Cross-ancestry genome-wide association study identifies implications of SORL1 in cerebral beta-amyloid deposition
(2025) Nature Communications, 16 (1), art. no. 3150, .
Kim, J.P.a b c , Jung, S.-H.d e f , Jang, B.e g h i j , Cho, M.e , Song, M.e , Kim, J.e , Kim, B.e , Lee, H.a k , Shin, D.a b c , Lee, E.H.a b c , Jang, H.l , Kim, B.-H.a , Ham, H.b , Kim, D.d , Raj, T.g h i j m n , Cruchaga, C.o p q r s , Kim, H.J.a b c k , Na, D.L.a b c , Seo, S.W.a b c k , Won, H.-H.e t
a Alzheimer’s Disease Convergence Research Center, Samsung Medical Center, Seoul, South Korea
b Department of Neurology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea
c Neuroscience Center, Samsung Medical Center, Seoul, South Korea
d Department of Biostatistics, Epidemiology and Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
e Department of Digital Health, Samsung Advanced Institute for Health Sciences & Technology (SAIHST), Sungkyunkwan University, Seoul, South Korea
f Department of Medical Informatics, Kangwon National University College of Medicine, Chuncheon, South Korea
g Ronald M. Loeb Center for Alzheimer’s Disease, Icahn School of Medicine at Mount Sinai, New York, NY, United States
h Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, United States
i Nash Family Department of Neuroscience & Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, United States
j Estelle and Daniel Maggin Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, United States
k Department of Health Sciences and Technology, SAIHST, Sungkyunkwan University, Seoul, South Korea
l Department of Neurology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, South Korea
m Windreich Department of Artificial Intelligence and Human Health, Icahn School of Medicine at Mount Sinai, New York, NY, United States
n Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, United States
o Department of Psychiatry, Washington University, St. Louis, MO, United States
p NeuroGenomics and Informatics, Washington University, St. Louis, MO, United States
q Knight Alzheimer’s Disease Research Center, Washington University, St. Louis, MO, United States
r Hope Center for Neurologic Diseases, Washington University, St. Louis, MO, United States
s Department of Genetics, Washington University School of Medicine, St. Louis, MO, United States
t Samsung Genome Institute, Samsung Medical Center, Seoul, South Korea
Abstract
GWAS of Alzheimer’s disease have been predominantly based on European ancestry cohorts with clinically diagnosed patients. Increasing the ancestral diversity of GWAS and focusing on imaging brain biomarkers for Alzheimer’s disease may lead to the identification of new genetic loci. Here, we perform a GWAS on cerebral β-amyloid deposition measured by PET imaging in 3,885 East Asians and a cross-ancestry GWAS meta-analysis with data from 11,816 European participants. Our GWAS analysis replicates known loci (APOE4, CR1, and FERMT2) and identifies a novel locus near SORL1 that is significantly associated with β-amyloid deposition. Single-nucleus expression analysis shows that SORL1 is differentially expressed according to β-amyloid positivity in microglia. Our joint association analysis using the SORL1 lead variant (rs76490923) and the APOE4 allele demonstrates that the risk of β-amyloid deposition is reduced by up to 43.5% in APOE4 non-carriers and up to 55.6% in APOE4 carriers, according to the allelic dosage of the rs76490923 T allele. Our findings suggest that SORL1 may play an important role in the pathogenesis of Alzheimer’s disease, particularly in relation to β-amyloid deposition. © The Author(s) 2025.
Funding details
Sungkyunkwan UniversitySKKU
Ministry of Health and WelfareMOHW
Korea Dementia Research CenterKDRC
Institute for Information and Communications Technology PromotionIITP
Korea National Institute of HealthKNIH2024-ER1003-01, 2023-ER1001-02
Korea National Institute of HealthKNIH
National Research Foundation of KoreaNRFRS-2023-00262527, RS-2023-00223277, RS-2019-NR040057, RS-2023-00247408
National Research Foundation of KoreaNRF
RS-2020-KH106434, RS-2022-KH125557
Samsung Medical Center, Sungkyunkwan UniversitySMCSMX1250081
Samsung Medical Center, Sungkyunkwan UniversitySMC
RS-2021-II212068
Document Type: Article
Publication Stage: Final
Source: Scopus
Plasma p-tau217 and tau-PET predict future cognitive decline among cognitively unimpaired individuals: implications for clinical trials
(2025) Nature Aging, art. no. 2311, .
Ossenkoppele, R.a b c , Salvadó, G.a , Janelidze, S.a , Pichet Binette, A.a , Bali, D.a , Karlsson, L.a , Palmqvist, S.a d , Mattsson-Carlgren, N.a e f , Stomrud, E.a d , Therriault, J.g h , Rahmouni, N.g h , Rosa-Neto, P.g h , Coomans, E.M.b c , van de Giessen, E.c i , van der Flier, W.M.b c j , Teunissen, C.E.c k , Jonaitis, E.M.l m , Johnson, S.C.l m , Villeneuve, S.n o , Benzinger, T.L.S.p q , Schindler, S.E.q r , Bateman, R.J.q r s , Doecke, J.D.t , Doré, V.t u , Feizpour, A.u v , Masters, C.L.v , Rowe, C.u v , Wiste, H.J.w , Petersen, R.C.x , Jack, C.R., Jr.y , Hansson, O.a d , PREVENT-AD Research Groupz
a Clinical Memory Research Unit, Department of Clinical Sciences in Malmö, Lund University, Lund, Sweden
b Alzheimer Center Amsterdam, Neurology, Vrije Universiteit Amsterdam, Amsterdam, Netherlands
c Neurodegeneration, Amsterdam Neuroscience, Amsterdam, Netherlands
d Memory Clinic, Skåne University Hospital, Malmö, Sweden
e Department of Neurology, Skåne University Hospital, Lund University, Lund, Sweden
f Wallenberg Center for Molecular Medicine, Lund University, Lund, Sweden
g Translational Neuroimaging Laboratory, McGill Research Centre for Studies in Aging, Montreal, QC, Canada
h Department of Neurology and Neurosurgery, Faculty of Medicine, McGill University, Montreal, QC, Canada
i Department of Radiology and Nuclear Medicine, Vrije Universiteit Amsterdam, Amsterdam, Netherlands
j Department of Epidemiology and Biostatistics, Vrije Universiteit Amsterdam, Amsterdam, Netherlands
k Neurochemistry Laboratory, Department of Laboratory Medicine, Vrije Universiteit Amsterdam, Amsterdam, Netherlands
l Wisconsin Alzheimer’s Institute, School of Medicine and Public Health, University of Wisconsin–Madison, Madison, WI, United States
m Wisconsin Alzheimer’s Disease Research Center, School of Medicine and Public Health, University of Wisconsin–Madison, Madison, WI, United States
n Centre for Studies on the Prevention of Alzheimer’s Disease (StoP-AD), Douglas Mental Health University Institute, Montreal, QC, Canada
o Department of Psychiatry, McGill University, Montreal, QC, Canada
p Department of Radiology, Washington University School of Medicine, St. Louis, MO, United States
q Charles F. and Joanne Knight Alzheimer Disease Research Center, Washington, Washington University School of Medicine, St. Louis, MO, United States
r Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
s The Tracy Family SILQ Center, Washington University School of Medicine, St. Louis, MO, United States
t Australian eHealth Research Centre, Commonwealth Scientific and Industrial Research Organization, Melbourne, VIC, Australia
u Department of Molecular Imaging and Therapy, Austin Health, Heidelberg, VIC, Australia
v The Florey Institute of Neuroscience and Mental Health, the University of Melbourne, Parkville, VIC, Australia
w Department of Quantitative Health Sciences, Mayo Clinic, Rochester, MN, United States
x Department of Neurology, Mayo Clinic, Rochester, MN, United States
y Department of Radiology, Mayo Clinic, Rochester, MN, United States
Abstract
Plasma p-tau217 and tau positron emission tomography (PET) are strong prognostic biomarkers in Alzheimer’s disease (AD), but their relative performance in predicting future cognitive decline among cognitively unimpaired (CU) individuals is unclear. In a head-to-head comparison study including nine cohorts and 1,474 individuals, we show that plasma p-tau217 and medial temporal lobe tau-PET signal display similar associations with cognitive decline on a global cognitive composite test (R2PET = 0.34 versus R2plasma = 0.33, Pdifference = 0.653) and with progression to mild cognitive impairment (hazard ratio (HR)PET = 1.61 (1.48–1.76) versus HRplasma = 1.57 (1.43–1.72), Pdifference = 0.322). Combined plasma and PET models were superior to the single-biomarker models (R2 = 0.35, P < 0.01). Sequential selection using plasma phosphorylated tau at threonine 217 (p-tau217) and then tau-PET reduced the number of participants required for a clinical trial by 94%, compared to a 76% reduction when using plasma p-tau217 alone. Thus, plasma p-tau217 and tau-PET showed similar performance for predicting future cognitive decline in CU individuals, and their sequential use enhances screening efficiency for preclinical AD trials. © The Author(s) 2025.
Funding details
Pfizer Canada
GE Healthcare
Stichting Dioraphte
Noaber FoundationNF
Government of Canada
National Multiple Sclerosis SocietyNMSS
Fondation Brain Canada
Alzheimer Nederland
EU Joint Programme – Neurodegenerative Disease ResearchJPND
National Institutes of HealthNIH
Konung Gustaf V:s och Drottning Victorias Frimurarestiftelse
Commonwealth Scientific and Industrial Research OrganisationCSIRO
KWF KankerbestrijdingKWF
McGill UniversityMGU
ZonMw
Lunds UniversitetLU
GHR FoundationGHR
Cure Alzheimer’s FundCAF
Alzheimer SocietyASC
Canadian Institutes of Health ResearchCIHR
Alzheimer’s Drug Discovery FoundationADDF
Innovative Medicines InitiativeIMI101034344
Innovative Medicines InitiativeIMI
2022-Projekt0080, 2022-Projekt0107
Nederlandse Organisatie voor Wetenschappelijk OnderzoekNWO73305095007, LSHM20106
Nederlandse Organisatie voor Wetenschappelijk OnderzoekNWO
National Institute on AgingNIAR01AG083740, U01 AG006786
National Institute on AgingNIA
European Research CouncilERCADG-101096455
European Research CouncilERC
AlzheimerfondenAF-994075, AF-994229, AF-980907
Alzheimerfonden
Canada Foundation for InnovationCFI2020-VICO-279314, 33397, 34874
Canada Foundation for InnovationCFI
SantéFRQS298314
SantéFRQS
VetenskapsrådetVR2022-00775, 2018-02052, ERAPERMED2021-184
VetenskapsrådetVR
P01AG003991, P01AG026276, RF1AG061900, R56AG061900
Alzheimer’s AssociationAAZEN24-1069572, SG-23-1061717
Alzheimer’s AssociationAA
Weston Brain InstituteWBIRFN 152985, 159815, 162303, MOP-11-51-31
Weston Brain InstituteWBI
University Hospital FoundationUHF2020-O000028
University Hospital FoundationUHF
2022-1259
European CommissionEC860197, 831434
European CommissionEC
HjärnfondenFO2023-0163, FO2021-0293, FO2022-0204
Hjärnfonden
Knut och Alice Wallenbergs Stiftelse2022-0231
Knut och Alice Wallenbergs Stiftelse
FRS-0003
Horizon 2020 Framework ProgrammeH2020AF-980942, AARF-22-972612, 101061836
Horizon 2020 Framework ProgrammeH2020
University of Wisconsin-MadisonUWR01 AG027161, R01AG070941, P30AG066444, R01 AG021155
University of Wisconsin-MadisonUW
WASP/DDLS22-066
BrightFocus FoundationBFFA2021013F
BrightFocus FoundationBFF
1412/22
Consortium canadien en neurodégénérescence associée au vieillissementCCNANIRG-12-92090, NIRP-12-259245
Consortium canadien en neurodégénérescence associée au vieillissementCCNA
National Health and Medical Research CouncilNHMRCAPP1140853, APP1132604, APP1152623
National Health and Medical Research CouncilNHMRC
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Phase 1, First-In-Human, Single-/Multiple-Ascending Dose Study of Iluzanebart in Healthy Volunteers
(2025) Annals of Clinical and Translational Neurology, .
Meier, A.a , Papapetropoulos, S.a , Marsh, A.a , Neelon, K.a , Stiles, D.a , O’Mara, R.b , Thackaberry, E.A.b , Colonna, M.c , Rajagovindan, R.a
a Formerly Vigil Neuroscience, Inc., Watertown, MA, United States
b Vigil Neuroscience, Inc., Watertown, MA, United States
c Department of Pathology and Immunology, Washington University School of Medicine, St Louis, MO, United States
Abstract
Objective: To evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of iluzanebart, a fully human monoclonal antibody TREM2 (triggering receptor expressed on myeloid cells 2) agonist, after single- (SAD) and multiple-ascending-dose (MAD) administration. Methods: Healthy adult volunteers (N = 136) received intravenous placebo or iluzanebart 1–60 mg/kg (SAD) or 10–60 mg/kg (MAD) followed by serial pharmacokinetics and safety assessments. Safety assessments included adverse events (AEs), vital signs, electrocardiograms, and clinical laboratory evaluations. Pharmacokinetics were assessed through noncompartmental analysis. The study also included open-label cohorts (3, 10, 20, 40, 60 mg/kg SAD; 10, 20, 40 mg/kg MAD) for cerebrospinal fluid (CSF) collection for exploratory pharmacodynamic biomarker analysis. Results: Iluzanebart was safe and well tolerated following single and multiple doses of up to 60 mg/kg. Most AEs were mild and resolved spontaneously. The most frequently reported AE was pruritus. No serious AEs or investigational product–related clinically meaningful changes in vital signs, electrocardiograms, or laboratory assessments were reported. Iluzanebart serum exposure was related to dose, with a 29-day half-life that is supportive of monthly dosing and confirmed central nervous system (CNS) exposure (≈0.15% CSF-to-serum ratio). Durable and dose-dependent target engagement, evidenced by marked reductions in soluble TREM2 and increased soluble CSF1R (colony-stimulating factor 1 receptor) and osteopontin/SPP1 (secreted phosphoprotein 1) levels in CSF, was observed, indicating that iluzanebart changes microglial activity following single and repeat dosing. Interpretation: Iluzanebart demonstrated favorable safety, tolerability, pharmacokinetics, and pharmacological activity in the CNS, supporting further clinical development for adult-onset leukoencephalopathy with axonal spheroids and pigmented glia. © 2025 The Author(s). Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.
Author Keywords
adult-onset leukoencephalopathy with axonal spheroids and pigmented glia; CSF-1 receptor; iluzanebart; microglia; TREM2
Document Type: Article
Publication Stage: Article in Press
Source: Scopus