Lei Yu1, Patricia A Boyle2, Aliza P Wingo2, Jingyun Yang2, Tianhao Wang2, Aron S Buchman2, Thomas S Wingo2, Nicholas T Seyfried2, Allan I Levey2, Philip L De Jager2, Julie A Schneider2, David A Bennett2. 1. From the Rush Alzheimer's Disease Center (L.Y., P.A.B., J.Y., T.W., A.S.B., J.A.S., D.A.B.), Department of Neurological Sciences (L.Y., J.Y., T.W., A.S.B., D.A.B.), Department of Psychiatry and Behavioral Sciences (P.A.B.), and Department of Pathology (J.A.S.), Rush University Medical Center, Chicago, IL; Division of Mental Health (A.P.W.), Atlanta VA Medical Center, Decatur; Departments of Psychiatry (A.P.W.), Neurology (T.S.W., A.I.L.), and Human Genetics (T.S.W.), Emory University School of Medicine; Department of Biochemistry (N.T.S.), Emory University, Atlanta, GA; and Center for Translational and Computational Neuroimmunology (P.L.D.J.), Department of Neurology and Taub Institute for Research on Alzheimer's Disease and the Aging Brain (P.L.D.J.), Columbia University Medical Center, New York, NY. lei_yu@rush.edu. 2. From the Rush Alzheimer's Disease Center (L.Y., P.A.B., J.Y., T.W., A.S.B., J.A.S., D.A.B.), Department of Neurological Sciences (L.Y., J.Y., T.W., A.S.B., D.A.B.), Department of Psychiatry and Behavioral Sciences (P.A.B.), and Department of Pathology (J.A.S.), Rush University Medical Center, Chicago, IL; Division of Mental Health (A.P.W.), Atlanta VA Medical Center, Decatur; Departments of Psychiatry (A.P.W.), Neurology (T.S.W., A.I.L.), and Human Genetics (T.S.W.), Emory University School of Medicine; Department of Biochemistry (N.T.S.), Emory University, Atlanta, GA; and Center for Translational and Computational Neuroimmunology (P.L.D.J.), Department of Neurology and Taub Institute for Research on Alzheimer's Disease and the Aging Brain (P.L.D.J.), Columbia University Medical Center, New York, NY.
Abstract
BACKGROUND AND OBJECTIVES: Alzheimer dementia is a complex clinical syndrome that can be defined broadly as an amnestic multidomain dementia. We previously reported human cortical proteins that are implicated in Alzheimer dementia. To understand the pathologic correlates of these proteins for underlying disease mechanisms, we investigated cortical protein associations with common age-related neuropathologies. METHODS: Participants were community-dwelling older adults from 2 cohort studies of aging and dementia. All underwent detailed annual clinical evaluations, and brain autopsies were performed after death. We use Alzheimer disease (AD) to refer to pathologically defined disease and Alzheimer dementia to refer to the clinical syndrome. Indices for AD, cortical Lewy bodies, limbic predominant age-related TAR DNA binding protein 43 encephalopathy neuropathologic changes (LATE-NC), hippocampal sclerosis, macroscopic infarcts, microinfarcts, cerebral amyloid angiopathy, atherosclerosis, and arteriolosclerosis were quantified during uniform structured neuropathologic evaluations. High-throughput protein abundances from frozen dorsolateral prefrontal cortex were quantified with mass spectrometry-based tandem mass tag proteomics analysis. Eleven human cortical proteins implicated in Alzheimer dementia, including angiotensin-converting enzyme, calcium-regulated heat-stable protein 1 (CHSP1), procathepsin H (CATH), double C2-like domain-containing protein α, islet cell autoantigen 1-like protein, serine β-lactamase-like protein LACTB, mitochondrial, pleckstrin homology domain-containing family A member 1, replication termination factor 2, sorting nexin-32, syntaxin-4, and syntaxin-6 (STX6), were previously identified with an integrative approach. Logistic regression analysis examined the association of protein expression with each of the neuropathologic indices. RESULTS: A total of 391 older adults were included. We did not observe associations of these protein targets with pathologic diagnosis of AD. In contrast, multiple proteins were associated with non-AD neurodegenerative and cerebrovascular conditions. In particular, higher CHSP1 expression was associated with cortical Lewy bodies and macroscopic infarcts, and higher CATH expression was associated with LATE-NC and arteriolosclerosis. Furthermore, while higher STX6 expression increased the risk of Alzheimer dementia, the protein was not associated with any of the neuropathologic indices investigated. DISCUSSION: Cortical proteins implicated in Alzheimer dementia do not necessarily work through AD pathogenesis; rather, non-AD neurodegenerative and vascular diseases and other pathways are at play. Furthermore, some proteins are pleiotrophic and associated with both neurodegenerative and cerebrovascular pathologies.
BACKGROUND AND OBJECTIVES: Alzheimer dementia is a complex clinical syndrome that can be defined broadly as an amnestic multidomain dementia. We previously reported human cortical proteins that are implicated in Alzheimer dementia. To understand the pathologic correlates of these proteins for underlying disease mechanisms, we investigated cortical protein associations with common age-related neuropathologies. METHODS: Participants were community-dwelling older adults from 2 cohort studies of aging and dementia. All underwent detailed annual clinical evaluations, and brain autopsies were performed after death. We use Alzheimer disease (AD) to refer to pathologically defined disease and Alzheimer dementia to refer to the clinical syndrome. Indices for AD, cortical Lewy bodies, limbic predominant age-related TAR DNA binding protein 43 encephalopathy neuropathologic changes (LATE-NC), hippocampal sclerosis, macroscopic infarcts, microinfarcts, cerebral amyloid angiopathy, atherosclerosis, and arteriolosclerosis were quantified during uniform structured neuropathologic evaluations. High-throughput protein abundances from frozen dorsolateral prefrontal cortex were quantified with mass spectrometry-based tandem mass tag proteomics analysis. Eleven human cortical proteins implicated in Alzheimer dementia, including angiotensin-converting enzyme, calcium-regulated heat-stable protein 1 (CHSP1), procathepsin H (CATH), double C2-like domain-containing protein α, islet cell autoantigen 1-like protein, serine β-lactamase-like protein LACTB, mitochondrial, pleckstrin homology domain-containing family A member 1, replication termination factor 2, sorting nexin-32, syntaxin-4, and syntaxin-6 (STX6), were previously identified with an integrative approach. Logistic regression analysis examined the association of protein expression with each of the neuropathologic indices. RESULTS: A total of 391 older adults were included. We did not observe associations of these protein targets with pathologic diagnosis of AD. In contrast, multiple proteins were associated with non-AD neurodegenerative and cerebrovascular conditions. In particular, higher CHSP1 expression was associated with cortical Lewy bodies and macroscopic infarcts, and higher CATH expression was associated with LATE-NC and arteriolosclerosis. Furthermore, while higher STX6 expression increased the risk of Alzheimer dementia, the protein was not associated with any of the neuropathologic indices investigated. DISCUSSION: Cortical proteins implicated in Alzheimer dementia do not necessarily work through AD pathogenesis; rather, non-AD neurodegenerative and vascular diseases and other pathways are at play. Furthermore, some proteins are pleiotrophic and associated with both neurodegenerative and cerebrovascular pathologies.
Authors: Patricia A Boyle; Lei Yu; Sukriti Nag; Sue Leurgans; Robert S Wilson; David A Bennett; Julie A Schneider Journal: Neurology Date: 2015-11-04 Impact factor: 9.910
Authors: David A Bennett; Aron S Buchman; Patricia A Boyle; Lisa L Barnes; Robert S Wilson; Julie A Schneider Journal: J Alzheimers Dis Date: 2018 Impact factor: 4.472
Authors: Janna H Neltner; Erin L Abner; Steven Baker; Frederick A Schmitt; Richard J Kryscio; Gregory A Jicha; Charles D Smith; Eleanor Hammack; Walter A Kukull; Willa D Brenowitz; Linda J Van Eldik; Peter T Nelson Journal: Brain Date: 2013-11-21 Impact factor: 13.501
Authors: Patricia A Boyle; Tianhao Wang; Lei Yu; Robert S Wilson; Robert Dawe; Konstantinos Arfanakis; Julie A Schneider; David A Bennett Journal: Brain Date: 2021-08-17 Impact factor: 13.501
Authors: Aliza P Wingo; Yue Liu; Ekaterina S Gerasimov; Jake Gockley; Benjamin A Logsdon; Duc M Duong; Eric B Dammer; Chloe Robins; Thomas G Beach; Eric M Reiman; Michael P Epstein; Philip L De Jager; James J Lah; David A Bennett; Nicholas T Seyfried; Allan I Levey; Thomas S Wingo Journal: Nat Genet Date: 2021-01-28 Impact factor: 38.330
Authors: Peter T Nelson; Dennis W Dickson; John Q Trojanowski; Clifford R Jack; Patricia A Boyle; Konstantinos Arfanakis; Rosa Rademakers; Irina Alafuzoff; Johannes Attems; Carol Brayne; Ian T S Coyle-Gilchrist; Helena C Chui; David W Fardo; Margaret E Flanagan; Glenda Halliday; Suvi R K Hokkanen; Sally Hunter; Gregory A Jicha; Yuriko Katsumata; Claudia H Kawas; C Dirk Keene; Gabor G Kovacs; Walter A Kukull; Allan I Levey; Nazanin Makkinejad; Thomas J Montine; Shigeo Murayama; Melissa E Murray; Sukriti Nag; Robert A Rissman; William W Seeley; Reisa A Sperling; Charles L White; Lei Yu; Julie A Schneider Journal: Brain Date: 2019-06-01 Impact factor: 15.255
Authors: Aliza P Wingo; Wen Fan; Duc M Duong; Ekaterina S Gerasimov; Eric B Dammer; Yue Liu; Nadia V Harerimana; Bartholomew White; Madhav Thambisetty; Juan C Troncoso; Namhee Kim; Julie A Schneider; Ihab M Hajjar; James J Lah; David A Bennett; Nicholas T Seyfried; Allan I Levey; Thomas S Wingo Journal: Nat Neurosci Date: 2020-05-18 Impact factor: 24.884
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