Evaluating pathogenic dementia variants in posterior cortical atrophy.

Posterior cortical atrophy (PCA) is an understudied visual impairment syndrome most often due to "posterior Alzheimer's disease (AD)" pathology. Case studies detected mutations in PSEN1, PSEN2, GRN, MAPT, and PRNP in subjects with clinical PCA. To detect the frequency and spectrum of mutations in known dementia genes in PCA, we screened 124 European-American subjects with clinical PCA (n = 67) or posterior AD neuropathology (n = 57) for variants in genes implicated in AD, frontotemporal dementia, and prion disease using NeuroX, a customized exome array.

Erratum to: Genetically-controlled Vesicle-Associated Membrane Protein 1 expression may contribute to Alzheimer's pathophysiology and susceptibility.

Following publication of this work, we noticed that we inadvertently failed to include Dr Ferenc Deák in the author list. The author list has now been corrected and the amended authors' contributions section has been modified accordingly below.

Genetically-controlled Vesicle-Associated Membrane Protein 1 expression may contribute to Alzheimer's pathophysiology and susceptibility.

Background: Alzheimer's disease is a neurodegenerative disorder in which extracellular deposition of β-amyloid (Aβ) oligomers causes synaptic injury resulting in early memory loss, altered homeostasis, accumulation of hyperphosphorylated tau and cell death. Since proteins in the SNAP (Soluble N-ethylmaleimide-sensitive factor Attachment Protein) REceptors (SNARE) complex are essential for neuronal Aβ release at pre-synaptic terminals, we hypothesized that genetically controlled SNARE expression could alter neuronal Aß release at the synapse and hence play an early role in Alzheimer's pathophysiology.

Results: Here we report 5 polymorphisms in Vesicle-Associated Membrane Protein 1 (VAMP1), a gene encoding a member of the SNARE complex, associated with bidirectionally altered cerebellar VAMP1 transcript levels (all p<0.

Late-onset Alzheimer's risk variants in memory decline, incident mild cognitive impairment, and Alzheimer's disease.

We tested association of nine late-onset Alzheimer's disease (LOAD) risk variants from genome-wide association studies (GWAS) with memory and progression to mild cognitive impairment (MCI) or LOAD (MCI/LOAD) in older Caucasians, cognitively normal at baseline and longitudinally evaluated at Mayo Clinic Rochester and Jacksonville (n>2000). Each variant was tested both individually and collectively using a weighted risk score. APOE-e4 associated with worse baseline memory and increased decline with highly significant overall effect on memory.

Linking protective GAB2 variants, increased cortical GAB2 expression and decreased Alzheimer's disease pathology.

GRB-associated binding protein 2 (GAB2) represents a compelling genome-wide association signal for late-onset Alzheimer's disease (LOAD) with reported odds ratios (ORs) ranging from 0.75-0.85.

Replication of EPHA1 and CD33 associations with late-onset Alzheimer's disease: a multi-centre case-control study.

Background: A recently published genome-wide association study (GWAS) of late-onset Alzheimer's disease (LOAD) revealed genome-wide significant association of variants in or near MS4A4A, CD2AP, EPHA1 and CD33. Meta-analyses of this and a previously published GWAS revealed significant association at ABCA7 and MS4A, independent evidence for association of CD2AP, CD33 and EPHA1 and an opposing yet significant association of a variant near ARID5B. In this study, we genotyped five variants (in or near CD2AP, EPHA1, ARID5B, and CD33) in a large (2,634 LOAD, 4,201 controls), independent dataset comprising six case-control series from the USA and Europe.

Multiple insulin degrading enzyme variants alter in vitro reporter gene expression.

The insulin degrading enzyme (IDE) variant, v311 (rs6583817), is associated with increased post-mortem cerebellar IDE mRNA, decreased plasma β-amyloid (Aβ), decreased risk for Alzheimer's disease (AD) and increased reporter gene expression, suggesting that it is a functional variant driving increased IDE expression. To identify other functional IDE variants, we have tested v685, rs11187061 (associated with decreased cerebellar IDE mRNA) and variants on H6, the haplotype tagged by v311 (v10; rs4646958, v315; rs7895832, v687; rs17107734 and v154; rs4646957), for altered in vitro reporter gene expression. The reporter gene expression levels associated with the second most common haplotype (H2) successfully replicated the post-mortem findings in hepatocytoma (0.

Replication of BIN1 association with Alzheimer's disease and evaluation of genetic interactions.

The most recent late-onset Alzheimer's disease (LOAD) genome-wide association study revealed genome-wide significant association of two new loci: rs744373 near BIN1 (p = 1.6 × 10-11) and rs597668 near EXOC3L2/BLOC1S3/MARK4 (p = 6.5 × 10-9).

Genome-wide screen identifies rs646776 near sortilin as a regulator of progranulin levels in human plasma.

Recent studies suggest progranulin (GRN) is a neurotrophic factor. Loss-of-function mutations in the progranulin gene (GRN) cause frontotemporal lobar degeneration (FTLD), a progressive neurodegenerative disease affecting ∼10% of early-onset dementia patients. Using an enzyme-linked immunosorbent assay, we previously showed that GRN is detectable in human plasma and can be used to predict GRN mutation status.

Association and heterogeneity at the GAPDH locus in Alzheimer's disease.

Glyceraldehyde-3-phosphate dehydrogenase gene (GAPDH) and its paralogs were implicated in late-onset Alzheimer's disease (LOAD), although the strength and direction of association have not been consistent. We genotyped 3 previously reported single nucleotide polymorphisms (SNPs; rs3741916-GAPDH 5' UTR, rs2029721-pGAPD, and rs4806173-GAPDHS) in 3 case-control series (2112 cases and 3808 controls). Rs3741916 showed the strongest LOAD association (p = 0.

Replication of CLU, CR1, and PICALM associations with alzheimer disease.

Objective: To test for replication of the association between variants in the CLU, CR1, and PICALM genes with Alzheimer disease.

Design: Follow-up case-control association study.

Setting: The Mayo Clinics at Jacksonville, Florida, and Rochester, Minnesota.

Genetic variation in PCDH11X is associated with susceptibility to late-onset Alzheimer's disease.

By analyzing late-onset Alzheimer's disease (LOAD) in a genome-wide association study (313,504 SNPs, three series, 844 cases and 1,255 controls) and evaluating the 25 SNPs with the most significant allelic association in four additional series (1,547 cases and 1,209 controls), we identified a SNP (rs5984894) on Xq21.3 in PCDH11X that is strongly associated with LOAD in individuals of European descent from the United States. Analysis of rs5984894 by multivariable logistic regression adjusted for sex gave global P values of 5.