BMI1 is associated with CS8F amyloid-β and rates of cognitive decline in Alzheimer's disease

Jun Pyo Kim; Bo-Hyun Kim; Paula J Bice; Sang Won Seo; David A Bennett; Andrew J Saykin; Kwangsik Nho; Alzheimer’s Disease Neuroimaging Initiative

doi:10.1186/s13195-021-00906-4

BMI1 is associated with CS8F amyloid-β and rates of cognitive decline in Alzheimer's disease

Alzheimers Res Ther. 2021 Oct 5;13(1):164. doi: 10.1186/s13195-021-00906-4.

Authors

Jun Pyo Kim^{1

2}, Bo-Hyun Kim³, Paula J Bice¹, Sang Won Seo⁴, David A Bennett⁵, Andrew J Saykin^{6

7

8}, Kwangsik Nho^{9

10

11}; Alzheimer’s Disease Neuroimaging Initiative

Affiliations

¹ Center for Neuroimaging, Radiology and Imaging Sciences, Indiana University School of Medicine, 355 W 16th St. Methodist hospital, GH 4101, Indianapolis, Indiana, 46202, USA.
² Medical Research Institute, Sungkyunkwan University School of Medicine, Seoul, South Korea.
³ Department of Biomedical Engineering, Hanyang University, Seoul, South Korea.
⁴ Department of Neurology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea.
⁵ Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL, USA.
⁶ Center for Neuroimaging, Radiology and Imaging Sciences, Indiana University School of Medicine, 355 W 16th St. Methodist hospital, GH 4101, Indianapolis, Indiana, 46202, USA. [email protected].
⁷ Indiana Alzheimer Disease Center, Indiana University School of Medicine, Indianapolis, Indiana, USA. [email protected].
⁸ Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA. [email protected].
⁹ Center for Neuroimaging, Radiology and Imaging Sciences, Indiana University School of Medicine, 355 W 16th St. Methodist hospital, GH 4101, Indianapolis, Indiana, 46202, USA. [email protected].
¹⁰ Indiana Alzheimer Disease Center, Indiana University School of Medicine, Indianapolis, Indiana, USA. [email protected].
¹¹ Center for Computational Biology and Bioinformatics, Indiana University School of Medicine, Indianapolis, Indiana, USA. [email protected].

Abstract

Background: Accumulating evidence suggests that BMI1 confers protective effects against Alzheimer's disease (AD). However, the mechanism remains elusive. Based on recent pathophysiological evidence, we sought for the first time to identify genetic variants in BMI1 as associated with AD biomarkers, including amyloid-β.

Methods: We used genetic, longitudinal cognition, and cerebrospinal fluid (CSF) biomarker data from participants in the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort (N = 1565). First, we performed a gene-based association analysis of common single nucleotide polymorphisms (SNPs) (minor allele frequency (MAF) > 5%) located within ± 20 kb of the gene boundary of BMI1, an optimal width for including potential regulatory SNPs in the 5' and 3' untranslated regions (UTR) of BMI1, with CSF Aβ_1-42 levels. Second, we performed cross-sectional and longitudinal association analyses of SNPs in BMI1 with cognitive performance using linear and mixed-effects models. We replicated association of SNPs in BMI1 with cognitive performance in an independent cohort (N=1084), Religious Orders Study and the Rush Memory and Aging Project (ROS/MAP).

Results: Gene-based genetic association analysis showed that BMI1 was significantly associated with CSF Aβ_1-42 levels after adjusting for multiple testing using permutation (permutation-corrected p value=0.005). rs17415557 in BMI1 showed the most significant association with CSF Aβ_1-42 levels. Participants with minor alleles of rs17415557 have increased CSF Aβ_1-42 levels compared to those with no minor alleles. Further analysis identified and replicated the minor allele of rs17415557 as being significantly associated with slower cognitive decline rates in AD.

Conclusions: Our findings provide fundamental evidence that BMI1 rs17415557 may serve as a protective mechanism related to AD pathogenesis, which supports the results of previous studies linking BMI1 to protection against AD.

Keywords: Alzheimer’s disease; Amyloid; Cognition; Neurogenetics.

Publication types

Research Support, N.I.H., Extramural
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Alzheimer Disease* / complications
Alzheimer Disease* / genetics
Amyloid beta-Peptides
Cognitive Dysfunction* / genetics
Cross-Sectional Studies
Humans
Polycomb Repressive Complex 1
tau Proteins

Substances

Amyloid beta-Peptides
BMI1 protein, human
tau Proteins
Polycomb Repressive Complex 1

Abstract

Publication types

MeSH terms

Substances

Grants and funding