Copy-number variants (CNVs) are major contributors to human disease. In Alzheimer disease (AD), APP duplications cause autosomal-dominant forms, but the role of CNVs in non-monogenic AD remains poorly characterized. We analyzed rare CNVs (frequency <1%) from 22,319 exomes (4,150 early-onset AD [EOAD, ≤65 years], 8,519 late-onset AD [LOAD], 9,650 unaffected control subjects) using harmonized calling and quality control. After identifying 17 individuals with a pathogenic CNV, we performed exome-wide and gene-set burden analyses. EOAD-affected individuals showed increased burdens of rare CNVs affecting coding genes, particularly deletions in AD-related genes. Integrated loss-of-function (LoF) analysis gathering short truncating variants with deletions showed that ABCA1 (odds ratio [OR] = 5.77 [95% confidence interval 2.25; 17.06], p = 0.0002) and ABCA7 deletions contribute to this deletion burden (OR = 2.29 [1.44; 3.65], p = 0.0006), while CTSB LoF alleles appear as candidates (OR = 5.03 [1.50; 20.71], p = 0.0089). We then performed exome-wide gene-level dosage analysis and highlighted 18 genes across five loci with a false discovery rate of <10%, including the 22q11.21 central region, where deletions were restricted to EOAD (including one de novo event) and duplications were enriched in control individuals, with intermediate frequencies in LOAD. We narrowed this locus to the SCARF2-KLHL22-MED15 region after integrating short truncating variants. Replication in 33,977 affected individuals and 362,322 control subjects confirmed association for 22q11.21 dosage with exome-wide significance (ORSCARF2 = 0.34 [0.21; 0.53]; mega-p value = 5.52 × 10-7). SCARF2 overexpression significantly increased amyloid-β uptake, congruent with duplication-associated decreased AD risk. We conclude that rare coding CNVs in a proportion of AD-associated genes and 22q11.21 deletions, including some found in DiGeorge syndrome, increase AD risk. Conversely, we identify 22q11.21 duplication as a strong AD-risk-decreasing factor.
O. Quenez, Catherine Schramm, K. Cassinari et al.· American Journal of Human Ge...· 0 citations
Background and Objectives Prion diseases can mimic Alzheimer disease (AD) at presentation. Alzheimer's Association AD diagnostic criteria suggest that a single abnormal highly specific plasma biomarker (including p-tau217) is sufficient for a biological diagnosis. We investigated the performance of AD plasma biomarkers in distinguishing AD and prion diseases. Methods We examined plasma biomarker data from patients with prion disease from a prospective cohort study recruited through the UK National Prion Clinic. Prion diseases were diagnosed clinically or with autopsy confirmation, and AD was diagnosed clinically with CSF biomarker confirmation. Plasma p-tau217, p-tau181, Aβ42/40 ratio, brain-derived tau (BD-tau), neurofilament light chain (NfL), and glial fibrillary acid protein (GFAP) were measured using Simoa. Median biomarker values in different groups were compared with Kruskal-Wallis test, and area under the receiver operating characteristic curve was used to compare accuracy in distinguishing prion diseases from sporadic AD (sAD). Lumipulse p-tau217 and NfL were measured in a validation study in a different laboratory. Results In the main study, we analyzed 345 samples from 278 individuals (mean age 58 [SD 13.5], 48.2% female), including 204 with prion diseases (121 sporadic Creutzfeldt-Jakob disease [CJD], 11 iatrogenic CJD, 9 variant CJD, 47 slow-progressing inherited prion disease (IPD) and 16 fast-progressing IPD), 33 with AD, and 41 healthy controls. For discriminating prion disease without AD copathology from sAD, none of p-tau217 (area under the curve [AUC] [95% CI] 0.605 [0.486–0.724]), p-tau181 (AUC 0.554 [0.446–0.661]), or GFAP (AUC 0.514 [0.389–0.640]) performed well. Aβ42/40 discriminated moderately (AUC 0.770 [0.684–0.856]). NfL/p-tau217 ratio (AUC 0.996 [0.987–1.000]), NfL (AUC 0.988 [0.974–1.000]), BD-tau/p-tau217 ratio (AUC 0.963 [0.929–0.996]), and BD-tau (AUC 0.934 [0.890–0.978]) discriminated very well. In an independent validation study, consecutive samples were analyzed from 32 patients with sAD and 35 patients with sporadic Creutzfeldt-Jakob disease (mean age 65.0 [SD 6.4], 56.7% female). NfL/p-tau217 again discriminated almost perfectly (AUC 0.986 [95% CI 0.966–1.000]). Discussion Plasma p-tau217 and p-tau181 are increased in both AD and prion diseases (regardless of burden of AD copathology). Diagnosing AD with a single abnormal p-tau plasma biomarker risks misdiagnosing prion diseases as AD. Plasma NfL/p-tau217 discriminates near-perfectly and could act as a flag to suspect prion diseases where this is a diagnostic possibility. Classification of Evidence This study provides Class II evidence that plasma NfL/p-tau217 discriminates patients with CJD from those with AD.
Thomas Coysh, Rhiannon Laban, Elena Veleva et al.· Neurology· 0 citations