The journey through moderate and advanced stages of dementia with Lewy bodies (DLB) — and through the end of life — remains one of the least understood parts of the disease, owing to a lack of research focused on later stages. Most studies focus on earlier disease stages, when diagnosis is the central challenge. Far less is known about what drives symptom progression in later disease, what shapes quality of life for people living with DLB and their care partners as the disease advances, and how treatment strategies might be adapted to meet the distinctive needs of this group. A new study published in the journal Neurology takes an important step toward filling that gap — and in doing so, identifies a factor that may be influencing some of the most burdensome features of moderate to advanced DLB.

That factor is autonomic dysfunction. The term autonomic refers to the body's involuntary functions: heart rate, blood pressure, digestion, bladder control, temperature regulation, and more. In DLB, this system that controls autonomic functions is frequently disrupted, producing symptoms that can include dizziness when standing, digestive problems, urinary difficulties, and abnormal sweating. Referred to as autonomic dysfunction, this is estimated to affect roughly half of all people with Lewy body disorders, and it has long been associated with reduced life expectancy. What has been less well understood is how it relates to the cognitive and behavioral features of DLB that most affect daily life — particularly in later stages of disease.

Two of the most disruptive daily experiences in moderate to advanced DLB are cognitive fluctuations and neuropsychiatric symptoms. Cognitive fluctuations — episodes in which alertness, attention, and thinking ability shift dramatically over the course of minutes or hours — affect as many as nine in ten people living with DLB. Neuropsychiatric symptoms, which include hallucinations, delusions, depression, anxiety, and agitation, can begin very early in the disease and are nearly universal as the disease advances. Together, they place an enormous burden on people living with DLB and the family members and friends who care for them — and both become increasingly difficult to manage as the disease progresses toward its later stages.

To investigate the relationship between autonomic dysfunction, cognitive fluctuations, and neuropsychiatric symptoms, researchers analyzed data from the PACE-DLB study — short for Predicting Accurately End-of-Life in Dementia with Lewy Bodies and Promoting Quality End-of-Life Experiences. PACE-DLB is a multi-site, observational study designed to examine factors that influence quality of life in people living with moderate to advanced DLB, including as they approach the end of life. It recruited participants from five LBDA Research Centers of Excellence — at the University of Florida, University of Michigan, Mayo Clinic Rochester, University of Virginia, and University of Miami — as well as a virtual cohort recruited in part through LBDA community outreach. In all, the analysis included 189 people living with DLB and their primary care partners, followed over an average of 16 months, producing 745 individual observations over time.

The researchers measured autonomic dysfunction using a checklist of 19 symptoms. They then examined whether higher autonomic burden — meaning more autonomic symptoms — was associated with greater cognitive fluctuations and greater neuropsychiatric burden, both at a single point in time and across follow-up visits.

The answer, consistently, was yes. At the start of the study, people with higher autonomic burden showed significantly more severe cognitive fluctuations and neuropsychiatric symptoms. That relationship held up over time: as autonomic burden increased across visits, so did both cognitive fluctuations and neuropsychiatric symptoms. The association was robust across multiple statistical approaches and remained significant even after accounting for factors like age, other medical conditions, medications, and disease severity. When the researchers broke autonomic dysfunction down into its components, they found that cardiovascular autonomic dysfunction was most closely linked to cognitive fluctuations, while autonomic dysfunction linked to the gastrointestinal system, temperature regulation, and sexual and urinary functions were more strongly tied to neuropsychiatric burden — a distinction that may eventually help guide targeted treatment approaches.

The findings extended to care partners as well. Over the course of the study, higher autonomic burden in the person with DLB was associated with lower quality of life for their care partner over time. Through statistical analysis, the researchers found that this effect may be partially explained by the neuropsychiatric symptoms that autonomic dysfunction appeared to worsen — in other words, autonomic dysfunction may affect caregiver well-being in part by intensifying the behavioral symptoms that are among the most difficult aspects of caregiving in later disease.

It is important to note that the study cannot definitively establish that autonomic dysfunction causes cognitive fluctuations or neuropsychiatric symptoms — that would require an interventional study designed to test that question directly. But the consistency of the findings across time points and statistical methods is notable, and the researchers point to plausible biological mechanisms. One involves blood pressure: fluctuations in blood pressure caused by cardiovascular autonomic dysfunction may reduce blood flow to the brain in ways that trigger or worsen cognitive fluctuations. Another involves the locus coeruleus, a small region of the brainstem that regulates attention, emotion, and autonomic function and is known to be affected early in Lewy body disease.

For the LBD community, these findings open a hopeful line of inquiry in a stage of disease that has too often been overlooked. Better characterizing how autonomic dysfunction interacts with cognition, behavior, and quality of life in moderate to advanced DLB could reshape how clinicians approach care in later disease — including how existing treatments for autonomic symptoms might be deployed or adjusted over time to reduce the cognitive and neuropsychiatric burden that people living with DLB and their care partners face. The authors call for future studies that explicitly examine whether treating autonomic dysfunction improves these outcomes, and for longitudinal research designed to trace this relationship from earlier stages of disease through end-of-life. Each study that takes up that challenge brings the field closer to care strategies that serve people living with DLB through every part of the journey.

REFERENCE

Mahajan A, Dwivedi AK, Galvin JE, Maixner SM, Paulson HL, Manning CA, Fields JA, Boeve BF, Mills KA, Morrow C, Pontone GM, Armstrong MJ. Cognitive Fluctuations, Neuropsychiatric Burden, and Quality of Life in Moderate-Advanced Dementia With Lewy Bodies: The Role of Dysautonomia. Neurology. 2026;106:e214934. doi:10.1212/WNL.0000000000214934

(Note: The published version of this article is behind a paywall. A free version of the unedited manuscript is available here through NIH’s National Library of Medicine.)