Citations

AbstractIntroductionAfrican‐American (AA) individuals have a higher risk for late‐onset Alzheimer's disease (LOAD) than Americans of primarily European ancestry (EA). Recently, the largest genome‐wide association study in AAs to date confirmed that six of the Alzheimer's disease (AD)‐related genetic variants originally discovered in EA cohorts are also risk variants in AA; however, the risk attributable to many of the loci (e.g., APOE, ABCA7) differed substantially from previous studies in EA. There likely are risk variants of higher frequency in AAs that have not been discovered.MethodsWe performed a comprehensive analysis of genetically determined local and global ancestry in AAs with regard to LOAD status.ResultsCompared to controls, LOAD cases showed higher levels of African ancestry, both globally and at several LOAD relevant loci, which explained risk for AD beyond global differences.DiscussionExploratory post hoc analyses highlight regions with greatest differences in ancestry as potential candidate regions for future genetic analyses.

Abstract Introduction This study assessed apolipoprotein E ( APOE ) ε4 carrier status effects on Alzheimer's disease imaging and cerebrospinal fluid (CSF) biomarkers in cognitively normal older adults with significant memory concerns (SMC). Methods Cognitively normal, SMC, and early mild cognitive impairment participants from Alzheimer's Disease Neuroimaging Initiative were divided by APOE ε4 carrier status. Diagnostic and APOE effects were evaluated with emphasis on SMC. Additional analyses in SMC evaluated the effect of the interaction between APOE and [ 18 F]Florbetapir amyloid positivity on CSF biomarkers. Results SMC ε4+ showed greater amyloid deposition than SMC ε4−, but no hypometabolism or medial temporal lobe (MTL) atrophy. SMC ε4+ showed lower amyloid beta 1–42 and higher tau/p‐tau than ε4−, which was most abnormal in APOE ε4+ and cerebral amyloid positive SMC. Discussion SMC APOE ε4+ show abnormal changes in amyloid and tau biomarkers, but no hypometabolism or MTL neurodegeneration, reflecting the at‐risk nature of the SMC group and the importance of APOE in mediating this risk.

We used whole‐exome sequencing to identify variants other than APOE associated with the rate of hippocampal atrophy in amnestic mild cognitive impairment. An in‐silico predicted missense variant in REST (rs3796529) was found exclusively in subjects with slow hippocampal volume loss and validated using unbiased whole‐brain analysis and meta‐analysis across 5 independent cohorts. REST is a master regulator of neurogenesis and neuronal differentiation that has not been previously implicated in Alzheimer's disease. These findings nominate REST and its functional pathways as protective and illustrate the potential of combining next‐generation sequencing with neuroimaging to discover novel disease mechanisms and potential therapeutic targets. Ann Neurol 2015;77:547–552

AbstractBackgroundLate‐onset Alzheimer's disease (AD) is heritable with 20 genes showing genome‐wide association in the International Genomics of Alzheimer's Project (IGAP). To identify the biology underlying the disease, we extended these genetic data in a pathway analysis.MethodsThe ALIGATOR and GSEA algorithms were used in the IGAP data to identify associated functional pathways and correlated gene expression networks in human brain.ResultsALIGATOR identified an excess of curated biological pathways showing enrichment of association. Enriched areas of biology included the immune response (P = 3.27 × 10−12 after multiple testing correction for pathways), regulation of endocytosis (P = 1.31 × 10−11), cholesterol transport (P = 2.96 × 10−9), and proteasome‐ubiquitin activity (P = 1.34 × 10−6). Correlated gene expression analysis identified four significant network modules, all related to the immune response (corrected P = .002–.05).ConclusionsThe immune response, regulation of endocytosis, cholesterol transport, and protein ubiquitination represent prime targets for AD therapeutics.

Abstract The lack of readily available biomarkers is a significant hindrance toward progressing to effective therapeutic and preventative strategies for Alzheimer's disease (AD). Blood‐based biomarkers have potential to overcome access and cost barriers and greatly facilitate advanced neuroimaging and cerebrospinal fluid biomarker approaches. Despite the fact that preanalytical processing is the largest source of variability in laboratory testing, there are no currently available standardized preanalytical guidelines. The current international working group provides the initial starting point for such guidelines for standardized operating procedures (SOPs). It is anticipated that these guidelines will be updated as additional research findings become available. The statement provides (1) a synopsis of selected preanalytical methods utilized in many international AD cohort studies, (2) initial draft guidelines/SOPs for preanalytical methods, and (3) a list of required methodological information and protocols to be made available for publications in the field to foster cross‐validation across cohorts and laboratories.