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. 2019 Jun;85(6):801-811.
doi: 10.1002/ana.25486.

TMEM106B Effect on cognition in Parkinson disease and frontotemporal dementia

Thomas F Tropea  1 , Jordan Mak  1 , Michael H Guo  2   3 , Sharon X Xie  4 , Eunran Suh  5 , Jacqueline Rick  1 , Andrew Siderowf  1 , Daniel Weintraub  6   7 , Murray Grossman  1 , David Irwin  1 , David A Wolk  1 , John Q Trojanowski  5   8 , Vivianna Van Deerlin  5 , Alice S Chen-Plotkin  1
Affiliations

TMEM106B Effect on cognition in Parkinson disease and frontotemporal dementia

Thomas F Tropea et al. Ann Neurol. 2019 Jun.

Abstract

Objective: Common variants near TMEM106B associate with risk of developing frontotemporal dementia (FTD). Emerging evidence suggests a role for TMEM106B in neurodegenerative processes beyond FTD. We evaluate the effect of TMEM106B genotype on cognitive decline across multiple neurogenerative diseases.

Methods: We longitudinally followed 870 subjects with diagnoses of Parkinson disease (PD; n = 179), FTD (n = 179), Alzheimer disease (AD; n = 300), memory-predominant mild cognitive impairment (MCI; n = 75), or neurologically normal control subjects (NC; n = 137) at the University of Pennsylvania (UPenn). All participants had annual Mini-Mental State Examination (MMSE; median follow-up duration = 3.0 years) and were genotyped at TMEM106B index single nucleotide polymorphism rs1990622. Genotype effects on cognition were confirmed by extending analyses to additional cognitive instruments (Mattis Dementia Rating Scale-2 [DRS-2] and Montreal Cognitive Assessment [MoCA]) and to an international validation cohort (Parkinson's Progression Markers Initiative [PPMI], N = 371).

Results: The TMEM106B rs1990622T allele, linked to increased risk of FTD, associated with greater MMSE decline over time in PD subjects but not in AD or MCI subjects. For FTD subjects, rs1990622T associated with more rapid decrease in MMSE only under the minor-allele, rs1990622C , dominant model. Among PD patients, rs1990622T carriers from the UPenn cohort demonstrated more rapid longitudinal decline in DRS-2 scores. Finally, in the PPMI cohort, TMEM106B risk allele carriers demonstrated more rapid longitudinal decline in MoCA scores.

Interpretation: Irrespective of cognitive instrument or cohort assessed, TMEM106B acts as a genetic modifier for cognitive trajectory in PD. Our results implicate lysosomal dysfunction in the pathogenesis of cognitive decline in 2 different proteinopathies. ANN NEUROL 2019;85:801-811.

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Conflict of interest statement

Conflicts of Interest: Authors do not report any known conflicts of interest related to this study.

Figures

Figure 1.
Figure 1.
Number of subjects followed at each year of follow-up for each cohort.
Figure 2.
Figure 2.
Mini Mental State Examination (MMSE) scores over time across neurologically normal and neurodegenerative disease states for the first 6 years of follow up. Data points reflect mean MMSE (± SEM) for all subjects evaluated at each time point. For sample size at each time point see Figure 1. NC=Neurologically normal control, PD=Parkinson’s disease, FTD=Frontotemporal dementia, MCI=Mild cognitive impairment, AD=Alzheimer’s disease.
Figure 3.
Figure 3.
Effects of TMEM106B genotype on longitudinal Mini Mental State Examination (MMSE) performance in each disease, assessed with linear mixed effects models adjusting for age, sex, and baseline MMSE. In panel A, genotypes are indicated by color, and bands represent 95% confidence intervals for PD and FTD in codominant models. In panel B, coefficients (β), standard error (SE), and p-values for TMEM106B genotype*time interaction shown, with time in years. PD=Parkinson’s disease, FTD=Frontotemporal dementia, MCI=Mild cognitive impairment, AD=Alzheimer’s disease.
Figure 4.
Figure 4.
A. Demographics and baseline characteristics of the University of Pennsylvania cohort who were administered the Mattis Dementia Rating Scale-2 (DRS-2). All values represent median (IQR) unless otherwise specified. B and C. Effects of TMEM106B genotype on longitudinal DRS-2 total and cognitive domain performance in Parkinson’s disease patients, assessed with linear mixed effects models adjusting for age, sex, and baseline DRS-2 total or domain score. In panel B, predicted DRS-2 scores are shown by TMEM106B genotype, indicated by color, and bands represent 95% confidence intervals. In panel C, coefficients (β), standard error (SE), and p-values (two-sided/one-sided) for TMEM106B genotype*time interaction shown, with time in years.
Figure 5.
Figure 5.
A. Demographics and baseline characteristics of the PPMI cohort who were administered the Montreal Cognitive Assessment (MoCA). All values are represented as median (IQR) unless otherwise specified. Race is not reported for N=7 subjects. B and C. Effects of TMEM106B genotype on longitudinal MoCA performance in Parkinson’s disease patients, assessed with linear mixed effects models adjusting for age, sex, and baseline MoCA. In panel B, predicted MoCA scores are shown by TMEM106B genotype, indicated by color, and bands represent 95% confidence intervals. In panel C, coefficients (β), standard error (SE), and p-values (two-sided/one-sided) for TMEM106B genotype*time interaction shown, with time in years.
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