Mutations

SORL1 A528T (SNP 13)

Other Names: SNP 13

Overview

Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr11:121522975 G>A
Position: (GRCh37/hg19):Chr11:121393684 G>A
dbSNP ID: rs2298813
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected Protein Consequence: Missense
Codon Change: GCC to ACC
Reference Isoform: SORL1 Isoform 1 (2214 aa)
Genomic Region: Exon 11
Research Models: 2

Findings

The A528T variant, also known as “SNP 13,” is among those initially described by Rogaeva et al. in 2007 (Rogaeva et al., 2007), when it was reported to be associated with AD in a dataset composed of families of Northern European ancestry. However, this variant was not associated with AD in other cohorts included in this study: case-control datasets of individuals of Northern European or Israeli-Arab ancestry, and African-American, Caribbean-Hispanic, and Caucasian family datasets. The variant was subsequently reported in several other studies (see table), where it did not associate with AD. A large meta-analysis of datasets from the International Genomics of Alzheimer’s Project did not find an association of this variant with AD in people of European descent (Liu et al., 2017). Analysis of data from the Alzheimer’s Disease Sequencing Project (ADSP) hinted at an association between the A528T variant and disease, but the p value did not the meet the Bonferroni-corrected threshold for exome-wide significance (Bis et al., 2020). Meta-analysis of five studies including more than 18,000 subjects of European or European American ancestry showed a nominal association between the A528T variant and AD (Campion et al., 2019); it should be noted that the ADSP contributed the largest number of subjects to this meta-analysis. More recently, the variant was found to associate with AD in a mega-analysis of nearly 32,000 subjects drawn from multiple European and American datasets, including some that contributed to the 2019 meta-analysis cited above (Holstege et al., 2022). This association was maintained when the mega dataset was expanded to more than 40,000 subjects and when cases were stratified by age of onset into early onset (less than 65 years of age) and late-onset (65 years of age or older) AD (Holstege et al., 2023).

Segregation

The A528T variant was found to segregate with disease under a dominant model in two studies. The first study included Caribbean-Hispanic families with a history of AD, where the variant was identified in 54 of 151 families examined (Vardarajan et al., 2015). In the second study, the variant was found in 56 of 345 families analyzed; among these 56 families, the variant segregated perfectly with disease in five families (Fernández et al., 2016).

Other Conditions

The A528T variant also has been studied in the context of Parkinson’s disease (PD). The variant was not associated with risk of PD in a Norwegian study that included 185 PD patients and 185 controls (Maple-Grødem et al., 2018). However, among those with PD, carriers of the variant had an increased risk of developing dementia (HR 2.31; 95 percent CI 1.09–4.90; p=0.03), compared with noncarriers. In an earlier study, all three carriers clinically diagnosed with AD had also received a diagnosis of Parkinson’s disease (Lee et al., 2007).

Endophenotypes

This variant was not associated with levels of the core cerebrospinal fluid biomarkers— Aβ42, total tau, and tau phosphorylated at threonine 181—in a group of more than 650 patients with probable AD enrolled in in the Alzheimer’s Disease Neuroimaging Initiative (ADNI), the German Dementia Competence Network (DCN), and the Amsterdam Dementia Cohort (ADC) (Louwersheimer et al., 2015). Nor did the levels of these biomarkers differ between A528T carriers and noncarriers suffering from Parkinson’s disease in the study mentioned above (Maple-Grødem et al., 2018), although carriers had a lower CSF Aβ42/phospho-tau ratio at the time of PD diagnosis than did noncarriers.

The A528T variant was not associated with atrophy of the whole brain (Assareh, et al., 2014) or of brain regions particularly susceptible to AD, including the hippocampus (Assareh, et al., 2014; Cuenco et al., 2008; Louwersheimer et al., 2015; Yin et al., 2016), the parahippocampal gyrus, entorhinal cortex, middle temporal gyrus, and the posterior cingulate cortex (Yin et al., 2016).

This variant did not associate with MRI indicators of cerebrovascular disease in African American and Caucasian sibships from the MIRAGE Study (Cuenco et al., 2008).

The variant did not associate with cognitive function in Han Chinese (Chou et al., 2016; Hsieh et al., 2021; Lin et al., 2017) or in the group of patients with probable AD from ADNI, DCN, and ADC mentioned above (Louwersheimer et al., 2015).

Functional Consequences

The effects of the A528T variant on the trafficking and, consequently, the metabolism of APP have been studied using HEK293 cells stably expressing human APPSwe and transfected with human SORL1 (Vardarajan et al., 2015). Mutant SORL1 protein bound only about half as much APP as did wild-type protein, and more APP was found on the surface of cells expressing the A528T variant, compared with cells expressing wild-type SORL1. These findings suggest that the mutant protein fails to direct APP from the cell surface to the retromer-recycling endosome pathway. In addition, expression of the A528T variant led to increased levels of extracellular sAPPα, sAPPβ, and Aβ42, but not Aβ40.

A second study examined the effects of the A528T variant in microglia-like cells derived from human embryonic stem cells (Liu et al., 2020). Although often considered a neuronal protein, SORL1 was shown to be expressed by microglia from aged human brains (Olah et al., 2018) and from mouse brains (Yang et al., 2021). Proteomic analysis found an accumulation of cell-surface and early endosomal proteins in microglia-like cells expressing SORL1 A528T and a decrease in late endosomal and lysosomal proteins, as well as increased levels of APOE. These cells also showed defects in binding and uptake of Aβ. Interestingly, the effect of the SORL1 mutation on Aβ phagocytosis depended upon APOE genotype: When the APOE genotype of the parental cell line was changed through CRISPR editing from E3/E4 to E3/E3, Aβ binding and uptake were restored to the levels seen in cells expressing wild-type SORL1.

The A528T variant did not associate with levels of SORL1 transcripts in autopsy samples of frontal or temporal cortices from individuals who were “neurologically normal” at the time of death (McCarthy et al., 2012).

Table

Risk Allele(s) N
Cases | Controls
(families)		 aAllele frequency
Cases | Controls		 Reported association measurements Ancestry
(Cohort)		 Reference
Large-scale studies, meta- and mega-analyses
  5740 | 5096   bp = 8.68×10-5 European-American, Caribbean Hispanic
(ADSP)		 Bis et al., 2018
(WES)
A 9204 | 9646 0.05 | 0.04 Fixed effect model
OR = 1.19
[CI: 1.07 – 1.32]
p = 1.03×10-3
Random effects model
OR = 1.16
[CI: 1.01 – 1.32]
p = 3.45×10-2		 European, European American Campion et al., 2019
(meta-analysis)
early onset AD
3180 | 8970		 0.04 | 0.04 Fixed effect model
OR = 1.10
[CI: 0.94 – 1.28]
p = 0.237
Random effects model
OR = 1.09
[CI: 0.91 – 1.31]
p = 0.339		 European, European American
A 15808 | 16097 0.05 | 0.04 OR = 1.14
[CI: 1.05 – 1.23]
p = 1.2×10-3		 Multiple European and American cohorts Holstege et al., 2022
(mega-analysis)
A 18,959 | 21,893   OR = 1.2
[CI: 1.08 – 1.26]
p = 6.15×10-5		 cMultiple European and American cohorts Holstege et al., 2023
early onset AD
6,154 | 21,893		   OR = 1.1
[CI: 1.03 – 1.27]
p = 0.012
late-onset AD
12,805 | 21,893		   OR = 1.2
[CI: 1.08 – 1.28]
p = 1.6×10-4
  2032 | 5328   OR = 1.10
[CI: 0.92 – 1.31]
p = 0.31		 French Caucasian Laumet et al., 2010
(GWAS)
A 17008 | 37154   p = 0.0974 European descent
(IGAP)		 Liu et al., 2017
(meta-analysis of GWAS)
A 1255 |1938 0.06 | 0.05 OR = 1.22
[CI: 0.94 – 1.59]
p = 0.14		 European
(European Early-Onset Dementia Consortium)		 Verheijen et al., 2016
(meta-analysis)
Other studies
A 111 | 175 all = 0.05 OR = 0.98
[CI: N.A.]
p = 0.979		 Australian Caucasian
(Sydney Older Persons Study)		 Assareh et al., 2014
female
57 | 85		   OR = 0.77
[CI: N.A.]
p = 0.623
male
54 | 90		   OR = 4.16
[CI: N.A.]
p = 0.150
A 550 | 634 N.A. | 0.03 reported as not significant Belgian
(Engelborghs et al., 2003)		 Bettens et al., 2008
A 785| 390 0.1274 | 0.1385 OR = 0.91
[CI: N.A.]
p = 0.455		 Han Chinese
(Taipei Veterans General Hospital and Taichung Veterans General Hospital, Taiwan)		 Chou et al., 2016
A 117 | N.A. 0.0214 | N.A.   Saudi Arabian
(King Faisal Specialist Hospital & Research Center)		 El Bitar et al., 2019
A sporadic LOAD
134 | 266		 0.0448 | 0.0489 OR = 0.912
[CI: N.A.]
p = 0.7971		 European American
(Knight ADRC, NIA-LOAD)		  Fernández et al., 2016
familial LOAD
875 | 328		 0 | 0  
A 640 | 1268 0.0406 | 0.0418   Dutch
(Rotterdam Study, Amsterdam Dementia Cohort, Alzheimer Centrum Zuidwest Nederland (ACZN), 100-plus Study)		 Holstege et al., 2017
A
 		 178 | 194  0.101 | 0.071  p = 0.1540  Caribbean Hispanic
(WHICAP)		  
 Lee et al., 2007
88 | 158 0.057 | 0.084 p = 0.2657 African-American
(WHICAP)
30 | 76 0.056 | 0.033 p = 0.4708  White, non-Hispanic European
(WHICAP)
  859 | 549 0 | 0   TGEN (Arizona)  Meng et al., 2007
A 321 | 342
(12)		 all = 0.039 p = 0.012 North European (family)  Rogaeva et al., 2007
605 | 517
(28)		 all = 0.108 p = 0.952 Caribbean Hispanic (family)
279 | 252
(22)		 all = 0.091 p = 0.399 MIRAGE Caucasian (family)
244 | 127
(24)		 all = 0.171 p = 0.479 MIRAGE African-American (family)
178 | 242 all = 0.046 OR = 1.33
[CI: 0 .65 - 2.74]
p = 0.431		 North European
(case-control)
111 | 114 all = 0   Israeli-Arab (case-control)
(Wadi Area population study)
A 332 | 676 0.057 | 0.047 OR = 1.257
[CI: 0.797 - 1.960]
p = 1		 UK and North American Caucasian
(NIH-UCL, Knight ADRC, ADNI, Cache County Study on Memory in Aging)		 Sassi et al., 2016
A 462 (87 families) | 498   dp = 6.09×10-7 Caribbean Hispanic
(family- and cohort-based)		 Vardarajan et al., 2015
211 | 0 0.045 | N.A.   North European ancestry
A 213 | 370 0.210 | 0.151 OR = 1.50
[CI: 1.10 - 2.04]
p = 9.29×10-3		 Japanese
(autopsy confirmed)
(Japanese ADNI)		 Wen et al., 2013

aAllele frequencies as reported by study authors or calculated by Alzforum curators from data provided in the study, assuming heterozygosity if not explicitly stated in the paper.
b“Suggestive” for association, per authors, but did not meet Bonferroni-corrected threshold for exome-wide significance (p <2.43×10-5).
cAddtional subjects added to the dataset reported by Holstege et al., 2022.
dLinkage and association analysis with PSEUDOMARKER20 using all family members and unrelated controls.

This table is meant to convey the range of results reported in the literature. As specific analyses, including co-variates, differ among studies, this information is not intended to be used for quantitative comparisons, and readers are encouraged to refer to the original papers. Thresholds for statistical significance were defined by the authors of each study. (Significant results are in bold.) Note that data from some cohorts may have contributed to multiple studies, so each row does not necessarily represent an independent dataset. While every effort was made to be accurate, readers should confirm any values that are critical for their applications.

Research Models

A triple-mutant mouse line carrying a humanized Apoe gene (E4 allele), the R47H mutation knocked into mouse Trem2, and the A528T mutation knocked into mouse Sorl1 is available from The Jackson Laboratory (Stock# 031940).

Last Updated: 18 Jul 2024

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References

Paper Citations

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  10. Lee JH, Chulikavit M, Pang D, Zigman WB, Silverman W, Schupf N. Association between genetic variants in sortilin-related receptor 1 (SORL1) and Alzheimer's disease in adults with Down syndrome. Neurosci Lett. 2007 Sep 25;425(2):105-9. PubMed.
  11. Louwersheimer E, Ramirez A, Cruchaga C, Becker T, Kornhuber J, Peters O, Heilmann S, Wiltfang J, Jessen F, Visser PJ, Scheltens P, Pijnenburg YA, Teunissen CE, Barkhof F, van Swieten JC, Holstege H, Van der Flier WM, Alzheimer's Disease Neuroimaging Initiative and Dementia Competence Network. The influence of genetic variants in SORL1 gene on the manifestation of Alzheimer's disease. Neurobiol Aging. 2015 Mar;36(3):1605.e13-20. Epub 2014 Dec 11 PubMed.
  12. Assareh AA, Piguet O, Lye TC, Mather KA, Broe GA, Schofield PR, Sachdev PS, Kwok JB. Association of SORL1 gene variants with hippocampal and cerebral atrophy and Alzheimer's disease. Curr Alzheimer Res. 2014;11(6):558-63. PubMed.
  13. T Cuenco K, Lunetta KL, Baldwin CT, McKee AC, Guo J, Cupples LA, Green RC, St George-Hyslop PH, Chui H, DeCarli C, Farrer LA, MIRAGE Study Group. Association of distinct variants in SORL1 with cerebrovascular and neurodegenerative changes related to Alzheimer disease. Arch Neurol. 2008 Dec;65(12):1640-8. PubMed.
  14. Yin RH, Li J, Tan L, Wang HF, Tan MS, Yu WJ, Tan CC, Yu JT, Tan L, Alzheimer’s Disease Neuroimaging Initiative. Impact of SORL1 genetic variations on MRI markers in non-demented elders. Oncotarget. 2016 May 31;7(22):31689-98. PubMed.
  15. Chou CT, Liao YC, Lee WJ, Wang SJ, Fuh JL. SORL1 gene, plasma biomarkers, and the risk of Alzheimer's disease for the Han Chinese population in Taiwan. Alzheimers Res Ther. 2016 Dec 30;8(1):53. PubMed.
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  31. McCarthy JJ, Saith S, Linnertz C, Burke JR, Hulette CM, Welsh-Bohmer KA, Chiba-Falek O. The Alzheimer's associated 5' region of the SORL1 gene cis regulates SORL1 transcripts expression. Neurobiol Aging. 2010 Dec 22; PubMed.

External Citations

  1. The Jackson Laboratory (Stock# 031940)

Further Reading

No Available Further Reading

Protein Diagram

Primary Papers

  1. Rogaeva E, Meng Y, Lee JH, Gu Y, Kawarai T, Zou F, Katayama T, Baldwin CT, Cheng R, Hasegawa H, Chen F, Shibata N, Lunetta KL, Pardossi-Piquard R, Bohm C, Wakutani Y, Cupples LA, Cuenco KT, Green RC, Pinessi L, Rainero I, Sorbi S, Bruni A, Duara R, Friedland RP, Inzelberg R, Hampe W, Bujo H, Song YQ, Andersen OM, Willnow TE, Graff-Radford N, Petersen RC, Dickson D, Der SD, Fraser PE, Schmitt-Ulms G, Younkin S, Mayeux R, Farrer LA, St George-Hyslop P. The neuronal sortilin-related receptor SORL1 is genetically associated with Alzheimer disease. Nat Genet. 2007 Feb;39(2):168-77. PubMed.

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