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Proteomic studies for Alzheimer's disease (AD) are instrumental in identifying AD pathways but often focus on single tissues and sporadic AD cases. Here, we present a proteomic study analyzing 1305 proteins in brain tissue, cerebrospinal fluid (CSF), and plasma from patients with sporadic AD, TREM2 risk variant carriers, patients with autosomal dominant AD (ADAD), and healthy individuals. We identified 8 brain, 40 CSF, and 9 plasma proteins that were altered in individuals with sporadic AD, and we replicated these findings in several external datasets. We identified a proteomic signature that differentiated TREM2 variant carriers from both individuals with sporadic AD and healthy individuals. The proteins associated with sporadic AD were also altered in patients with ADAD, but with a greater effect size. Brain-derived proteins associated with ADAD were also replicated in additional CSF samples. Enrichment analyses highlighted several pathways, including those implicated in AD (calcineurin and Apo E), Parkinson's disease (α-synuclein and LRRK2), and innate immune responses (SHC1, ERK-1, and SPP1). Our findings suggest that combined proteomics across brain tissue, CSF, and plasma can be used to identify markers for sporadic and genetically defined AD. Editor's summary: Biomarkers for Alzheimer's disease (AD) are important for diagnosis and treatment monitoring. Sung and colleagues performed a proteomic study using brain, cerebrospinal fluid (CSF), and plasma samples from a cohort of patients with sporadic AD or autosomal dominant AD (ADAD), TREM2 risk carriers, and healthy individuals. The authors identified proteins that could be used to classify patients depending on disease status. Proteins cross-validated in brain, CSF, and plasma were more likely to be also replicated in external datasets, indicating that across-tissue and fluid validation of disease markers could serve as an alternative when external validation is not possible. —Daniela Neuhofer [ABSTRACT FROM AUTHOR]

Late-onset Alzheimer's disease (LOAD) risk is strongly influenced by genetic factors such as the presence of the apolipoprotein E ζ4 allele (referred to here as APOE4), as well as non-genetic determinants including ageing. To pursue mechanisms by which these affect human brain physiology and modify LOAD risk, we initially analysed whole-transcriptome cerebral cortex gene expression data in unaffected APOE4 carriers and LOAD patients. APOE4 carrier status was associated with a consistent transcriptomic shift that broadly resembled the LOAD profile. Differential co-expression correlation network analysis of the APOE4 and LOAD transcriptomic changes identified a set of candidate core regulatory mediators. Several of these--including APBA2, FYN, RNF219 and SV2A--encode known or novel modulators of LOAD associated amyloid beta A4 precursor protein (APP) endocytosis and metabolism. Furthermore, a genetic variant within RNF219 was found to affect amyloid deposition in human brain and LOAD age-of-onset. These data implicate an APOE4 associated molecular pathway that promotes LOAD., Alzheimer's disease is the most common form of dementia worldwide, and is characterized by cognitive decline with distinctive brain pathology that includes regional neuron loss, amyloid plaques and neurofibrillary tangles [...]

Nature 500, 45-50(2013); doi:10.1038/nature12415 In this Article, we described integrative genomics analyses of Alzheimer's disease and associated risk factors. However, reanalysis of the data has showed that sample numbers, image [...]

Background: Alzheimer disease (AD) is a complex and heterogeneous disease. Most AD cases present sporadically, while 1‐2% of the cases have autosomal dominant AD (ADAD), carrying mutations in APP, PSEN1, and PSEN2. Among sporadic cases, several rare variants in TREM2, which is involved in immune response, are shown to increase AD risk. Most proteomic studies, while instrumental in identifying novel AD genes and pathways, focus on single tissues and mainly sporadic AD cases. Proteomic signatures for each genetically defined AD case will advance the understanding of the underlying biology of this heterogeneous disease and help us create prediction models for AD risk, onset, and progression. Method: We generated deep proteomic profiles of brain (n=370), cerebrospinal fluid (CSF; n=699), and plasma (n=486) for sporadic AD, ADAD, and TREM2 risk‐variant carriers, from the Knight‐ADRC and DIAN cohorts. After stringent QC, 1079 proteins in brain, 713 in CSF, and 931 in plasma remained. Result: We identified 150 proteins with differential levels between sporadic cases and controls, 371 for ADAD, and 134 for TREM2 carriers in at least one tissue (with Bonferroni‐corrected statistical significance). Of these, 36, 74 and 31 were replicated across tissue types for sporadic AD, ADAD, and TREM2 carriers, respectively. Using proteins that replicated across tissues, we created a prediction model for CSF and plasma with an AUC (AUC=0.79‐1.0) similar to (or better than) that of the well‐accepted CSF pTau/Aβ42 ratio. A model using 23 TREM2‐specific plasma proteins was able to discriminate between TREM2 carriers and controls (AUC=0.94) or sporadic AD cases (AUC=0.91) with high sensitivity and selectivity. Our pathway enrichment analysis validated pathways previously implicated in AD (such as APP, APOE, GSK3B, NOTCH3, PPP3R1 and PPP3CA) and identified novel pathways such as a Parkinson's disease pathway (LRRK2 and α‐synuclein) and innate immune response pathways (MEK1, SHC1, and PDGF‐BB), including cytokine‐mediated signaling and a DAP12‐mediated pathway. Conclusion: With the first multi‐tissue proteomic study of genetically defined AD cases, we have uncovered multiple novel AD biomarker candidates. These findings not only help to elucidate specific pathways implicated in AD but ultimately support the clinical utility of predictive models based on proteomic signatures. [ABSTRACT FROM AUTHOR]

A retraction of the article "Integrative genomics identifies APOE ε4 effectors in Alzheimer's disease" by Herve Rhinn and colleagues is presented.

Summary: Directed conversion of mature human cells, as from fibroblasts to neurons, is of potential clinical utility for neurological disease modeling as well as cell therapeutics. Here, we describe the efficient generation of human-induced neuronal (hiN) cells from adult skin fibroblasts of unaffected individuals and Alzheimer''s patients, using virally transduced transcription regulators and extrinsic support factors. hiN cells from unaffected individuals display morphological, electrophysiological, and gene expression profiles that typify glutamatergic forebrain neurons and are competent to integrate functionally into the rodent CNS. hiN cells from familial Alzheimer disease (FAD) patients with presenilin-1 or -2 mutations exhibit altered processing and localization of amyloid precursor protein (APP) and increased production of Aβ, relative to the source patient fibroblasts or hiN cells from unaffected individuals. Together, our findings demonstrate directed conversion of human fibroblasts to a neuronal phenotype and reveal cell type-selective pathology in hiN cells derived from FAD patients. [Copyright &y& Elsevier]