Mendelian adult-onset leukodystrophy genes in Alzheimer's disease: critical influence of CSF1R and NOTCH3

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Mendelian adult-onset leukodystrophies are a spectrum of rare inherited progressive neurodegenerative disorders affecting the white matter of the central nervous system. Among these, cerebral autosomal dominant and recessive arteriopathy with subcortical infarcts and leukoencephalopathy, cerebroretinal vasculopathy, metachromatic leukodystrophy, hereditary diffuse leukoencephalopathy with spheroids, and vanishing white matter disease present with rapidly progressive dementia as dominant feature and are caused by mutations in NOTCH3, HTRA1, TREX1, ARSA, CSF1R, EIF2B1, EIF2B2, EIF2B3, EIF2B4, and EIF2B5, respectively. Given the rare incidence of these disorders and the lack of unequivocally diagnostic features, leukodystrophies are frequently misdiagnosed with common sporadic dementing diseases such as Alzheimer's disease (AD), raising the question of whether these overlapping phenotypes may be explained by shared genetic risk factors. To investigate this intriguing hypothesis, we have combined gene expression analysis (1) in 6 different AD mouse strains (APPPS1, HOTASTPM, HETASTPM, TPM, TAS10, and TAU) at 5 different developmental stages (embryo [E15], 2, 4, 8, and 18 months), (2) in APPPS1 primary cortical neurons under stress conditions (oxygen-glucose deprivation) and single-variant–based and single-gene–based (c-alpha test and sequence kernel association test (SKAT)) genetic screening in a cohort composed of 332 Caucasian late-onset AD patients and 676 Caucasian elderly controls. Csf1r was significantly overexpressed (log2FC > 1, adj. p-value < 0.05) in the cortex and hippocampus of aged HOTASTPM mice with extensive Aβ dense-core plaque pathology. We identified 3 likely pathogenic mutations in CSF1R TK domain (p.L868R, p.Q691H, and p.H703Y) in our discovery and validation cohort, composed of 465 AD and mild cognitive impairment (MCI) Caucasian patients from the United Kingdom. Moreover, NOTCH3 was a significant hit in the c-alpha test (adj p-value = 0.01). Adult-onset Mendelian leukodystrophy genes are not common factors implicated in AD. Nevertheless, our study suggests a potential pathogenic link between NOTCH3, CSF1R, and sporadic late-onset AD, which warrants further investigation.

Original languageEnglish
Number of pages13
JournalNeurobiology of Aging
Early online date02 Feb 2018
Publication statusPublished - 01 Jun 2018

Bibliographical note

Funding Information:
All the authors declare no competing financial or personal interests that can influence the presented work. However, MAN's participation is supported by a consulting contract between Data Tecnica International and the National Institute on Aging NIH, Bethesda, MD, USA, as a possible conflict of interest, and he also consults Illumina Inc, the Michael J. Fox Foundation, and the University of California Healthcare among others.

Funding Information:
This study was supported by the Alzheimer's Research UK, the Medical Research Council (MRC), the Wellcome Trust/MRC Joint Call in Neurodegeneration Award (WT089698) to the UK Parkinson's Disease Consortium (whose members are from the University College London Institute of Neurology, the University of Sheffield, and the MRC Protein Phosphorylation Unit at the University of Dundee), grants (P50 AG016574, U01 AG006786, and R01 AG18023), the National Institute for Health Research Biomedical Research Unit in Dementia at University College London Hospitals, University College London; the Big Lottery (to KM); JB and RG's work is funded by fellowships from the Alzheimer's Society; Humboldt Fellowship (to CS) and the Intramural Research Programs of the National Institute on Aging and the National Institute of Neurological Disease and Stroke, National Institutes of Health (Department of Health and Human Services Project number, ZO1 AG000950-10). MAN's participation is supported by a consulting contract between Data Tecnica International and the National Institute on Aging NIH, Bethesda, MD, USA. The MRC London Neurodegenerative Diseases Brain Bank and the Manchester Brain Bank from Brains for Dementia Research are jointly funded from ARUK and AS. The Alzheimer's Research UK (ARUK) Consortium funded PP, DC, JJ, BMcG, ST, Queen's University Belfast, UK; RH, Royal Derby Hospital, UK; HK, University of Bonn, Germany; PGK, University of Bristol, UK; NMH, University of Leeds, UK; ERLCV, University of Newcastle, UK; DMM, SP-B, University of Manchester, UK; KB, JL, KM, University of Nottingham, UK; ADS, GW, DW, University of Oxford (OPTIMA), UK; CH, University of Southampton, UK. Tissue samples were supplied by The London Neurodegenerative Diseases Brain Bank, which receives funding from the MRC and as part of the Brains for Dementia Research programme, jointly funded by Alzheimer's Research UK and Alzheimer's Society. Appendix A

Publisher Copyright:
© 2018 The Authors

Copyright 2020 Elsevier B.V., All rights reserved.


  • Alzheimer's disease
  • CSF1R
  • Mendelian leukodystrophies
  • NOTCH3

ASJC Scopus subject areas

  • Neuroscience(all)
  • Ageing
  • Clinical Neurology
  • Developmental Biology
  • Geriatrics and Gerontology

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