News Release

Blood-based Assessment of Comorbid Alzheimer’s Disease Pathology inLewy Body Disease: Comparative Analysis of Patients and High-risk
Individuals

Key Points•Lewy body disease includes Parkinson’s disease and dementia with Lewy
bodies, which are neurodegenerative disorders associated with intraneuronal α-synuclein accumulation.
•Recent studies have shown that in addition to α-synuclein, comorbid
Alzheimer’s disease pathology contributes to the onset and progression ofdementia in Lewy body disease, potentially serving as a treatment target.
•This study analyzed plasma biomarkers of Alzheimer’s disease (amyloid-βand phosphorylated tau 181) and that of neurodegeneration (neurofilament
light chain) in 84 patients with Parkinson’s disease, 16 patients withdementia with Lewy bodies, 82 high-risk individuals (prodromal stage) who
were identified in our previous research, and 37 low-risk individuals (healthycontrols).
•Patients with Parkinson’s disease and dementia with Lewy bodies showedchanges related to Alzheimer’s disease, while high-risk individuals did not.
•Elevated levels of the neurodegeneration marker were observed in patientswith Parkinson’s disease, dementia with Lewy bodies, as well as in high-risk
individuals.
•The results suggest that comorbid Alzheimer’s disease pathology in Lewy
body disease is not present in the prodromal phase but develops after
disease onset. Additionally, the neurodegeneration marker neurofilament
light chain may potentially detect α-synuclein-induced neurodegenerationeven in the prodromal phase.

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Summary
A research group led by Professor Masahisa Katsuno and Dr. Keita Hiraga (leadauthor) from the Department of Neurology, Nagoya University Graduate Schoolof Medicine, in collaboration with the National Center for Geriatrics andGerontology and National Institutes for Quantum Science and Technology,
analyzed the coexistence of Alzheimer’s disease in the pre- and post- onset
stages of Lewy body disease using plasma biomarkers from patients and highrisk individuals.
Lewy body disease is a neurodegenerative disorder characterized by intraneuronal accumulation of α-synuclein. Recent post-mortem brain studies havereported that in addition to α-synuclein, comorbid Alzheimer’s disease
pathology (amyloid-β and tau) contributes to the onset and progression ofdementia in Lewy body disease. However, it was unclear when these
Alzheimer’s disease-related changes emerge in Lewy body disease.
This study measured plasma biomarkers of Alzheimer’s disease (amyloid-β andphosphorylated tau 181) and that of neurodegeneration (neurofilament lightchain) in 84 patients with Parkinson’s disease, 16 patients with dementia withLewy bodies, 82 high-risk individuals (prodromal stage) who were identified
using a questionnaire-based screening developed by Professor Katsuno’sresearch group (Hattori et al. J Neurol 267(5):1516-1526, 2020, Hattori et al.

NPJ Parkinsons Dis 9:1-9, 2023), and 37 low-risk individuals (healthy controls).
The results showed that patients with Parkinson’s disease and dementia withLewy bodies exhibited changes related to Alzheimer’s disease, while high-risk
individuals did not show changes in plasma biomarkers of Alzheimer’s disease.
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However, the neurodegeneration marker was elevated in high-risk individuals,
as well as patients with Parkinson’s disease and dementia with Lewy bodies.
These findings suggest that comorbid Alzheimer’s disease pathology in
Parkinson’s disease and dementia with Lewy bodies is not present in theprodromal phase but begins to develop after the onset. Furthermore, the results
indicate that the neurodegeneration marker neurofilament light chain may
potentially detect α-synuclein-induced neurodegeneration from the prodromalphase.
This research will be published in the U.S. scientific journal “npj Parkinson’sDisease” on July 31, 2024.
Research Background
Recent research has shown that inneurodegenerative
includingdiseases,dementia,

theaccumulation of abnormal proteinsprecedes clinical symptoms by more
than20years,

importanceof

highlighting

thesuppressing

pathology before symptom onset(Figure 1). Lewy body disease is a neurodegenerative disorder characterized byintra-neuronal

accumulationof

α-synuclein,encompassing

Parkinson’s

disease and dementia with Lewy bodies. Parkinson’s disease, affecting anestimated 200,000 people in Japan, presents with motor symptoms such as
bradykinesia and cognitive impairment. Dementia with Lewy bodies, the second
most common form of dementia after Alzheimer’s disease, affects an estimated600,000-900,000 people in Japan and is characterized by cognitive impairmentwith visual hallucinations and Parkinsonism. Recent attention has focused on
prodromal symptoms of Lewy body disease, such as autonomic dysfunction (e.g.,constipation), olfactory dysfunction, and REM sleep behavior disorder, whichappear 10-20 years before the onset of motor or cognitive symptoms.
Our previous research identified that 5.7% of healthy individuals over 50 years
old have two or more prodromal symptoms, defining this group as high risk fordeveloping Lewy body disease (Hattori et al. J Neurol 267(5):1516-1526, 2020).
High-risk individuals had mild cognitive decline and hyposmia compared with
low-risk individuals with no prodromal symptoms. Approximately one-third ofthehigh-risk

individuals

haddeficits

inDaT-SPECTor

cardiac

MIBG

scintigraphy, and the prevalence of abnormalities on DaT-SPECT was 4 times
higher in the high-risk individuals than that in the low-risk individuals (Hattoriet al. NPJ Parkinsons Dis 9:1-9, 2023) (Figure 2).
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While α-synuclein pathology is
known to contribute to dementia
inParkinson’s

diseaseanddementia

with

Lewy

bodies,previouspost-mortem

studieshave shown that over 70% ofpatients with dementia with Lewy
bodies and 50% of patients withParkinson’s

diseasedementia

also have comorbid Alzheimer’s
diseasepathology.

recentapproval

Givenoftheantibody

treatments for Alzheimer’s disease, understanding the comorbid Alzheimer’s
pathology in Lewy body disease is crucial as it may serve as a potential
treatment target.
This study aimed to elucidate the comorbid Alzheimer’s disease pathology inthe pre- and post-onset stages of Lewy body disease by measuring plasma
biomarkers for Alzheimer’s disease (amyloid-β and phosphorylated tau 181)
and neurodegeneration (neurofilament light chain) in 84 patients with
Parkinson’s disease, 16 patients with dementia with Lewy bodies, 82 high-risk
individuals, and 37 low-risk individuals.
Research Results
The study found that patientswith Parkinson’s disease withcognitivepatients

impairmentwithanddementiawith

Lewy bodies showed elevatedlevels of Alzheimer’s diseaserelated

biomarkers(Aβcompositeandp-tau181)

comparedtolow-risk

individuals. However, high-risk individuals did not show an increase in thesebiomarkers. The neurodegeneration marker neurofilament light chain (NfL) waselevated in patients with Parkinson’s disease and dementia with Lewy bodies
and high-risk individuals compared to low-risk individuals (Figure 3).
Classifying the progression of Alzheimer’s pathology based on the presence(+) or absence (-) of amyloid-β (A), tau (T), and neurodegeneration (N)revealed that Parkinson’s disease and dementia with Lewy bodies patients had
a higher proportion of A+T+(N)+, indicating comorbid Alzheimer’s pathology.
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In contrast, high-risk individuals showed a higher proportion of A-T-(N)+,suggesting neurodegeneration without Alzheimer’s pathology (Table 1).

In patients with Parkinson's disease, Aβ composite levels were associated withcognitive function, while p-tau181 levels were associated with motor and nonmotor symptoms. NfL levels were associated with cognitive function, motorsymptoms,

andnon-motorsymptoms.

Thesefindings

suggestedthat

Alzheimer’s disease-related changes affect both cognitive and motor functions.
High-risk individuals showed no correlation between these biomarkers andclinical symptoms, but those with higher NfL levels had a higher rate ofabnormal cardiac MIBG scintigraphy images.
These results suggest that comorbid Alzheimer’s disease pathology in
Parkinson’s disease and dementia with Lewy bodies begins to appear after thedisease onset rather than in the prodromal phase. Additionally, the elevation of
NfL in high-risk individuals, despite the absence of increased Alzheimer’s
disease-related biomarkers, suggests that NfL may potentially detect αsynuclein-induced neurodegeneration in the prodromal phase.
Research Summary and Future Perspective
This study suggests that Alzheimer’s disease-related changes in Lewy bodydisease begin to appear after the disease onset rather than in the prodromalphase. With the recent introduction of anti-amyloid-β antibody treatments forearly-stage Alzheimer’s disease patients, comorbid Alzheimer’s pathology inLewy body disease may become a future treatment target. Our research groupis currently conducting annual evaluations of high-risk individuals for Lewy
body disease. We aim to elucidate further when comorbid Alzheimer’s pathology
appears in Lewy body disease and how it affects neurological prognosis bylongitudinally following and evaluating both Lewy body disease patients andhigh-risk individuals.

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Acknowledgement
This study were conducted as a part of the BATON (Blood-based Amyloid, Tau,and Other Neuropathological Biomarkers) and STREAM (Stratification of superEarly Alzheimer disease by Multimodal biomarkers) projects, with support fromAMED.
Publication
Journal：npj Parkinson’s Disease
Title ： Plasma biomarkers of neurodegeneration in patients and high risk
subjects with Lewy body disease
Author Names and Affiliations：Keita Hiraga, MD1, Makoto Hattori, MD, PhD1,Yuki Satake, MD1,2, Daigo Tamakoshi, MD1, Taiki Fukushima, MD1, Takashi
Uematsu, MD1, Takashi Tsuboi, MD, PhD1, Maki Sato1, Katsunori Yokoi, MD, PhD3,Keisuke Suzuki, MD, PhD4, Yutaka Arahata, MD, PhD3, Yukihiko Washimi, MD,PhD5, Akihiro Hori, MD, PhD6,Masayuki Yamamoto, MD, PhD6, Hideaki Shimizu, MD, PhD7, Masakazu Wakai, MD,PhD8, Harutsugu Tatebe, PhD9, Takahiko Tokuda, MD, PhD9, Akinori Nakamura,MD, PhD10, Shumpei Niida, PhD11, Masahisa Katsuno, MD, PhD1,12
1

Department of Neurology, Nagoya University Graduate School of Medicine,Nagoya, Japan2

Department of Neurology, Daido Hospital, Nagoya, Japan3

Department of Neurology, National Hospital for Geriatric Medicine, National

Center for Geriatrics and Gerontology, Obu, Aichi, Japan
4

Innovation Center for Translational Research, National Center for Geriatrics

and Gerontology, Obu, Aichi, Japan
5

Department of Comprehensive Care and Research on Memory Disorders,National Center for Geriatrics and Gerontology, Obu, Aichi, Japan
6Kumiai kosei Hospital, Takayama, Gifu, Japan

7

Medical Examination Center, Daido Clinic, Nagoya, Japan

8

Chutoen General Medical Center, Kakegawa, Shizuoka, Japan

9Department of Functional Brain Imaging, Institute for Quantum MedicalScience, National Institutes for Quantum Science and Technology, Chiba, Japan10

Department of Biomarker Research, Center for Development of Advanced

Medicine for Dementia, National Center for Geriatrics and Gerontology, Obu,Aichi, Japan
11

Core Facility Administration, Research Institute, National Center for Geriatrics

and Gerontology, Obu, Aichi, Japan
12

Department of Clinical Research Education, Nagoya University Graduate

School of Medicine, Nagoya, Japan
DOI: 10.1038/s41531-024-00745-8
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Japanese ver.
https://www.med.nagoya-u.ac.jp/medical_J/research/pdf/npj_240731.pdf

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