Overview

Coding/Non-Coding: Non-Coding
Reference Isoform: SORL1 Isoform 1 (2214 aa)
Genomic Region: Chromosome 11

Findings

This haplotype, composed of 31 intronic variants in SORL1, was found to be associated with a reduced risk of Alzheimer’s disease and with certain AD-related endophenotypes in people of East Asian ancestry (Zhou et al., 2024).

In a meta-analysis of three cohorts from mainland China, Hong Kong, and Japan—including 2,570 AD subjects and 2,679 age- and sex-matched controls—Haplotype A (Hap A) substantially reduced the risk of AD (odds ratio 0.685 [95 percent confidence interval: 0.611−0.768]). The protective effect of the haplotype was seen in both APOE4 carriers (0.602 [0.481−0.753]) and non-carriers (0.727 [0.601−0.878]).

In a previously reported cohort from Hong Kong (Jiang et al., 2021), Hap A was associated with increased levels of plasma Aβ42 in controls, decreased levels of total tau in AD subjects, and an increased ratio of Aβ42/Aβ40 and decreased levels of p-tau181 when AD subjects and controls were pooled. Plasma Aβ40 and NfL were not affected by Hap A. Proteomic analysis revealed increased levels of proteins associated with synaptic structure and decreased levels of pro-inflammatory markers in Hap A carriers.

MRI studies of subjects from Hong Kong showed some associations of Hap A with regional volumes. Among AD subjects, the volumes of the amygdala and caudate were greater in Hap A carriers than non-carriers. However, the haplotype did not influence the volumes of other regions, including the hippocampus, and frontal, temporal, and parietal lobes. Nor were ventricular volumes or white-matter hyperintensities associated with Hap A.

While Hap A did not affect cognition measured using the Montreal Cognitive Assessment (MoCA) in AD subjects from Hong Kong, it did influence the relationship between amyloid load and cognition. Amyloid load, measured by PiB-PET, was negatively associated with cognition in AD subjects who did not carry Hap A (16 subjects, all homozygous for APOE3), but there was not an association between amyloid load and MoCA scores in Hap A carriers (32 APOE3 homozygotes).

In a cohort from mainland China, cognition measured using the Mini-Mental Status Exam was associated with Hap A when AD subjects (n = 1082) and controls (n = 310) were combined.

Seven of the variants within Hap A are located in candidate cis-regulatory elements (cCREs): rs3781831, rs75279208, rs1620130, rs3781836, rs73595281, rs2282647, and rs11218360. The protective alleles of two of these variants, rs3781831 and rs75279208, were associated with increased SORL1 expression, measured in a peripheral nerve.

The variant rs2282647 within Hap A has received particular attention. This variant is among the seven variants in a cCRE and is located in intron 30 of the canonical 2214-amino acid SORL1 isoform (SORL1 isoform 1: Ensembl ENST00000260197, NM_003105.6, Uniprot Q92673-1). There also exists a truncated SORL1 isoform, which has 829-amino acids (“SORL1-206” or “sorLA-30B,” ENST00000527934.1, Uniprot E9PKB0). The N-terminal of this isoform is formed by a fragment of intron 30 spliced in-frame to exon 31 (numbered according to full-length SORL1) (Blechingberg et al., 2018). The isoform contains only three of the complement-type repeat domains found in full-length SORL1, but all six fibronectin-type III domains and the transmembrane and intracellular domains, and is expressed in human brain, most prominently in the hippocampus and temporal lobe (Blechingberg et al., 2018). Variant rs2282647 is a coding variant in this truncated isoform, introducing a tryptophan-to-cysteine substitution at residue 15 (numbered according to the SORL1-206 sequence). In silico analyses predicted that the Trp15Cys mutation might affect the stability or localization of the protein, and the mutation resulted in a 17 percent reduction in the level of SORLA protein in HEK cells transfected with a vector encoding Trp15Cys SORL1-206, compared with cells transfected with wild-type SORL1-206 (Zhou et al., 2024).

*RefSeq NM_003105.6

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References

Mutations Citations

1. SORL1 c.4214-117G>C
2. SORL1 c.2267-1094C>T
3. SORL1 c.3049+2554C>T
4. SORL1 c.3049+3560C>A
5. SORL1 c.3050-2179G>A
6. SORL1 c.3050-2062T>C
7. SORL1 c.3050-1645G>A
8. SORL1 c.3050-1379G>T
9. SORL1 c.3050-78A>G
10. SORL1 c.3338-139G>C
11. SORL1 c.3460+868A>G
12. SORL1 c.3460+1146C>G
13. SORL1 c.3461-1391T>C
14. SORL1 c.3580+229G>A
15. SORL1 c.3580+863T>C
16. SORL1 c.3580+2223G>A
17. SORL1 c.3581-2466A>G
18. SORL1 c.3581-1813G>A
19. SORL1 c.3581-388A>T
20. SORL1 c.3581-384C>T
21. SORL1 c.3707-870G>A
22. SORL1 c.3707-275C>G
23. SORL1 c.3815-84G>A
24. SORL1 c.4519+2811G>A
25. SORL1 c.4519+3954A>G
26. SORL1 c.4519+4139C>G
27. SORL1 c.4519+4165C>T
28. SORL1 c.4520-1511T>C
29. SORL1 c.4520-877T>C
30. SORL1 c.4520-663A>G
31. SORL1 c.5062-79C>T

Paper Citations

1. Zhou X, Cao H, Jiang Y, Chen Y, Zhong H, Fu WY, Lo RM, Wong BW, Cheng EY, Mok KY, Kwok TC, Mok VC, Ip FC, Alzheimer's Disease Neuroimaging Initiative, Miyashita A, Hara N, Ikeuchi T, Hardy J, Chen Y, Fu AK, Ip NY. Transethnic analysis identifies SORL1 variants and haplotypes protective against Alzheimer's disease. Alzheimers Dement. 2025 Jan;21(1):e14214. Epub 2024 Dec 10 PubMed.
2. Jiang Y, Zhou X, Ip FC, Chan P, Chen Y, Lai NC, Cheung K, Lo RM, Tong EP, Wong BW, Chan AL, Mok VC, Kwok TC, Mok KY, Hardy J, Zetterberg H, Fu AK, Ip NY. Large-scale plasma proteomic profiling identifies a high-performance biomarker panel for Alzheimer's disease screening and staging. Alzheimers Dement. 2021 May 25; PubMed.
3. Blechingberg J, Poulsen AS, Kjølby M, Monti G, Allen M, Ivarsen AK, Lincoln SJ, Thotakura G, Vægter CB, Ertekin-Taner N, Nykjær A, Andersen OM. An alternative transcript of the Alzheimer's disease risk gene SORL1 encodes a truncated receptor. Neurobiol Aging. 2018 Nov;71:266.e11-266.e24. Epub 2018 Jun 28 PubMed.

Further Reading