Common and rare TBK1 variants in early-onset Alzheimer disease in a European cohort

Abstract

TANK-binding kinase 1 (TBK1) loss-of-function (LoF) mutations are known to cause frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS), often combined with memory deficits early in the disease course. We performed targeted resequencing of TBK1 in 1253 early onset Alzheimer's disease (EOAD) patients from 8 European countries to investigate whether pathogenic TBK1 mutations are enriched among patients with clinical diagnosis of EOAD. Variant frequencies were compared against 2117 origin-matched controls. We identified only 1 LoF mutation (p.Thr79del) in a patient clinically diagnosed with Alzheimer's disease and a positive family history of ALS. We did not observe enrichment of rare variants in EOAD patients compared to controls, nor of rare variants affecting NFκB induction. Of 3 common coding variants, rs7486100 showed evidence of association (OR 1.46 [95% CI 1.13-1.9]; p-value 0.01). Homozygous carriers of the risk allele showed reduced expression of TBK1 (p-value 0.03). Our findings are not indicative of a significant role for TBK1 mutations in EOAD. The association between common variants in TBK1, disease risk and reduced TBK1 expression warrants follow-up in FTD/ALS cohorts.

MicroRNA regulation of persistent stress-enhanced memory

“…These changes are likely a combination of secondary responses to the overexpression and true, direct mir-135b-5p mediated suppression that warrant additional investigation. These include CASK Interacting Protein 1 (Caskin1), a cytosolic protein that binds scaffolding membrane proteins such as CASK at presynaptic sites 41 ; ADP Ribosylation Factor GTPase Activating Protein 1 (Arfgap1), a GTPase that regulates vesicle release and protein trafficking within the Golgi and endoplasmic reticulum 42 ; and TANK Binding Kinase 1 (Tbk1), a serine/threonine kinase for which variants have been associated with early-onset Alzheimer disease 43 . It will be interesting to determine if disruption of a single mir-135b-5p target is sufficient to recapitulate the impact of inhibiting the miRNA itself, or if the simultaneous inhibition of several targets, a unique capability of miRNAs, is required.…”

Gene mutations in a Han Chinese Alzheimer's disease cohort

“…TBK1 is a multifunctional kinase involved in the regulation of various cellular pathways, including immune response, inflammation, autophagy, cell proliferation, and insulin signaling (Freischmidt, Muller, Ludolph, Weishaupt, & Andersen, 2017). The loss of function of TBK1 variants or functional deficits of TBK1 missense mutations cause a dominant form of ALS, FTD, ALS-FTD (Freischmidt et al, 2015), and other rare phenotypes such as corticobasal syndrome (CBS; van der Zee et al, 2017) and AD (Verheijen et al, 2018). The patient carrying TBK1 p.D534H experienced memory loss and disorientation, which was in line with the diagnosis of AD.…”

Activate or Inhibit? Implications of Autophagy Modulation as a Therapeutic Strategy for Alzheimer’s Disease

“…Of the 31 missense variants identified, seven were exclusive to patients and four of these had combined annotation dependent depletion (CADD) Phred scores of >20, which can be indicative of pathogenicity. However, control-specific and shared variants also attained high (>20) CADD Phred scores and no enrichment of rare variants in cases compared with controls was observed [81]. There have been no reports of an association of OPTN or UBQLN2 variants with AD.…”