ArticleMolecular psychiatry2021
Discovery of autism/intellectual disability somatic mutations in Alzheimer's brains: mutated ADNP cytoskeletal impairments and repair as a case study.
Article in Molecular psychiatry, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 65 papers, 2 of them syntheses that pooled it.
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Who cites it
65 citing papers in PubMed, 2 syntheses or guidelines pooled it, 109 citations in OpenAlex.
- Cognitive and brain morphological deviations in middle-to-old aged autistic adults: A systematic review and meta-analysis.Neuroscience and biobehavioral reviews · 2024Pooled it
- Neurometabolite levels in the brains of patients with autism spectrum disorders: A meta-analysis of proton magnetic resonance spectroscopy studies (N = 1501).Molecular psychiatry · 2023Pooled it
- Systemic davunetide provides sex-specific neuroprotection during Coronary Artery Bypass Grafting (CABG).Translational psychiatry · 2025Trial
- Davunetide sex-dependently boosts memory in prodromal Alzheimer's disease.Translational psychiatry · 2024Trial
- Integration of cell-specific gene expression and chromatin accessibility facilitates localization of neurodegenerative risk in microglia.bioRxiv : the preprint server for biology · 2026Article
- Opposite molecular sex correlations in tauopathy paralleled by motor and cognitive efficacy of davunetide in women.Molecular psychiatry · 2026Article
- Disruption of DNA Repair as an Emerging Epigenetic Mechanism Underlying Autism Spectrum Disorder.Current psychiatry reports · 2026Review
- Diminished activity-dependent neuroprotective protein (ADNP) contributes to complement gene elevation in Alzheimer's disease.Journal of Alzheimer's disease : JAD · 2026Article
- Targeting protein aggregate co-pathologies in neurodegeneration: a viable therapeutic strategy?Molecular neurodegeneration advances · 2026Review
- CRISPRi-based screen of autism spectrum disorder risk genes in microglia uncovers roles of ADNP in microglia endocytosis and synaptic pruning.Molecular psychiatry · 2025Article
- ADNP is essential for sex-dependent hippocampal neurogenesis, through male unfolded protein response and female mitochondrial gene regulation.Molecular psychiatry · 2025Article
- The multifaceted role of mitochondria in autism spectrum disorder.Molecular psychiatry · 2025Review
- Extremely Low-Frequency and Low-Intensity Electromagnetic Field Technology (ELF-EMF) Sculpts Microtubules.The European journal of neuroscience · 2025Article
- DeepDrug as an expert guided and AI driven drug repurposing methodology for selecting the lead combination of drugs for Alzheimer's disease.Scientific reports · 2025Article
- Pathophysiologic similarities between autism spectrum disorder and Alzheimer's disease: therapeutic possibilities.Frontiers in neuroscience · 2025Article
- CRISPRi-based screen of Autism Spectrum Disorder risk genes in microglia uncovers roles ofbioRxiv : the preprint server for biology · 2024Article
- Transcriptomic alterations in APP/PS1 mice astrocytes lead to early postnatal axon initial segment structural changes.Cellular and molecular life sciences : CMLS · 2024Article
- Sex-Specific ADNP/NAP (Davunetide) Regulation of Cocaine-Induced Plasticity.Journal of molecular neuroscience : MN · 2024Article
- Genetic and Environmental Factors Co-Contributing to Behavioral Abnormalities inInternational journal of molecular sciences · 2024Article
- Modeling late-onset Alzheimer's disease neuropathology via direct neuronal reprogramming.Science (New York, N.Y.) · 2024Article
5 more citing papers are in PubMed but not listed here.
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Authors and funding
12 authors at 6 institutions in 6 countries.
Funding
Abstract
With Alzheimer's disease (AD) exhibiting reduced ability of neural stem cell renewal, we hypothesized that de novo mutations controlling embryonic development, in the form of brain somatic mutations instigate the disease. A leading gene presenting heterozygous dominant de novo autism-intellectual disabilities (ID) causing mutations is activity-dependent neuroprotective protein (ADNP), with intact ADNP protecting against AD-tauopathy. We discovered a genomic autism ADNP mutation (c.2188C>T) in postmortem AD olfactory bulbs and hippocampi. RNA-Seq of olfactory bulbs also identified a novel ADNP hotspot mutation, c.2187_2188insA. Altogether, 665 mutations in 596 genes with 441 mutations in AD patients (389 genes, 38% AD-exclusive mutations) and 104 genes presenting disease-causing mutations (OMIM) were discovered. OMIM AD mutated genes converged on cytoskeletal mechanisms, autism and ID causing mutations (about 40% each). The number and average frequencies of AD-related mutations per subject were higher in AD subjects compared to controls. RNA-seq datamining (hippocampus, dorsolateral prefrontal cortex, fusiform gyrus and superior frontal gyrus-583 subjects) yielded similar results. Overlapping all tested brain areas identified unique and shared mutations, with ADNP singled out as a gene associated with autism/ID/AD and presenting several unique aging/AD mutations. The large fusiform gyrus library (117 subjects) with high sequencing coverage correlated the c.2187_2188insA ADNP mutation frequency to Braak stage (tauopathy) and showed more ADNP mutations in AD specimens. In cell cultures, the ADNP-derived snippet NAP inhibited mutated-ADNP-microtubule (MT) toxicity and enhanced Tau-MT association. We propose a paradigm-shifting concept in the perception of AD whereby accumulating mosaic somatic mutations promote brain pathology.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.