TMEM106B Effect on cognition in Parkinson disease and frontotemporal dementia

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 rs1990622 T 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, rs1990622 T associated with more rapid decrease in MMSE only under the minor-allele, rs1990622 C , dominant model. Among PD patients, rs1990622 T 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.

The FTLD Risk Factor TMEM106B Regulates the Transport of Lysosomes at the Axon Initial Segment of Motoneurons

“…Genetic variants in TMEM106B have been linked with differential aging and various neurodegenerative diseases, including frontotemporal lobar degeneration (FTLD), limbic-predominant age-related TDP-43 encephalopathy (LATE), and Parkinson's disease (Nelson et al, 2019;Tropea et al, 2019;van der Zee et al, 2011). The precise molecular function of TMEM106B is, however, still enigmatic.…”

Loss of TMEM 106B and PGRN leads to severe lysosomal abnormalities and neurodegeneration in mice

“…These two genes were also found to be associated with TDP‐43 proteinopathy and coordinate with each other to regulate gene expression in a genome‐wide transcription study (Yang et al , ). Furthermore, GRN and/or TMEM106B polymorphisms are associated with FTLD caused by C9ORF72 mutations (van Blitterswijk et al , ; Deming & Cruchaga, ; Gallagher et al , ; Lattante et al , ), cognitive impairment in amyotrophic lateral sclerosis (ALS) (Vass et al , ) and Parkinson's disease (PD) (Baizabal‐Carvallo & Jankovic, ; Tropea et al , ), and pathological presentation of Alzheimer's disease (AD) (Lee et al , ; Rutherford et al , ; Kamalainen et al , ; Perry et al , ; Sheng et al , ; Xu et al , ). Thus, it is critical to understand the functions of GRN and TMEM106B and how they genetically interact to affect neurodegeneration.…”

rs1990622 variant associates with Alzheimer’s disease and regulates TMEM106B expression in human brain tissues

“…A sex-specific analysis in UK Biobank further indicated that rs1990622 T allele only contributed to increased AD risk in females, but not in males (Table 2 ). Tropea and colleagues have also evaluated the association of rs1990622 variant with AD using 300 AD cases and 137 neurologically normal control subjects [ 7 ]. However, Tropea and colleagues did not identify any significant association of rs1990622 with AD [ 7 ].…”

“…However, Yang and colleagues did not directly evaluate the association between rs1990622 variant and AD risk. Until now, it remains unclear whether rs1990622 variant is associated with AD risk, although a lack of significant association between rs1990622 variant and AD risk [ 7 ]. We think that this may be caused by inadequate sample sizes (300 AD cases and 137 controls) [ 7 ], and large-scale samples are needed.…”