Evidence map›Paper›PMID 39655505›Full record

ArticleAlzheimer's & dementia : the journal of the Alzheimer's Association2025

Transethnic analysis identifies SORL1 variants and haplotypes protective against Alzheimer's disease.

Xiaopu Zhou, Han Cao, Yuanbing Jiang, Yuewen Chen, Huan Zhong, Wing Yu Fu, Ronnie Ming Nok Lo, Bonnie Wing Yan Wong, Elaine Yee Ling Cheng, Kin Ying Mok and 11 more

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Alzheimer's & dementia : the journal of the Alzheimer's Association, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 8 papers.

0numbers the graph read from it
0cells of the map it votes in
8citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

8 citing papers in PubMed.

  1. Review
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  8. Transethnic analysis identifies SORL1 variants and haplotypes protective against Alzheimer's disease.Alzheimer's & dementia : the journal of the Alzheimer's Association · 2025
    Article
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

21 authors.

Xiaopu ZhouDivision of Life Science, State Key Laboratory of Molecular Neuroscience, Molecular Neuroscience Center, The Hong Kong University of Science and Technology, Hong Kong, China.
Han CaoDivision of Life Science, State Key Laboratory of Molecular Neuroscience, Molecular Neuroscience Center, The Hong Kong University of Science and Technology, Hong Kong, China.
Yuanbing JiangDivision of Life Science, State Key Laboratory of Molecular Neuroscience, Molecular Neuroscience Center, The Hong Kong University of Science and Technology, Hong Kong, China.
Yuewen ChenDivision of Life Science, State Key Laboratory of Molecular Neuroscience, Molecular Neuroscience Center, The Hong Kong University of Science and Technology, Hong Kong, China.
Huan ZhongDivision of Life Science, State Key Laboratory of Molecular Neuroscience, Molecular Neuroscience Center, The Hong Kong University of Science and Technology, Hong Kong, China.
Wing Yu FuDivision of Life Science, State Key Laboratory of Molecular Neuroscience, Molecular Neuroscience Center, The Hong Kong University of Science and Technology, Hong Kong, China.
Ronnie Ming Nok LoDivision of Life Science, State Key Laboratory of Molecular Neuroscience, Molecular Neuroscience Center, The Hong Kong University of Science and Technology, Hong Kong, China.
Bonnie Wing Yan WongDivision of Life Science, State Key Laboratory of Molecular Neuroscience, Molecular Neuroscience Center, The Hong Kong University of Science and Technology, Hong Kong, China.
Elaine Yee Ling ChengDivision of Life Science, State Key Laboratory of Molecular Neuroscience, Molecular Neuroscience Center, The Hong Kong University of Science and Technology, Hong Kong, China.
Kin Ying MokDivision of Life Science, State Key Laboratory of Molecular Neuroscience, Molecular Neuroscience Center, The Hong Kong University of Science and Technology, Hong Kong, China.
Timothy C Y KwokTherese Pei Fong Chow Research Centre for Prevention of Dementia, Division of Geriatrics, Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong, China.
Vincent C T MokGerald Choa Neuroscience Centre, Lui Che Woo Institute of Innovative Medicine, Therese Pei Fong Chow Research Centre for Prevention of Dementia, Division of Neurology, Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong, China.
Fanny C F IpDivision of Life Science, State Key Laboratory of Molecular Neuroscience, Molecular Neuroscience Center, The Hong Kong University of Science and Technology, Hong Kong, China.
Alzheimer's Disease Neuroimaging Initiative
Akinori MiyashitaDepartment of Molecular Genetics, Brain Research Institute, Niigata University, Niigata, Japan.
Norikazu HaraDepartment of Molecular Genetics, Brain Research Institute, Niigata University, Niigata, Japan.
Takeshi IkeuchiDepartment of Molecular Genetics, Brain Research Institute, Niigata University, Niigata, Japan.
John HardyHong Kong Center for Neurodegenerative Diseases, Hong Kong, China.
Yu ChenDivision of Life Science, State Key Laboratory of Molecular Neuroscience, Molecular Neuroscience Center, The Hong Kong University of Science and Technology, Hong Kong, China.
Amy K Y FuDivision of Life Science, State Key Laboratory of Molecular Neuroscience, Molecular Neuroscience Center, The Hong Kong University of Science and Technology, Hong Kong, China.
Nancy Y IpDivision of Life Science, State Key Laboratory of Molecular Neuroscience, Molecular Neuroscience Center, The Hong Kong University of Science and Technology, Hong Kong, China.ORCID 0000-0002-2763-8907

Funding

Alzheimer's Disease Neuroimaging Initiative - SupplementU01AG024904 · NIA · NORTHERN CALIFORNIA INSTITUTE RES &EDUC · PI WEINER, MICHAEL W · 2004 to 2015
$121.0M
Areas of Excellence Scheme of the University Grants Committee AoE/M-604/16Chow Tai Fook Charity Foundation CTFCF18SC01Fundamental Research Program of Shenzhen Virtual University Park 2021Szvup137General Research Fund HKUST16103122Grants-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science, and Technology (MEXT) of Japan 21H03537Grants-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science, and Technology (MEXT) of Japan 21K07271Guangdong Provincial Fund for Basic and Applied Basic Research 2019B1515130004Innovation and Technology Commission InnoHK ITCPD/17-9Innovation and Technology Commission ITS/207/18FPInnovation and Technology Commission MRP/042/18XInnovation and Technology Commission MRP/097/20XJapan Agency for Medical Research and Development JP23dk0207060National Natural Science Foundation of China (NSFC)/RGC Joint Research Scheme 32061160472National Natural Science Foundation of China (NSFC)/RGC Joint Research Scheme N_HKUST605/20NIA NIH HHS U01 AG024904Research Grants Council of Hong Kong C6027-19GFTheme-Based Research Scheme T13-605/18 W
6 · The paper itself

Abstract

introductionThe SORL1 locus exhibits protective effects against Alzheimer's disease (AD) across ancestries, yet systematic studies in diverse populations are sparse.

methodsLogistic regression identified AD-associated SORL1 haplotypes in East Asian (N = 5249) and European (N = 8588) populations. Association analysis between SORL1 haplotypes and AD-associated traits or plasma biomarkers was conducted. The effects of non-synonymous mutations were assessed in cell-based systems.

resultsProtective SORL1 variants/haplotypes were identified in the East Asian and European populations. Haplotype Hap_A showed a strong protective effect against AD in East Asians, linked to less severe AD phenotypes, higher SORL1 transcript levels, and plasma proteomic changes. A missense variant within Hap_A, rs2282647-C allele, was linked to a lower risk of AD and decreased expression of a truncated SORL1 protein isoform. DISCUSSION: Our transethnic analysis revealed key SORL1 haplotypes that exert protective effects against AD, suggesting mechanisms of the protective role of SORL1 in AD. HIGHLIGHTS: We examined the AD-protective mechanisms of SORL1 in the general population across diverse ancestral backgrounds by jointly analyzing data from three East Asian cohorts (ie, mainland China, Hong Kong, and Japan) and a European cohort. Comparative analysis unveiled key ethnic-specific SORL1 genetic variants and haplotypes. Among these, the SORL1 minor haplotype, Hap_A, emerged as the primary AD-protective factor in East Asians. Hap_A exerts significant AD-protective effects in both APOE ε4 carriers and non-carriers. SORL1 haplotype Hap_A is associated with cognitive function, brain volume, and the activity of specific neuronal and immune-related pathways closely connected to AD risk. Protective variants within Hap_A are linked to increased SORL1 expression in human tissues. We identified an isoform-specific missense variant in Hap_A that modifies the function and levels of a truncated SORL1 protein isoform that is poorly investigated.

Indexed as

Alzheimer DiseaseHaplotypesLDL-Receptor Related ProteinsMembrane Transport ProteinsAgedEast Asian PeopleFemaleGenetic Predisposition to DiseaseHumansMalePolymorphism, Single NucleotideWhite PeopleLDL-Receptor Related ProteinsMembrane Transport ProteinsSORL1 protein, humanamyloid loadAPOEassociationEast AsianEuropeanPETPittsburgh compound Bplasma biomarkerprotective

Identifiers

PMID39655505
PMCPMC11772736

What Socratic holds

Textmetadata
LicenceCC BY-NC-ND
Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.