We have implicated the neuronal sortilin-related receptor gene (S0RL1) as a susceptibility gene for Alzheimer's disease (AD). S0RL1 is involved in intracellular sorting of APP, and under-expression of S0RL1 leads to over-expression of A? and an increased risk of AD. Our preliminary studies suggest that at least two additional genes in the same sorting pathway play a role. The purpose of this study is to use functional genomics and genetic linkage and association analyses to identify additional causative genes in this pathway. The study will capitalize on 3 established cohorts;ADRC AD and control brains;Caribbean Hispanics from the population-based WHICAP project who have genome-wide screening;a cohort of Caribbean Hispanic families multiply affected by AD which has genome wide screening.
Aim 1 : To identify additional causative genes in the sortilin-related pathway through computational network reconstruction and gene expression profiling of pathologically defined AD cases and controls. Hypothesis 1: Besides S0RL1, additional genes in the sortilin pathway are involved in AD and will be differentially expressed in AD and control brains.
Aim 2 : To identify the specific causative variants in the candidate genes identified through Aim 1 by fine-mapping and linkage and association analyses in the epidemiological cohort of Caribbean Hispanics and the cohort of Caribbean Hispanic families. To further explore the mechanisms by which these variants act on AD by examining their association with age-of-onset of AD and AD endophenotypes (i.e. plasma A?40 and A?42 levels, memory). Hypothesis 2: Causative variants in the sortilin-related pathway that were identified through Aim 1 and are differentially expressed in AD and control brains will be associated with AD status in case control association analyses and family based linkage analyses. Hypothesis 3: Causative variants will be associated with differences in A?40, A?42 and memory.
Aim 3 : To confirm identified candidate genes through functional analyses (real-time PCR, siRNA suppression). Hypothesis 4: Causative genes in the sortilin pathway will be differentially expressed in real-time PCR of AD and control tissue. Suppression of siRNA will lead to changes in levels of APPs?, A?40 and A?42.

Public Health Relevance

Pathways regulating protein sorting play a major role in Alzheimer's disease (AD). Our robust preliminary findings suggest that besides S0RL1, at least two additional genes in the sortilin pathway are involved. Mapping the additional causative factors in the sortilin pathway that are mechanistically involved in AD will help elucidate the etiology of AD and will identify targets for prevention, treatment and genetic testing.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Mentored Patient-Oriented Research Career Development Award (K23)
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Special Emphasis Panel (ZAG1-ZIJ-4 (M1))
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Petanceska, Suzana
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Columbia University (N.Y.)
Schools of Medicine
New York
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Reitz, Christiane (2015) The role of the retromer complex in aging-related neurodegeneration: a molecular and genomic review. Mol Genet Genomics 290:413-27
Chouraki, V; De Bruijn, R F A G; Chapuis, J et al. (2014) A genome-wide association meta-analysis of plasma A? peptides concentrations in the elderly. Mol Psychiatry 19:1326-35
Reitz, Christiane; Mayeux, Richard (2014) Alzheimer disease: epidemiology, diagnostic criteria, risk factors and biomarkers. Biochem Pharmacol 88:640-51
Reitz, Christiane (2014) Genetic loci associated with Alzheimer's disease. Future Neurol 9:119-122
Lambert, J-C; Grenier-Boley, B; Harold, D et al. (2013) Genome-wide haplotype association study identifies the FRMD4A gene as a risk locus for Alzheimer's disease. Mol Psychiatry 18:461-70
Reitz, Christiane (2013) Dyslipidemia and the risk of Alzheimer's disease. Curr Atheroscler Rep 15:307
Reitz, Christiane; Jun, Gyungah; Naj, Adam et al. (2013) Variants in the ATP-binding cassette transporter (ABCA7), apolipoprotein E ýý4,and the risk of late-onset Alzheimer disease in African Americans. JAMA 309:1483-92
Reitz, C; Tosto, G; Vardarajan, B et al. (2013) Independent and epistatic effects of variants in VPS10-d receptors on Alzheimer disease risk and processing of the amyloid precursor protein (APP). Transl Psychiatry 3:e256
Tosto, Giuseppe; Reitz, Christiane (2013) Genome-wide association studies in Alzheimer's disease: a review. Curr Neurol Neurosci Rep 13:381
Richard, Edo; Reitz, Christiane; Honig, Lawrence H et al. (2013) Late-life depression, mild cognitive impairment, and dementia. JAMA Neurol 70:374-82

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