Elsevier

Neurobiology of Aging

Volume 34, Issue 6, June 2013, Pages 1710.e11-1710.e18
Neurobiology of Aging

Genetic reports abstract
Sortilin receptor 1 predicts longitudinal cognitive change

https://doi.org/10.1016/j.neurobiolaging.2012.12.006Get rights and content

Abstract

The gene encoding sortilin receptor 1 (SORL1) has been associated with Alzheimer's disease risk. We examined 15 SORL1 variants and single nucleotide polymorphism (SNP) set risk scores in relation to longitudinal verbal, spatial, memory, and perceptual speed performance, testing for age trends and sex-specific effects. Altogether, 1609 individuals from 3 population-based Swedish twin studies were assessed up to 5 times across 16 years. Controlling for apolipoprotein E genotype (APOE), multiple simple and sex-moderated associations were observed for spatial, episodic memory, and verbal trajectories (p = 1.25E-03 to p = 4.83E-02). Five variants (rs11600875, rs753780, rs7105365, rs11820794, rs2070045) were associated across domains. Notably, in those homozygous for the rs2070045 risk allele, men demonstrated initially favorable performance but accelerating declines, and women showed overall lower performance. SNP set risk scores predicted spatial (Card Rotations, p = 5.92E-03) and episodic memory trajectories (Thurstone Picture Memory, p = 3.34E-02), where higher risk scores benefited men's versus women's performance up to age 75 but with accelerating declines. SORL1 is associated with cognitive aging, and might contribute differentially to change in men and women.

Introduction

The neuronal sorting receptor, sortilin receptor 1 (SORL1), is involved in the trafficking of amyloid precursor protein (APP), a precursor of beta-amyloid (Aβ) peptides (Rogaeva et al., 2009) and may bind with lipoproteins and mediate endocytotic processes (Wollmer, 2010). In 2007, variants of the SORL1 gene were associated with Alzheimer's disease (AD) risk (Rogaeva et al., 2007). Subsequent replication efforts, though mixed, have been predominantly positive (Alexopoulos et al., 2010; Bettens et al., 2008; Cousin et al., 2011; Feulner et al., 2009; Kimura et al., 2009; Kölsch et al., 2009; Lee et al., 2007, 2008; Li et al., 2008; Liu et al., 2009; Meng et al., 2007; Minster et al., 2008; Patel et al., 2010; Reitz et al., 2011; Reynolds et al., 2010; Schjeide et al., 2009; Tan et al., 2009; Webster et al., 2008). Recently, we reported no significant association of 6 SORL1 markers with dementia risk, age of onset, cerebrospinal fluid amyloid-beta or tau (Reynolds et al., 2010). However, meta-analysis of our findings with previous studies included in AlzGene (Bertram et al., 2007) indicated a weak association for dementia risk. Likewise, a subsequent meta-analysis of all variants published to date (Reitz et al., 2011) supports association with AD risk even when controlling for age, sex, and APOE. A study of Italian AD patients reported that sex and APOE e4 status might moderate the association of SORL1 with AD risk (Cellini et al., 2009). Although sex moderation might be a source of disparate findings, it has not received additional attention.

SORL1 has less often been examined for association with cognitive performance in nondemented adults, and to our knowledge never previously with change in cognition over time. A study of 705 stroke- and dementia-free individuals from the Framingham study reported 2 of 7 SORL1 variants (rs1131497, rs726601) were associated with abstract verbal reasoning performance (best p = 3.2 × 10−6) but not verbal memory, visuospatial memory, or attention composites (Seshadri et al., 2007). A later study of the 1936 Lothian Birth Cohort reported that 1 of 2 SORL1 variants (rs3824968) was associated with a spatial span task (p = 0.029) (Houlihan et al., 2009). Sex was statistically controlled for or residualized in these studies and not directly considered as an effect moderator.

In the current report we examine associations of SORL1 variants with cognitive decline trajectories, especially considering sex-specific trends. We note that this study, with up to 16 years of follow-up, is the first to report findings of SORL1 on longitudinal cognitive performance across multiple domains in a population-based sample.

Section snippets

Participants

Participants were drawn from 3 similarly-designed population-based studies originating from the Swedish Twin Registry (Lichtenstein et al., 2002): the Swedish Adoption/Twin Study of Aging (SATSA) (Finkel and Pedersen, 2004; Pedersen et al., 1991), the Origins of Variance in the Oldest-Old (OCTO-Twin) (McClearn et al., 1997), and the Sex Differences in Health and Aging Study (GENDER) (Gold et al., 2002). Across these studies, SORL1 genotypes, APOE genotype, covariates, and cognitive outcomes

Results

Significant model comparisons (testing SNP, sex by SNP, or full association) were observed across the 15 SORL1 SNPs for 3 of the 4 primary cognitive tests: Synonyms, Thurstone Picture Memory, and Block Design (p = 6.13E-03 to p = 4.51E-02; Table 2). Model comparisons were not significant for Symbol Digit (not shown). For  the additional cognitive tests, significant comparisons were observed for Card Rotations and Figure Logic (p = 1.25E-03 to p = 4.83E-02; Table 2), whereas significance was not

Discussion

Our findings support the conclusion that SORL1 is related to cognitive change trajectories across multiple domains and furthermore may contribute differentially to change in men and women. Several SORL1 SNPs were associated with cognitive trajectories in adults aged 50–93 with up to 16 years of follow-up, primarily in the spatial domain but also episodic memory and verbal abilities. Five SNPs were significant across more than 1 cognitive domain (rs11600875, rs753780, rs7105365, rs11820794, and

Disclosure statement

The authors declare no conflicts of interest.

The study was done in accord with the ethical standards of the Swedish Data Inspection Authority and the Karolinska Institute with approval by the relevant local Institutional Review Boards where the original grants for data collection were housed, and the investigators' institutions.

Acknowledgements

This work was supported by the US National Institutes of Health (AG028555, AG08724, AG04563, AG10175, AG08861), and the Swedish Research Council (2007-2722).

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