Impact of Genetic Variation in SORCS1 on Memory Retention

Objective We previously reported that genetic variants in SORCS1 increase the risk of AD, that over-expression of SorCS1 reduces γ-secretase activity and Aβ levels, and that SorCS1 suppression increases γ-secretase processing of APP and Aβ levels. We now explored the effect of variation in SORCS1 on memory. Methods We explored associations between SORCS1-SNPs and memory retention in the NIA-LOAD case control dataset (162 cases,670 controls) and a cohort of Caribbean Hispanics (549 cases,544 controls) using single marker and haplotype analyses. Results Three SNPs in intron 1, were associated with memory retention in the NIA-LOAD dataset or the Caribbean Hispanic dataset (rs10884402(A allele:β = −0.15,p = 0.008), rs7078098(C allele:β = 0.18,p = 0.007) and rs950809(C allele:β = 0.17,p = 0.008)) and all three SNPs were significant in a meta-analysis of both datasets (0.002<p<0.03). The corresponding A-T-T haplotype for these SNPs was associated with lower scores in both datasets (p = 0.02,p = 0.0009), and the complementary G-C-C haplotype was associated with higher scores in NIA-LOAD (p = 0.02). These associations were restricted to cases. Conclusions Variation in intron 1 in SORCS1 is associated with memory changes in AD.

[1]  R. Mayeux,et al.  Memory performance is related to amyloid and tau pathology in the hippocampus , 2009, Journal of Neurology, Neurosurgery, and Psychiatry.

[2]  S. Heath,et al.  Systematic analysis of candidate genes for Alzheimer's disease in a French, genome-wide association study. , 2010, Journal of Alzheimer's disease : JAD.

[3]  J. Regula,et al.  Reconstitution of gamma-secretase activity. , 2003, Nature cell biology.

[4]  J. Schneider,et al.  Individual differences in rates of change in cognitive abilities of older persons. , 2002, Psychology and aging.

[5]  E. Kaplan,et al.  The Boston naming test , 2001 .

[6]  N. Tommerup,et al.  Molecular Characterization of a Novel Human Hybrid-type Receptor That Binds the α2-Macroglobulin Receptor-associated Protein* , 1996, The Journal of Biological Chemistry.

[7]  Y. Stern,et al.  Normative data for a brief neuropsychological battery administered to English- and Spanish-speaking community-dwelling elders , 1998, Journal of the International Neuropsychological Society.

[8]  H. Schaller,et al.  The three sorCS genes are differentially expressed and regulated by synaptic activity , 2004, Journal of neurochemistry.

[9]  S. Folstein,et al.  "Mini-mental state". A practical method for grading the cognitive state of patients for the clinician. , 1975, Journal of psychiatric research.

[10]  P. S. St George-Hyslop,et al.  Identification of novel loci for Alzheimer disease and replication of CLU, PICALM, and BIN1 in Caribbean Hispanic individuals. , 2011, Archives of neurology.

[11]  R. Mayeux,et al.  Diagnosis of dementia in a heterogeneous population. Development of a neuropsychological paradigm-based diagnosis of dementia and quantified correction for the effects of education. , 1992, Archives of neurology.

[12]  E. Kaplan,et al.  The assessment of aphasia and related disorders , 1972 .

[13]  J. Regula,et al.  Reconstitution of γ-secretase activity , 2003, Nature Cell Biology.

[14]  H. Schaller,et al.  Identification and characterization of SorCS, a third member of a novel receptor family. , 1999, Biochemical and biophysical research communications.

[15]  Taylor J. Maxwell,et al.  A scan of chromosome 10 identifies a novel locus showing strong association with late-onset Alzheimer disease. , 2006, American journal of human genetics.

[16]  M. Gobbi,et al.  Synthetic amyloid-β oligomers impair long-term memory independently of cellular prion protein , 2010, Proceedings of the National Academy of Sciences.

[17]  HERMAN BUSCHKE,et al.  Evaluating storage, retention, and retrieval in disordered memory and learning , 1974, Neurology.

[18]  Cindee M. Madison,et al.  Episodic memory loss is related to hippocampal-mediated beta-amyloid deposition in elderly subjects. , 2009, Brain : a journal of neurology.

[19]  Y. Benjamini,et al.  Controlling the false discovery rate in behavior genetics research , 2001, Behavioural Brain Research.

[20]  N. Nomura,et al.  Prediction of the coding sequences of unidentified human genes. XIV. The complete sequences of 100 new cDNA clones from brain which code for large proteins in vitro. , 1999, DNA research : an international journal for rapid publication of reports on genes and genomes.

[21]  Sorcs1 Alters APP Processing and Variants may Increase Alzheimer's Disease Risk , 2010, Alzheimer's & Dementia.

[22]  M. Schlossberg.  The Assessment of Aphasia and Related Disorders. 2nd ed. , 1984 .

[23]  C. Reinhard,et al.  The secretory pathway from history to the state of the art. , 2000, Sub-cellular biochemistry.

[24]  C. Clark,et al.  The Consortium to Establish a Registry for Alzheimer's Disease (CERAD) , 1994, Neurology.

[25]  A. J. Slater,et al.  Candidate single-nucleotide polymorphisms from a genomewide association study of Alzheimer disease. , 2008, Archives of neurology.

[26]  B. Hoflack,et al.  Protein transport from the secretory to the endocytic pathway in mammalian cells. , 1998, Biochimica et biophysica acta.

[27]  I. Hermans-Borgmeyer,et al.  SorCS1, a member of the novel sorting receptor family, is localized in somata and dendrites of neurons throughout the murine brain , 2001, Neuroscience Letters.

[28]  R. Mohs,et al.  Consortium to establish a registry for Alzheimer's disease (CERAD) clinical and neuropsychological assessment of Alzheimer's disease. , 2002, Psychopharmacology bulletin.

[29]  J. Haines,et al.  SORCS1 alters amyloid precursor protein processing and variants may increase Alzheimer's disease risk , 2011, Annals of neurology.

[30]  D. Bennett,et al.  Assessment of Cognitive Decline in Old Age with Brief Tests Amenable to Telephone Administration , 2005, Neuroepidemiology.

[31]  N. Butters,et al.  The Consortium to Establish a Registry for Alzheimer's Disease (CERAD). Part V. A normative study of the neuropsychological battery , 1994, Neurology.

[32]  R. Mayeux,et al.  Analyses of the National Institute on Aging Late-Onset Alzheimer's Disease Family Study: implication of additional loci. , 2008, Archives of neurology.

[33]  H. Schaller,et al.  Identification of SorCS2, a novel member of the VPS10 domain containing receptor family, prominently expressed in the developing mouse brain , 2001, Mechanisms of Development.

[34]  R. Nass,et al.  The assessment of aphasia and related disorders By Harold Goodglass and edith kaplan philadelphia, lea & febiger, 1983 illustrated, $27.50 (package) , 1984 .