alzheimer’s disease.

“We don’t yet know whether anyone in this study will develop Alzheimer’s disease dementia, but one of the reasons that our studies enroll participants in midlife is so that we can potentially detect problems before people develop disease symptoms,” said co-author Barbara Bendlin, PhD, professor of medicine at the University of Wisconsin–Madison.

“These findings show that the effects of brain inflammation on sleep spindles and memory occur through its effects on neuronal activity and Alzheimer’s disease-related proteins and are apparent even before pathological positivity,” said Dr. Ruth Benca, the study’s senior and co-corresponding author and Wake Forest professor and chair of psychiatry and behavioral medicine. “This offers a promising therapeutic target to stop cognitive decline associated with aging and Alzheimer’s.”

The team included health professionals and academics from the United States, England, Germany, Sweden and Switzerland.

This work was supported by the National Institute on Aging under grants R56 AG052698, R01 AG027161, R01 AG021155, ADRC P50 AG033514, R01 AG037639 and K01 AG068353; the National Institutes of Health’s Ruth L. Kirschstein National Research Service Award F31 AG048732; the Swedish Research Council; the European Research Council; Swedish State Support for Clinical Research; the Swedish Alzheimer’s Foundation; and the UK Dementia Research Institute at University College London.

About Bryce Mander, PhD — Mander's research explores the relationships between sleep quality, brain structure and function in the neuropathology of Alzheimer’s disease as well as in healthy older adults. Another critical focus of his work is to determine why some older adults show more disrupted sleep than others and whether that disruption contributes to the cognitive impairment associated with the progression of Alzheimer's disease. Mander also studies the relationships between sleep physiology, cognition, mood, health and brain development throughout childhood.

About the University of California, Irvine: Founded in 1965, UCI is the youngest member of the prestigious Association of American Universities and is ranked among the nation’s top 10 public universities by U.S. News & World Report. The campus has produced five Nobel laureates and is known for its academic achievement, premier research, innovation and anteater mascot. Led by Chancellor Howard Gillman, UCI has more than 36,000 students and offers 224 degree programs. It’s located in one of the world’s safest and most economically vibrant communities and is Orange County’s second-largest employer, contributing $7 billion annually to the local economy and $8 billion statewide. For more on UCI, visit www.uci.edu.

About the University of Wisconsin School of Medicine and Public Health: The University of Wisconsin School of Medicine and Public Health is recognized as a leading institution in health sciences education, research, and service. Founded in 1907 as the medical school of the University of Wisconsin-Madison, we became the nation’s first to integrate medical and public health approaches throughout our missions in 2005. Powered by more than 5,400 faculty and staff, our impact spans the state of Wisconsin and beyond. With deep commitment to a vision of healthy people and healthy communities, we translate discovery into application and foster interconnections between clinical care, education, and research. We are consistently ranked among the nation’s top medical schools, with more than 2,700 students and trainees enrolled in our high-performance academic programs. 

About Atrium Health Wake Forest Baptist: Atrium Health Wake Forest Baptist is a pre-eminent academic health system based in Winston-Salem, N.C., and part of Atrium Health Enterprise. Atrium Health Wake Forest Baptist’s two main components are an integrated clinical system — anchored by Atrium Health Wake Forest Baptist Medical Center, an 885-bed tertiary-care hospital in Winston-Salem — that includes Brenner Children’s Hospital, five community hospitals, more than 300 primary and specialty care locations and more than 2,700 physicians; and Wake Forest University School of Medicine, the academic core of Atrium Health Enterprise and a recognized leader in experiential medical education and groundbreaking research.