Genetic evaluation of dementia with Lewy bodies implicates distinct disease subgroups

Karri Kaivola, Zalak Shah, Ruth Chia, Sandra E. Black, Ziv Gan-Or, Julia Keith, Mario Masellis, Ekaterina Rogaeva, Alexis Brice, Suzanne Lesage, Georgia Xiromerisiou, Andrea Calvo, Antonio Canosa, Adriano Chio, Giancarlo Logroscino, Gabriele Mora, Reijko Krüger, Patrick May, Daniel Alcolea, Jordi ClarimonJuan Fortea, Isabel Gonzalez-Aramburu, Jon Infante, Carmen Lage, Alberto Lleó, Pau Pastor, Pascual Sanchez-Juan, Francesca Brett, Dag Aarsland, Safa Al-Sarraj, Johannes Attems, Steve Gentleman, John A. Hardy, Angela K. Hodges, Seth Love, Ian G. Mckeith, Christopher M. Morris, Huw R. Morris, Laura Palmer, Stuart Pickering-Brown, Mina Ryten, Alan J. Thomas, Claire Troakes, Marilyn S. Albert, Matthew J. Barrett, Thomas G. Beach, Lynn M. Bekris, David A. Bennett, Bradley F. Boeve, Clifton L. Dalgard, Ted M. Dawson, Dennis W. Dickson, Kelley Faber, Tanis Ferman, Luigi Ferrucci, Margaret E. Flanagan, Tatiana M. Foroud, Bernardino Ghetti, J. Raphael Gibbs, Alison Goate, David S. Goldstein, Neill R. Graff-Radford, Horacio Kaufmann, Walter A. Kukull, James B. Leverenz, Qinwen Mao, Eliezer Masliah, Edwin Monuki, Kathy L. Newell, Jose Alberto Palma, Olga Pletnikova, Alan E. Renton, Susan M. Resnick, Liana S. Rosenthal, Owen A. Ross, Clemens R. Scherzer, Geidy E. Serrano, Vikram G. Shakkottai, Ellen Sidransky, Toshiko Tanaka, Eric Topol, Ali Torkamani, Juan C. Troncoso, Randy Woltjer, Zbigniew K. Wszolek, Sonja W. Scholz, Sonja W. Scholz

Research output: Contribution to journalArticlepeer-review

Abstract

The APOE locus is strongly associated with risk for developing Alzheimer's disease and dementia with Lewy bodies. In particular, the role of the APOE ϵ4 allele as a putative driver of α-synuclein pathology is a topic of intense debate. Here, we performed a comprehensive evaluation in 2466 dementia with Lewy bodies cases versus 2928 neurologically healthy, aged controls. Using an APOE-stratified genome-wide association study approach, we found that GBA is associated with risk for dementia with Lewy bodies in patients without APOE ϵ4 (P = 6.58 × 10-9, OR = 3.41, 95% CI = 2.25-5.17), but not with dementia with Lewy bodies with APOE ϵ4 (P = 0.034, OR = 1.87, 95%, 95% CI = 1.05-3.37). We then divided 495 neuropathologically examined dementia with Lewy bodies cases into three groups based on the extent of concomitant Alzheimer's disease co-pathology: Pure dementia with Lewy bodies (n = 88), dementia with Lewy bodies with intermediate Alzheimer's disease co-pathology (n = 66) and dementia with Lewy bodies with high Alzheimer's disease co-pathology (n = 341). In each group, we tested the association of the APOE ϵ4 against the 2928 neurologically healthy controls. Our examination found that APOE ϵ4 was associated with dementia with Lewy bodies + Alzheimer's disease (P = 1.29 × 10-32, OR = 4.25, 95% CI = 3.35-5.39) and dementia with Lewy bodies + intermediate Alzheimer's disease (P = 0.0011, OR = 2.31, 95% CI = 1.40-3.83), but not with pure dementia with Lewy bodies (P = 0.31, OR = 0.75, 95% CI = 0.43-1.30). In conclusion, although deep clinical data were not available for these samples, our findings do not support the notion that APOE ϵ4 is an independent driver of α-synuclein pathology in pure dementia with Lewy bodies, but rather implicate GBA as the main risk gene for the pure dementia with Lewy bodies subgroup.

Original languageEnglish (US)
Pages (from-to)1757-1762
Number of pages6
JournalBrain
Volume145
Issue number5
DOIs
StatePublished - May 1 2022

Keywords

  • Alzheimer's disease
  • APOE
  • co-pathology
  • dementia with Lewy bodies

ASJC Scopus subject areas

  • Medicine(all)

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