A novel temporal‐predominant neuro‐astroglial tauopathy associated with TMEM106B gene polymorphism in FTLD/ALS‐TDP. (11th February 2021)

• Record Type: Journal Article
• Authors: Llibre‐Guerra, Jorge J.; Lee, Suzee E.; Suemoto, Claudia K.; Ehrenberg, Alexander J.; Kovacs, Gabor G.; Karydas, Anna; Staffaroni, Adam; Franca Resende, Elisa De Paula; Kim, Eun‐Joo; Hwang, Ji‐Hye; Ramos, Eliana Marisa; Wojta, Kevin J.; Pasquini, Lorenzo; Pang, Shirley Yin‐Yu; Spina, Salvatore; Allen, Isabel E.; Kramer, Joel; Miller, Bruce L.; Seeley, William W.; Grinberg, Lea T.
• Is Part Of: Brain pathology. Volume 31:Number 2(2021)
• Page Start: 267
• Page End: 282
• Publication Date: 2021-02-11
• Subjects: frontotemporal dementia -- frontotemporal lobar degeneration -- neuropathologic diagnosis -- TDP‐43 proteinopathy -- tauopathy -- TMEM106B -- polymorphism -- Rs1990622 -- genetic association -- risk factor; Nervous system -- Diseases -- Periodicals; Brain -- Diseases -- Periodicals; Neurology -- Periodicals; Brain Diseases -- Periodicals; Cerveau -- Maladies -- Périodiques; Système nerveux -- Maladies -- Périodiques; Neurologie -- Périodiques; 616.805
• DOI: 10.1111/bpa.12924
• Languages: English
• ISSNs: 1015-6305

Abstract

Abstract: Polymorphisms in TMEM106B, a gene on chromosome 7p21.3 involved in lysosomal trafficking, correlates to worse neuropathological, and clinical outcomes in frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS) with TDP‐43 inclusions. In a small cohort of C9orf72 expansion carriers, we previously found an atypical, neuroglial tauopathy in cases harboring a TMEM106B rs1990622 A/A genotype. To test whether TMEM106B genotype affects the risk of developing atypical tauopathy under a recessive genotype model (presence versus absence of two major alleles: A/A vs. A/G and G/G). We characterized the atypical tauopathy neuropathologically and determined its frequency by TMEM106B rs1990622 genotypes in 90 postmortem cases with a primary diagnosis of FTLD/ALS‐TDP [mean age at death 65.5 years (±8.1), 40% female]. We investigated the effect of this new atypical tauopathy on demographics and clinical and neuropsychological metrics. We also genotyped TMEM106B in an independent series with phenotypically similar cases. Sixteen cases (16/90, 17.7 %) showed the temporal‐predominant neuro‐astroglial tauopathy, and 93.7% of them carried an A/A genotype (vs. ~35% in a population cohort). The odds ratio of FTLD/ALS‐TDP individuals with the A/A genotype showing neuro‐astroglial tauopathy was 13.9. Individuals with this tauopathy were older at onset ( p = 0.01). The validation cohort had a similarly high proportion of rs1990622 A/A genotype. TDP‐43 and tau changes co‐occur in a subset of neurons. Our data add to the growing body of evidence that TMEM106B polymorphisms may modulate neurodegeneration. A distinctive medial temporal predominant, 4‐repeat, neuro‐astroglial tauopathy strongly correlates to TMEM106B A/A genotype in FTLD/ALS‐TDP cases. Abstract : noFTLD‐TDP cases with a TMEM106b A/A genotype have a much‐increased odds to show a distinct temporal‐predominant neuro‐astroglial tauopahty.