Abstract

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.

Highlights

  • Mendelian adult-onset leukodystrophies are a spectrum of rare chronic progressive disorders affecting the white matter of the central nervous system

  • Considering that ischemic stroke is a common feature in several leukodystrophies and frequent comorbidity in Alzheimer’s disease (AD), we used an in vitro model of ischemic stroke and performed oxygen-glucose deprivation (OGD) experiments in APPPS1 primary cortical neurons to test whether leukodystrophy gene expression pattern may have significantly differed between APPPS1 and wild-type (WT) mice under stress conditions

  • Mendelian adult-onset leukodystrophies clinically resemble common dementias such as AD, potentially implying they may be influenced by shared genetic risk factors

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Summary

Introduction

Mendelian adult-onset leukodystrophies are a spectrum of rare chronic progressive disorders affecting the white matter of the central nervous system. Motor features like ataxia and spasticity may appear in the course of AD progression, in the cases caused by or associated to PSEN1 mutations (Rossor et al, 2010) and AD patients may display MRI patterns and neuropathological features typical of adult-onset leukodystrophies (Smith et al, 2000; Marnane et al, 2016; Barber et al, 1999; Guerreiro et al, 2013), suggesting a potential common pathogenic ground. We used exome and genome sequencing data in a cohort composed of 332 Caucasian late-onset AD (LOAD) patients and 676 Caucasian elderly controls to investigate rare coding variability in these main adultonset Mendelian leukodystrophy genes. CSF1R coding variants clustering in the TK domain and NOTCH3 may influence AD susceptibility

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