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Ann Neurol. 2019 Apr 11. doi: 10.1002/ana.25486. [Epub ahead of print]

TMEM106B Effect on Cognition in Parkinson's Disease and Frontotemporal Dementia.

Author information

1
Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.
2
Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA.
3
Department of Medicine, University of North Carolina Hospitals, Chapel Hill, NC.
4
Department of Biostatistics, Epidemiology, and Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.
5
Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.
6
Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.
7
Parkinson's Disease and Mental Illness Research, Education and Clinical Centers (PADRECC and MIRECC), Philadelphia Veterans Affairs Medical Center, Philadelphia, PA.
8
Center for Neurodegenerative Disease Research, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.

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. The objective of this study is to evaluate the effect of TMEM106B genotype on cognitive decline across multiple neurogenerative diseases.

METHODS:

870 subjects with diagnoses of Parkinson's disease (PD, N=179), FTD (N=179), Alzheimer's disease (AD, N=300), or memory-predominant mild cognitive impairment (MCI, N=75), and neurologically-normal control subjects (NC, N=137) were followed longitudinally at the University of Pennsylvania (UPenn). All participants had annual MMSE (median follow-up duration 3.0 years), and were genotyped at TMEM106B index SNP 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 two different proteinopathies. This article is protected by copyright. All rights reserved.

PMID:
30973966
DOI:
10.1002/ana.25486

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