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Emerging evidence suggests a role for <jats:italic>TMEM106B<\/jats:italic> in neurodegenerative processes beyond FTD. We evaluate the effect of <jats:italic>TMEM106B<\/jats:italic> genotype on cognitive decline across multiple neurogenerative diseases.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We longitudinally followed 870 subjects with diagnoses of Parkinson disease (PD; n = 179), FTD (n = 179), Alzheimer disease (AD; n = 300), memory\u2010predominant 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\u2010Mental State Examination (MMSE; median follow\u2010up duration = 3.0 years) and were genotyped at <jats:italic>TMEM106B<\/jats:italic> index single nucleotide polymorphism rs1990622. Genotype effects on cognition were confirmed by extending analyses to additional cognitive instruments (Mattis Dementia Rating Scale\u20102 [DRS\u20102] and Montreal Cognitive Assessment [MoCA]) and to an international validation cohort (Parkinson's Progression Markers Initiative [PPMI], N = 371).<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>The <jats:italic>TMEM106B<\/jats:italic> rs1990622<jats:sup>T<\/jats:sup> 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<jats:sup>T<\/jats:sup> associated with more rapid decrease in MMSE only under the minor\u2010allele, rs1990622<jats:sup>C<\/jats:sup>, dominant model. Among PD patients, rs1990622<jats:sup>T<\/jats:sup> carriers from the UPenn cohort demonstrated more rapid longitudinal decline in DRS\u20102 scores. Finally, in the PPMI cohort, <jats:italic>TMEM106B<\/jats:italic> risk allele carriers demonstrated more rapid longitudinal decline in MoCA scores.<\/jats:p><\/jats:sec><jats:sec><jats:title>Interpretation<\/jats:title><jats:p>Irrespective of cognitive instrument or cohort assessed, <jats:italic>TMEM106B<\/jats:italic> 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. <jats:bold>ANN NEUROL 2019;85:801\u2013811.<\/jats:bold><\/jats:p><\/jats:sec>","DOI":"10.1002\/ana.25486","type":"journal-article","created":{"date-parts":[[2019,4,12]],"date-time":"2019-04-12T04:40:00Z","timestamp":1555044000000},"page":"801-811","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":89,"title":["<i>TMEM106B<\/i> Effect on cognition in Parkinson disease and frontotemporal dementia"],"prefix":"10.1002","volume":"85","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0766-1496","authenticated-orcid":false,"given":"Thomas F.","family":"Tropea","sequence":"first","affiliation":[{"name":"Department of Neurology, Perelman School of Medicine University of Pennsylvania  Philadelphia 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