Open AccessA novel temporal‐predominant neuro‐astroglial tauopathy associated with TMEM106B gene polymorphism in FTLD/ALS‐TDP
Author(s) -
LlibreGuerra Jorge J.,
Lee Suzee E.,
Suemoto Claudia K.,
Ehrenberg Alexander J.,
Kovacs Gabor G.,
Karydas Anna,
Staffaroni Adam,
Franca Resende Elisa De Paula,
Kim EunJoo,
Hwang JiHye,
Ramos Eliana Marisa,
Wojta Kevin J.,
Pasquini Lorenzo,
Pang Shirley YinYu,
Spina Salvatore,
Allen Isabel E.,
Kramer Joel,
Miller Bruce L.,
Seeley William W.,
Grinberg Lea T.
Publication year - 2021
Publication title -
brain pathology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.986
H-Index - 132
eISSN - 1750-3639
pISSN - 1015-6305
DOI - 10.1111/bpa.12924
Subject(s) - tauopathy , frontotemporal lobar degeneration , c9orf72 , amyotrophic lateral sclerosis , genotype , biology , neurodegeneration , pathology , frontotemporal dementia , neuroscience , genetics , medicine , disease , dementia , gene
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.