ArticleMolecular psychiatry2022
Aβ profiles generated by Alzheimer's disease causing PSEN1 variants determine the pathogenicity of the mutation and predict age at disease onset.
Article in Molecular psychiatry, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 68 papers.
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Who cites it
68 citing papers in PubMed, 107 citations in OpenAlex.
- Article
- Emerging diagnostic biomarkers and therapeutic targets in Alzheimer's disease.Inflammopharmacology · 2026Review
- Rodent Models of Alzheimer's Disease: Bridging the Translational Gap Through Systems-Level Integration.Biomedicines · 2026Review
- Identification of genetic modifiers of autosomal dominant Alzheimer's disease: a genome-wide association study.The Lancet. Neurology · 2026Article
- Low Brain Levels of Dietary Polyphenols and Their Conjugates: Reassessing Mechanisms of Alzheimer's Disease Prevention.Journal of dementia and alzheimer's disease · 2026Article
- Presenilin-dependent regulation of neuronal tau pathology via the autophagy and proteasome pathways.Acta neuropathologica communications · 2026Article
- Alzheimer's Disease: From Pathogenesis to Emerging Therapeutic Targets.Journal of clinical medicine · 2026Review
- Review
- Alzheimer's Disease: From Molecular Pathogenesis to Disease-Modifying Therapies and Clinical Implementation in Aging Populations.Clinical interventions in aging · 2026Review
- Natural Chiral Scaffolds in Alzheimer's Disease: Therapeutic Potential, Mechanism, and Clinical Aspects.BioMed research international · 2026Review
- Unbiased data-driven analysis of five amyloid-beta peptides for biomarker investigations in familial Alzheimer's disease.Brain communications · 2026Article
- Exploration and validation of biomarkers for Alzheimer's disease based on GEO database.IBRO neuroscience reports · 2025Article
- The relationship between amyloid-β peptide spectrum and the spastic paraparesis phenotype in autosomal dominant Alzheimer's disease.Alzheimer's research & therapy · 2025Article
- CTAD taskforce: genetic therapies in Alzheimer's disease.The journal of prevention of Alzheimer's disease · 2025Review
- Gut microbial metabolites and the brain-gut axis in Alzheimer's disease: A review.Biomolecules & biomedicine · 2025Review
- A manifesto for Alzheimer's disease drug discovery in the era of disease-modifying therapies.Molecular neurodegeneration · 2025Review
- Alzheimer's Disease: Treatment Challenges for the Future.Journal of neurochemistry · 2025Review
- Alterations in MRI-visible perivascular spaces precede dementia diagnosis by 18 years in autosomal dominant Alzheimer's disease.Alzheimer's & dementia : the journal of the Alzheimer's Association · 2025Article
- Alzheimer's Disease Etiology Hypotheses and Therapeutic Strategies: A Perspective.International journal of molecular sciences · 2025Review
- AI-Driven Transcriptome Prediction in Human Pathology: From Molecular Insights to Clinical Applications.Biology · 2025Review
8 more citing papers are in PubMed but not listed here.
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Authors and funding
11 authors at 5 institutions in 4 countries.
Funding
Abstract
Familial Alzheimer's disease (FAD), caused by mutations in Presenilin (PSEN1/2) and Amyloid Precursor Protein (APP) genes, is associated with an early age at onset (AAO) of symptoms. AAO is relatively consistent within families and between carriers of the same mutations, but differs markedly between individuals carrying different mutations. Gaining a mechanistic understanding of why certain mutations manifest several decades earlier than others is extremely important in elucidating the foundations of pathogenesis and AAO. Pathogenic mutations affect the protease (PSEN/γ-secretase) and the substrate (APP) that generate amyloid β (Aβ) peptides. Altered Aβ metabolism has long been associated with AD pathogenesis, with absolute or relative increases in Aβ42 levels most commonly implicated in the disease development. However, analyses addressing the relationships between these Aβ42 increments and AAO are inconsistent. Here, we investigated this central aspect of AD pathophysiology via comprehensive analysis of 25 FAD-linked Aβ profiles. Hypothesis- and data-driven approaches demonstrate linear correlations between mutation-driven alterations in Aβ profiles and AAO. In addition, our studies show that the Aβ (37 + 38 + 40) / (42 + 43) ratio offers predictive value in the assessment of 'unclear' PSEN1 variants. Of note, the analysis of PSEN1 variants presenting additionally with spastic paraparesis, indicates that a different mechanism underlies the aetiology of this distinct clinical phenotype. This study thus delivers valuable assays for fundamental, clinical and genetic research as well as supports therapeutic interventions aimed at shifting Aβ profiles towards shorter Aβ peptides.
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