Connecting dementia risk loci to the CSF proteome identifies pathophysiological leads for dementia

Lianne M Reus; Iris E Jansen; Betty M Tijms; Pieter Jelle Visser; Niccoló Tesi; Sven J van der Lee; Lisa Vermunt; Carel F W Peeters; Lisa A De Groot; Yanaika S Hok-A-Hin; Alice Chen-Plotkin; David J Irwin; William T Hu; Lieke H Meeter; John C van Swieten; Henne Holstege; Marc Hulsman; Afina W Lemstra; Yolande A L Pijnenburg; Wiesje M van der Flier; Charlotte E Teunissen; Marta Del Campo Milan

doi:10.1093/brain/awae090

Connecting dementia risk loci to the CSF proteome identifies pathophysiological leads for dementia

Brain. 2024 Mar 25:awae090. doi: 10.1093/brain/awae090. Online ahead of print.

Authors

Lianne M Reus^{1

2

3}, Iris E Jansen^{1

2

4}, Betty M Tijms^{1

2}, Pieter Jelle Visser^{1

2

5}, Niccoló Tesi^{1

2

6}, Sven J van der Lee^{1

2

6}, Lisa Vermunt^{1

2

7}, Carel F W Peeters⁸, Lisa A De Groot^{1

2}, Yanaika S Hok-A-Hin⁷, Alice Chen-Plotkin⁹, David J Irwin⁹, William T Hu^{10

11}, Lieke H Meeter¹², John C van Swieten¹², Henne Holstege^{1

2

6}, Marc Hulsman^{1

2

6}, Afina W Lemstra^{1

2}, Yolande A L Pijnenburg^{1

2}, Wiesje M van der Flier^{1

2}, Charlotte E Teunissen⁷, Marta Del Campo Milan^{7

13

14}

Affiliations

¹ Alzheimer Center Amsterdam, Neurology, Vrije Universiteit Amsterdam, Amsterdam UMC location VUmc, 1081 HZ Amsterdam, The Netherlands.
² Amsterdam Neuroscience, Neurodegeneration, Amsterdam, 1081 HV Amsterdam, The Netherlands.
³ Center for Neurobehavioral Genetics, University of California Los Angeles, Los Angeles, CA 90095 California, USA.
⁴ Department of Complex Trait Genetics, Center for Neurogenomics and Cognitive research, VU University Amsterdam, 1081 HV Amsterdam, The Netherlands.
⁵ Department of Psychiatry, Maastricht University, 6229 ET Maastricht The Netherlands.
⁶ Genomics of Neurodegenerative Diseases and Aging, Department of Human Genetics, Vrije Universiteit Amsterdam, Amsterdam UMC, Amsterdam, 1081 HZ Amsterdam, The Netherlands.
⁷ Neurochemistry Laboratory, Department of Clinical Chemistry, Amsterdam Neuroscience, Amsterdam University Medical Centers, Location VUmc, Amsterdam, 1081 HZ Amsterdam, The Netherlands.
⁸ Mathematical & Statistical Methods group (Biometris), Wageningen University & Research, Wageningen, 6708 PB Wageningen, The Netherlands.
⁹ Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
¹⁰ Department of Neurology, Emory University School of Medicine, Atlanta, GA 30322, USA.
¹¹ Rutgers-RWJ Medical School, Institute for Health, Health Care Policy, and Aging Research, Rutgers Biomedical and Health Sciences, New Brunswick, NJ 08901, USA.
¹² Department of Neurology and Alzheimer Center, Erasmus Medical Center Rotterdam, Rotterdam, 3015 GD, The Netherlands.
¹³ Departamento de Ciencias Farmacéuticas y de la Salud, Facultad de Farmacia, Universidad San Pablo-CEU, CEU Universities, Madrid, 28003 Madrid, Spain.
¹⁴ Barcelonaβeta Brain Research Center (BBRC), Pasqual Maragall Foundation, Barcelona, 08005 Barcelona, Spain.

PMID: 38527854
DOI: 10.1093/brain/awae090

Abstract

Genome-wide association studies have successfully identified many genetic risk loci for dementia, but exact biological mechanisms through which genetic risk factors contribute to dementia remains unclear. Integrating CSF proteomic data with dementia risk loci could reveal intermediate molecular pathways connecting genetic variance to the development of dementia. We tested to what extent effects of known dementia risk loci can be observed in CSF levels of 665 proteins (proximity extension-based (PEA) immunoassays) in a deeply-phenotyped mixed-memory clinic cohort (n=502, mean age (sd) = 64.1 [8.7] years, 181 female [35.4%]), including patients with Alzheimer's disease (AD, n=213), dementia with Lewy bodies (DLB, n=50) and frontotemporal dementia (FTD, n=93), and controls (n=146). Validation was assessed in independent cohorts (n=99 PEA platform, n=198, MRM-targeted mass spectroscopy and multiplex assay). We performed additional analyses stratified according to diagnostic status (AD, DLB, FTD and controls separately), to explore whether associations between CSF proteins and genetic variants were specific to disease or not. We identified four AD risk loci as protein quantitative trait loci (pQTL): CR1-CR2 (rs3818361, P=1.65e-08), ZCWPW1-PILRB (rs1476679, P=2.73e-32), CTSH-CTSH (rs3784539, P=2.88e-24) and HESX1-RETN (rs186108507, P=8.39e-08), of which the first three pQTLs showed direct replication in the independent cohorts. We identified one AD-specific association between a rare genetic variant of TREM2 and CSF IL6 levels (rs75932628, P = 3.90e-7). DLB risk locus GBA showed positive trans effects on seven inter-related CSF levels in DLB patients only. No pQTLs were identified for frontotemporal dementia, either for the total sample as for analyses performed within FTD only. pQTL variants were involved in the immune system, highlighting the importance of this system in the pathophysiology of dementia. We further identified pQTLs in stratified analyses for AD and DLB, hinting at disease-specific pQTLs in dementia. Dissecting the contribution of risk loci to neurobiological processes aids in understanding disease mechanisms underlying dementia.

Keywords: Alzheimer’s disease (AD); CSF; dementia; protein quantitative trait loci (pQTL).