Among the more than 90 identified genetic risk loci for late-onset Alzheimer's disease (AD) and related dementias, the apolipoprotein E (APOE) gene ɛ2/ɛ3/ɛ4 polymorphisms remain the longstanding benchmark for genetic disease risk with a consistently large effect across studies1-10. Despite this massive signal, the exact mechanisms by which ɛ4 increases and ɛ2 decreases dementia risk remain poorly understood. Notably, recent trials of anti-amyloid therapies suggest less efficacy and higher risks of severe side effects in ε4 carriers11-13, hampering the treatment of those with the highest unmet need. To improve our understanding of the genetic architecture of AD in the context of its main genetic driver, we performed genome-wide association studies (GWASs) stratified by ε4 and ε2 carrier status. HP1BP3, SLC50A1, PTPRC, NPAS3, DDHD1, CHST9, SMYD2, PRAMEF1 and GFRA1 emerged as new genomic signals for AD risk, appearing only when stratified by APOE carrier status. DDHD1 appeared especially promising, showing protective effects in ε4 carriers, being identified as an expression quantitative trait locus and being involved in rare neuronal diseases. Such APOE-stratified insights may help understand and overcome side effects, inform clinical trial enrollment strategies, and create the scientific basis for targeted, mechanism-driven therapies in neurodegenerative diseases.
J. Thomassen, H. Leonard, Brittany Ulms et al.· Nature Genetics· 0 citations
Biological definitions of neuronal α-synuclein disease are advancing diagnosis beyond traditional clinical syndromes, but the trajectories preceding dementia and the influence of concomitant Alzheimer’s disease neuropathologic change (ADNC) remain uncertain. We analyzed longitudinal data from 1,543 participants without dementia at baseline who underwent repeated cognitive, functional, neuropsychiatric, and motor assessments and had neuropathological characterization at autopsy. Participants were classified as having neuronal α-synuclein neuropathologic change (NSNC), ADNC, or both. NSNC without intermediate or high ADNC was associated with the greatest motor burden. Among participants without mild cognitive impairment at baseline, concomitant ADNC was associated with earlier cognitive impairment and faster cognitive decline; mixed NSNC/ADNC also showed faster functional worsening than NSNC alone. Across participants with NSNC, baseline mild cognitive impairment, neuropsychiatric manifestations and concomitant ADNC predicted progression to dementia, whereas prespecified motor signs did not. These findings reveal heterogeneous pre-dementia trajectories and support combining α-synuclein detection with Alzheimer biomarkers, cognitive staging and multidomain clinical measures to improve prognosis and trial design.
I. Illán-Gala, E. Vera, J. Selma-González et al.· Research Square· 0 citations
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...· 1 citation
We use cookies to run the site and, with your consent, for analytics and to show ads.
See our Cookie Policy.
