Mendelian adult-onset leukodystrophy genes in Alzheimer's disease: critical influence of CSF1R and NOTCH3
Creators: name: Sassi, Celeste
name: Nalls, Michael A.
name: Ridge, Perry G.
name: Gibbs, Jesse R.
name: Lupton, Michelle K.
name: Troakes, Claire
name: Lunnon, Katie
name: Al-Sarraj, Safa
name: Brown, Kristelle S.
name: Medway, Christopher
name: Lord, Jenny
name: Turton, James
name: Bras, Jose
name: Passmore, Peter
name: Craig, David
name: Johnston, Janet
name: McGuinness, Bernadette
name: Todd, Stephen
name: Heun, Reinhard
name: Kölsch, Heike
name: Kehoe, Patrick G.
name: Vardy, Emma R. L. C.
name: Hooper, Nigel M.
name: Smith, A. David
name: Wilcock, Gordon
name: Warden, Donald
name: Holmes, Clive
name: Blumenau, Sonja
name: Thielke, Mareike
name: Josties, Christa
name: Freyer, Dorette
name: Dietrich, Annette
name: Hammer, Monia
name: Baier, Michael
name: Dirnagl, Ulrich
name: Morgan, Kevin
name: Powell, John F.
name: Kauwe, John S.
name: Cruchaga, Carlos
name: Goate, Alison M.
name: Singleton, Andrew B.
name: Guerreiro, Rita
name: Hodges, Angela
name: Hardy, John
Publisher: name: Robert Koch-Institut
Year: 2018
Subjects: subject: Alzheimer's disease
subject: Mendelian leukodystrophies
subject: CSF1R
subject: NOTCH3
subject: 610 Medizin und Gesundheit

description: 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 &gt; 1, adj. p-value &lt; 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.