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

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.

Association of Rare Coding Mutations With Alzheimer Disease and Other Dementias Among Adults of European Ancestry

“…A previous study reported an association of AD with a distinct NOTCH3 mutation (p.R1231C) in a Turkish family 46 ; however, this variant was detected in only 1 affected member and there is conflicting information about its pathogenicity. 47 Sassi et al 48 tested the hypothesis that genes associated with mendelian adult-onset leukodystrophy are also associated with AD in a sample including 332 sporadic participants with AD and 676 controls and found a significant gene-based association with NOTCH3 , a result driven primarily by a common synonymous coding variant.…”

CSF1R inhibitor JNJ-40346527 attenuates microglial proliferation and neurodegeneration in P301S mice

“…The critical contribution of inflammation to Alzheimer’s disease pathogenesis has been further implicated by recent genome-wide association studies (GWAS), which highlight multiple immune-related genes in association with Alzheimer’s disease (Efthymiou and Goate, 2017), including the colony-stimulating factor 1 receptor ( CSF1R ) (Sassi et al , 2018). This evidence indicates that neuroinflammation and microglial activation are key drivers of Alzheimer’s disease pathology.…”

Phenotypic impacts of CSF1R deficiencies in humans and model organisms

“…The brain pathology and symptoms of ALSP vary significantly between affected individuals and the disease has been misdiagnosed antemortem as various other dementias and neurodegenerative diseases. For example, Sassi et al 24 identified 3 likely pathogenic CSF1R mutations in a cohort of 465 lateonset Alzheimer's patients.…”