Neuropathologic Correlates of Human Cortical Proteins in Alzheimer Disease and Related Dementias

Background and Objectives:Alzheimer’s 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’s 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 two cohort studies of aging and dementia. All underwent detailed annual clinical evaluations, and brain autopsies were performed after death. We refer Alzheimer’s disease (AD) to pathologically defined disease, and refer Alzheimer’s dementia to the clinical syndrome. Indices for AD, cortical Lewy bodies, limbic predominant age-related TDP-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 using mass spectrometry based tandem mass tag proteomics analysis. Eleven human cortical proteins implicated in Alzheimer’s dementia, including ACE, CHSP1, CATH, DOC2A, ICA1L, LACTB, PKHA1, RTF2, SNX32, STX4, and STX6, were previously identified using 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. By 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. Further, while higher STX6 expression increased the risk of Alzheimer’s dementia, the protein was not associated with any of the neuropathologic indices investigated.Discussion:Cortical proteins implicated in Alzheimer’s dementia do not necessarily work through AD pathogenesis; rather, non-AD neurodegenerative and vascular diseases, as well as other pathways are at play. Further, some proteins are pleiotrophic and associated with both neurodegenerative and cerebrovascular pathologies.