Susana Ruiz

The membrane-spanning 4-domains, subfamily A (MS4A) gene cluster contains a common variant associated with Alzheimer's disease.

BackgroundIn order to identify novel loci associated with Alzheimers disease (AD), we conducted a genome-wide association study (GWAS) in the Spanish population.MethodsWe genotyped 1,128 individuals using the Affymetrix Nsp I 250K chip. A sample of 327 sporadic AD patients and 801 controls with unknown cognitive status from the Spanish general population were included in our initial study. To increase the power of the study, we combined our results with those of four other public GWAS datasets by applying identical quality control filters and the same imputation methods, which were then analyzed with a global meta-GWAS. A replication sample with 2,200 sporadic AD patients and 2,301 controls was genotyped to confirm our GWAS findings.ResultsMeta-analysis of our data and independent replication datasets allowed us to confirm a novel genome-wide significant association of AD with the membrane-spanning 4-domains subfamily A (MS4A) gene cluster (rs1562990, P = 4.40E-11, odds ratio = 0.88, 95% confidence interval 0.85 to 0.91, n = 10,181 cases and 14,341 controls).ConclusionsOur results underscore the importance of international efforts combining GWAS datasets to isolate genetic loci for complex diseases.

Blood Amyloid Beta Levels in Healthy, Mild Cognitive Impairment and Alzheimer's Disease Individuals: Replication of Diastolic Blood Pressure Correlations and Analysis of Critical Covariates

Plasma amyloid beta (Aβ) levels are being investigated as potential biomarkers for Alzheimer’s disease. In AB128 cross-sectional study, a number of medical relevant correlates of blood Aβ40 or Aβ42 were analyzed in 140 subjects (51 Alzheimer’s disease patients, 53 healthy controls and 36 individuals diagnosed with mild cognitive impairment). We determined the association between multiple variables with Aβ40 and Aβ42 levels measured in three different blood compartments called i) Aβ directly accessible (DA) in the plasma, ii) Aβ recovered from the plasma matrix (RP) after diluting the plasma sample in a formulated buffer, and iii) associated with the remaining cellular pellet (CP). We confirmed that diastolic blood pressure (DBP) is consistently correlated with blood DA Aβ40 levels (r=-0.19, P=0.032). These results were consistent in the three phenotypic groups studied. Importantly, the observation resisted covariation with age, gender or creatinine levels. Observed effect size and direction of Aβ40 levels/DBP correlation are in accordance with previous reports. Of note, DA Aβ40 and the RP Aβ40 were also strongly associated with creatinine levels (r=0.599, P<<0.001) and to a lesser extent to urea, age, hematocrit, uric acid and homocysteine (p<0.001). DBP and the rest of statistical significant correlates identified should be considered as potential confounder factors in studies investigating blood Aβ levels as potential AD biomarker. Remarkably, the factors affecting Aβ levels in plasma (DA, RP) and blood cell compartments (CP) seem completely different.

Cognitive Composites Domain Scores Related to Neuroimaging Biomarkers within Probable-Amnestic Mild Cognitive Impairment-Storage Subtype

The probable-amnestic (Pr-a) mild cognitive impairment (MCI)-storage subtype is a phenotype with 8.5 times more risk of conversion to dementia, mainly Alzheimer’s disease (AD), than the possible non-amnestic (Pss-na) MCI. The aim of this study was to find the optimized cognitive composites (CCs) domain scores most related to neuroimaging biomarkers within Pr-aMCI-storage subtype patients. The Fundació ACE (ACE) study with 20 Pr-aMCI-storage subtype subjects (MCI) were analyzed. All subjects underwent a neuropsychological assessment, a structural MRI, FDG-PET, and PIB-PET. The adjusted hippocampal volume (aHV) on MRI, the standard uptake value ratio (SUVR) on FDG-PET and PIB-PET SUVR measures were analyzed. The construction of the CCs domain scores, and the aHV on MRI and FDG-PET SUVR measures, were replicated in the parental AB255 study database (n = 133 MCI). Partial correlations adjusted by age, gender, and education were calculated with the associated p-value among every CC domain score and the neuroimaging biomarkers. The results were replicated in the “MCI due to AD” with memory storage impairments from ADNI. Delayed Recall CC domain score was significantly correlated with PIB-PET SUVR (β= –0.61, p = 0.003) in the ACE study and also with aHV on MRI (β= 0.27, p = 0.01) and FDG-PET SUVR (β= 0.27, p = 0.01) in the AB255 study. After a median survival time of 20.6 months, 85% from the ACE MCI converted to AD. The replication of our results in the ADNI dataset also confirmed our findings. Delayed Recall is the CC domain score best correlated with neuroimaging biomarkers associated with prodromal AD diagnosis.

Genome-wide significant risk factors on chromosome 19 and the APOE locus

The apolipoprotein E (APOE) gene on chromosome 19q13.32, was the first, and remains the strongest, genetic risk factor for Alzheimer’s disease (AD). Additional signals associated with AD have been located in chromosome 19, including ABCA7 (19p13.3) and CD33 (19q13.41). The ABCA7 gene has been replicated in most populations. However, the contribution to AD of other signals close to APOE gene remains controversial. Possible explanations for inconsistency between reports include long range linkage disequilibrium (LRLD). We analysed the contribution of ABCA7 and CD33 loci to AD risk and explore LRLD patterns across APOE region. To evaluate AD risk conferred by ABCA7 rs4147929:G>A and CD33 rs3865444:C>A, we used a large Spanish population (1796 AD cases, 2642 controls). The ABCA7 rs4147929:G>A SNP effect was nominally replicated in the Spanish cohort and reached genome-wide significance after meta-analysis (odds ratio (OR)=1.15, 95% confidence interval (95% CI)=1.12–1.19; P = 1.60 x 10-19). CD33 rs3865444:C>A was not associated with AD in the dataset. The meta-analysis was also negative (OR=0.98, 95% CI=0.93–1.04; P=0.48). After exploring LRLD patterns between APOE and CD33 in several datasets, we found significant LD (D’ >0.20; P <0.030) between APOE-Ɛ2 and CD33 rs3865444C>A in two of five datasets, suggesting the presence of a non-universal long range interaction between these loci affecting to some populations. In conclusion, we provide here evidence of genetic association of the ABCA7 locus in the Spanish population and also propose a plausible explanation for the controversy on the contribution of CD33 to AD susceptibility.

Exploring APOE genotype effects on Alzheimer's disease risk and amyloid β burden in individuals with subjective cognitive decline: The FundacioACE Healthy Brain Initiative (FACEHBI) study baseline results

Subjective cognitive decline (SCD) has been proposed as a potential preclinical stage of Alzheimers disease (AD). Nevertheless, the genetic and biomarker profiles of SCD individuals remain mostly unexplored.

GENETIC DETERMINANTS OF ALZHEIMER'S DISEASE PROGRESSION: EXPLORATORY ANALYSIS OF INTERNATIONAL GENOMICS OF ALZHEIMER PROJECT (IGAP) GENETIC MARKERS IN MMSE RATE OF DECLINE AND GDS

tion with dose of the e2 in total sample including e2+ and e33 subjects. The most significant SNP was examined for gene expression of all the genes within +/500kb from the SNP. Results:Genomewide significant association (P<5x10) was identified among e2+ subjects with rs192939675, resides near the 5’ end of PPP2CB and has a minor allele frequency of 7% in this subgroup (P1⁄49.8 x10, OR1⁄42.86, 95% CI1⁄42.01-4.07) but not associated with AD among e33 subjects (P1⁄40.44). Interaction between rs192939675 and dose of the e2 was significant in the total sample (P1⁄41.4x10). Rs192939675 significantly modulates expression of PPP2CB in blood (P1⁄45.9 x10), but not of other transcripts in the region. The most significant SNP from the MAPT/KANSL1 region (rs187270294) is located in KANSL1 and is more strongly associated in e2+ (P1⁄44.5 x10) than in e33 (P1⁄40.02) subjects. We also observed significant interaction between rs187270294 and dose of the e2 in the total sample (P1⁄42.6 x10). Conclusions: We identified a novel AD gene, PPP2CB, for which the effect on AD risk is modulated by the APOE e2 allele. PPP2CB encodes the catalytic subunit (beta isozyme) of protein phosphatase 2A, which is known to dephosphorylate tau protein. Future studies are needed to confirm the novel gene association and determine its precise roles in AD pathogenesis.

FUNDACIÓ ACE HEALTHY BRAIN INITIATIVE: A STUDY OF COGNITION AND BIOMARKERS IN INDIVIDUALS WITH SUBJECTIVE COGNITIVE DECLINE

appropriate increase in dilation at moderate loads. Conclusions: These results suggest that pupillometry is associated with altered brain activity, inflammatory state, and cognitive performance. This provides converging evidence for LC involvement, an early site of AD pathology which may provide the neural substrate linking these measures together. Given the relatively young age of the sample, TEPD may provide a simple and useful psychophysiological biomarker for early identification of AD risk.

WHITE MATTER MICROSTRUCTURE DISRUPTION COULD BE AN EARLY PHENOMENON IN THE PATHOPHYSIOLOGY OF PRECLINICAL ALZHEIMER'S DISEASE: FUNDACIÓ ACE HEALTHY BRAIN INITIATIVE

analysis. Searches were conducted through PubMed and Google Scholar. Only English papers that contained search terms in title and/or abstract: AD or MCI, and MRI, and grey matter, whole brain, cortical thickness, hippocampus, medial temporal lobe were taken into account. In total, 1930 articles were found. Reviews (n1⁄4138), case reports (n1⁄47), papers about animal models (n1⁄499), medication trails (n1⁄445), autopsy-based studies (n1⁄442), articles that compared AD with other dementias (n1⁄4174), and articles that not fulfilled the criteria (n1⁄41053) were deselected. Of the remaining 372 articles, 252 described cross-sectional studies based on structural MRI in patients within the AD spectrum and/or controls, 120 described studies based on a volumetric MRI technique. Results:Further analyses, including evidence based grading of the selected 372 papers are planned in the first quartile of 2016. Conclusions:This systematic review gives an overview of methodological developments that allow volumetric assessment of different brain regions in vivo, and summarize the results of structural imaging studies covering the entire AD spectrum as compared to healthy ageing.