TY - JOUR
T1 - Genetics contributes to concomitant pathology and clinical presentation in dementia with lewy bodies
AU - van der Lee, Sven J
AU - van Steenoven, Inger
AU - van de Beek, Marleen
AU - Tesi, Niccolò
AU - Jansen, Iris E
AU - van Schoor, Natasja M
AU - Reinders, Marcel J T
AU - Huisman, Martijn
AU - Scheltens, Philip
AU - Teunissen, Charlotte E
AU - Holstege, Henne
AU - van der Flier, Wiesje M
AU - Lemstra, Afina W
N1 - Funding Information: The main strength of this study is the CSF measures and structured assessment of the patients with DLB. A total of 190 patients is low in absolute numbers of patients for genetic association studies, yet we were able to replicate the associations with DLB of all genetic factors, possibly because all underwent standardized work up with comprehensive clinical assessment and extensive diagnostics. A limitation is that our ascertainment of some of the clinical core symptoms was retrospective from patient medical records as not all patients were systematically assessed for the presence/absence of the four core symptoms. For example, the use of standardized Research of Alzheimer center Amsterdam is part of the neurodegeneration research program of Amsterdam Neuroscience. Alzheimer Center Amsterdam is supported by Stichting Alzheimer Nederland and Stichting VUmc fonds. Wiesje van der Flier holds the Pasman chair. The clinical database structure was developed with funding from Stichting Dioraphte. Genotyping of the ADC samples was performed in the context of EADB (European Alzheimer DNA biobank) funded by the JPco-fuND FP-829-029 (ZonMW projectnumber 733051061). DLB-specific research was further funded by the Scientific Excellence Program of Amsterdam Neuroscience, the Memorabel grant programme of the Netherlands Organisation for Health Research and Development (ZonMW grant 733050509), and Stichting Alzheimer Nederland. The Longitudinal Aging Study Amsterdam is supported by a grant from the Netherlands Ministry of Health Welfare and Sports, Directorate of Long-Term Care. The work of S.J. van der Lee is supported by ZonMW-Memorabel (grant number 73305012). S.J. van der Lee, Wiesje M. van der Flier, and Henne H. Holstege are recipient of ABOARD, which is a public-private partnership receiving funding from ZonMW (#73305095007) and Health Holland, Topsector Life Sciences & Health (PPP-allowance; #LSHM20106). More than 30 partners participate in ABOARD. ABOARD also receives funding from Edwin Bouw Fonds and Gieskes-Strijbisfonds. Publisher Copyright: © 2021 - The authors. Published by IOS Press.
PY - 2021
Y1 - 2021
N2 - BACKGROUND: Dementia with Lewy bodies (DLB) is a complex, progressive neurodegenerative disease with considerable phenotypic, pathological, and genetic heterogeneity.OBJECTIVE: We tested if genetic variants in part explain the heterogeneity in DLB.METHODS: We tested the effects of variants previously associated with DLB (near APOE, GBA, and SNCA) and polygenic risk scores for Alzheimer's disease (AD-PRS) and Parkinson's disease (PD-PRS). We studied 190 probable DLB patients from the Alzheimer's dementia cohort and compared them to 2,552 control subjects. The p-tau/Aβ1-42 ratio in cerebrospinal fluid was used as in vivo proxy to separate DLB cases into DLB with concomitant AD pathology (DLB-AD) or DLB without AD (DLB-pure). We studied the clinical measures age, Mini-Mental State Examination (MMSE), and the presence of core symptoms at diagnosis and disease duration.RESULTS: We found that all studied genetic factors significantly associated with DLB risk (all-DLB). Second, we stratified the DLB patients by the presence of concomitant AD pathology and found that APOE ɛ4 and the AD-PRS associated specifically with DLB-AD, but less with DLB-pure. In addition, the GBA p.E365K variant showed strong associated with DLB-pure and less with DLB-AD. Last, we studied the clinical measures and found that APOE ɛ4 associated with reduced MMSE, higher odds to have fluctuations and a shorter disease duration. In addition, the GBA p.E365K variant reduced the age at onset by 5.7 years, but the other variants and the PRS did not associate with clinical features.CONCLUSION: These finding increase our understanding of the pathological and clinical heterogeneity in DLB.
AB - BACKGROUND: Dementia with Lewy bodies (DLB) is a complex, progressive neurodegenerative disease with considerable phenotypic, pathological, and genetic heterogeneity.OBJECTIVE: We tested if genetic variants in part explain the heterogeneity in DLB.METHODS: We tested the effects of variants previously associated with DLB (near APOE, GBA, and SNCA) and polygenic risk scores for Alzheimer's disease (AD-PRS) and Parkinson's disease (PD-PRS). We studied 190 probable DLB patients from the Alzheimer's dementia cohort and compared them to 2,552 control subjects. The p-tau/Aβ1-42 ratio in cerebrospinal fluid was used as in vivo proxy to separate DLB cases into DLB with concomitant AD pathology (DLB-AD) or DLB without AD (DLB-pure). We studied the clinical measures age, Mini-Mental State Examination (MMSE), and the presence of core symptoms at diagnosis and disease duration.RESULTS: We found that all studied genetic factors significantly associated with DLB risk (all-DLB). Second, we stratified the DLB patients by the presence of concomitant AD pathology and found that APOE ɛ4 and the AD-PRS associated specifically with DLB-AD, but less with DLB-pure. In addition, the GBA p.E365K variant showed strong associated with DLB-pure and less with DLB-AD. Last, we studied the clinical measures and found that APOE ɛ4 associated with reduced MMSE, higher odds to have fluctuations and a shorter disease duration. In addition, the GBA p.E365K variant reduced the age at onset by 5.7 years, but the other variants and the PRS did not associate with clinical features.CONCLUSION: These finding increase our understanding of the pathological and clinical heterogeneity in DLB.
KW - Aged
KW - Alzheimer Disease/genetics
KW - Amyloid beta-Peptides/cerebrospinal fluid
KW - Apolipoprotein E4/genetics
KW - Cohort Studies
KW - Dementia with Lewy bodies
KW - Female
KW - Glucosylceramidase/genetics
KW - Humans
KW - Lewy Body Disease/diagnosis
KW - Male
KW - Mental Status and Dementia Tests/statistics & numerical data
KW - Mutation/genetics
KW - Parkinson Disease/genetics
KW - genetic risk factors
KW - genotype-phenotype associations
KW - polygenic risk scores
KW - tau Proteins/cerebrospinal fluid
UR - http://www.scopus.com/inward/record.url?scp=85114387434&partnerID=8YFLogxK
U2 - https://doi.org/10.3233/JAD-210365
DO - https://doi.org/10.3233/JAD-210365
M3 - Article
C2 - 34308904
SN - 1387-2877
VL - 83
SP - 269
EP - 279
JO - Journal of Alzheimer's Disease
JF - Journal of Alzheimer's Disease
IS - 1
ER -
