Skip to main content

Research Repository

Advanced Search

Mendelian adult-onset leukodystrophy genes in Alzheimer´s disease. Critical influence of CSF1R and NOTCH3

Sassi, C.; Nalls, M.A.; Ridge, P.G.; Gibbs, R.; Lupton, M.K.; Troakes, C.; Lunnon, K.; Al-Sarraj, S.; Brown, K.S.; Medway, C.; Lord, J.; Turton, J.; Bras, J.; Blumenau, S.; Thielke, M.; Josties, C.; Freyer, D.; Dietrich, A.; Hammer, M.; Baier, M.; Dirnagl, U.; Morgan, Kevin; Powell, J.F.; Kauwe, J.S.; Cruchaga, C.; Goate, A.M.; Singleton, A.B.; Guerreiro, R.; Hodges, Angela; Hardy, J.


C. Sassi

M.A. Nalls

P.G. Ridge

R. Gibbs

M.K. Lupton

C. Troakes

K. Lunnon

S. Al-Sarraj

C. Medway

J. Lord

J. Turton

J. Bras

S. Blumenau

M. Thielke

C. Josties

D. Freyer

A. Dietrich

M. Hammer

M. Baier

U. Dirnagl

Kevin Morgan

J.F. Powell

J.S. Kauwe

C. Cruchaga

A.M. Goate

A.B. Singleton

R. Guerreiro

Angela Hodges

J. Hardy


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 (CADASIL and CARASIL), Cerebroretinal vasculopathy (CRV), Metachromatic leukodystrophy (MLD), Hereditary diffuse Leukoencephalopathy with spheroids (HDLS), Vanishing white matter disease (VWM) present with rapidly progressive dementia as dominant feature and are caused by mutations in NOTCH3, HTRA1, TREX1, ARSA, CSF1R, EIF2B1, EIF2B2, EIF2B3, EIF2B4, 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 months, 4 months, 8 months and 18 months), 2) in APPPS1 primary cortical neurons under stress conditions (oxygen-glucose deprivation) and single-variant and single-gene (c-alpha and SKAT tests) based 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-val


Sassi, C., Nalls, M., Ridge, P., Gibbs, R., Lupton, M., Troakes, C., …Hardy, J. (in press). Mendelian adult-onset leukodystrophy genes in Alzheimer´s disease. Critical influence of CSF1R and NOTCH3. Neurobiology of Aging, 66, Article 179.e17-179.e29.

Journal Article Type Article
Acceptance Date Jan 21, 2018
Online Publication Date Feb 2, 2018
Deposit Date Feb 23, 2018
Publicly Available Date Feb 23, 2018
Journal Neurobiology of Aging
Print ISSN 0197-4580
Electronic ISSN 1558-1497
Publisher Elsevier
Peer Reviewed Peer Reviewed
Volume 66
Article Number 179.e17-179.e29
Keywords Alzheimer’s disease; Mendelian Leukodystrophies; CSF1R; NOTCH3
Public URL
Publisher URL


PIIS019745801830023X.pdf (2.4 Mb)

Copyright Statement
Copyright information regarding this work can be found at the following address:

You might also like

Downloadable Citations