Brain proteomic analysis implicates actin filament processes and injury response in resilience to Alzheimer’s disease

Abstract

Resilience to Alzheimer’s disease is an uncommon combination of high disease burden without dementia that offers valuable insights into limiting clinical impact. Here we assessed 43 research participants meeting stringent criteria, 11 healthy controls, 12 resilience to Alzheimer’s disease and 20 Alzheimer’s disease with dementia and analyzed matched isocortical regions, hippocampus, and caudate nucleus by mass spectrometry-based proteomics. Of 7115 differentially expressed soluble proteins, lower isocortical and hippocampal soluble Aβ levels is a significant feature of resilience when compared to healthy control and Alzheimer’s disease dementia groups. Protein co-expression analysis reveals 181 densely-interacting proteins significantly associated with resilience that were enriched for actin filament-based processes, cellular detoxification, and wound healing in isocortex and hippocampus, further supported by four validation cohorts. Our results suggest that lowering soluble Aβ concentration may suppress severe cognitive impairment along the Alzheimer’s disease continuum. The molecular basis of resilience likely holds important therapeutic insights.

Unveiling Resilience to Alzheimer’s Disease: Insights From Brain Regional Proteomic Markers

“…The remaining 5 proteins were chosen due to the presence of more than 1 significant comparison observed within their associated brain regions, based on earlier findings. 1 A decision tree classifier was constructed using these 6 proteins (yielding a total of 9 features) while considering balanced class weights. We constructed the classifier using Python version 3.9.15 and the "DecisionTreeClassifier" module from scikit-learn version 0.24.2.…”

“…However, there are unusual people with high tissue and cellular changes of AD who exhibit normal clinical behavior by rigorous research testing, a state called cognitive resilience to Alzheimer's disease (RAD). 1 Our previous study harnessed multiple brain regions from 43 research participants who met stringent cohort inclusion and exclusion criteria for healthy controls (HC), individuals with AD dementia (ADD) only, and individuals with RAD only. 1 This stringent cohort selection allowed us to rule out potential confounding comorbidities including vascular brain injury (VBI), Lewy body disease (LBD), hippocampal sclerosis (HS), and limbic-associated TDP-43 encephalopathy neuropathologic change (LATE-NC).…”

“…1 Our previous study harnessed multiple brain regions from 43 research participants who met stringent cohort inclusion and exclusion criteria for healthy controls (HC), individuals with AD dementia (ADD) only, and individuals with RAD only. 1 This stringent cohort selection allowed us to rule out potential confounding comorbidities including vascular brain injury (VBI), Lewy body disease (LBD), hippocampal sclerosis (HS), and limbic-associated TDP-43 encephalopathy neuropathologic change (LATE-NC). 2-4. With the comorbidities excluded, the cohort consisted of 11 HC, 12 RAD, and 20 ADD.…”

A Continuous Extension of Gene Set Enrichment Analysis Using the Likelihood Ratio Test Statistics Identifies Vascular Endothelial Growth Factor as a Candidate Pathway for Alzheimer’s Disease via ITGA5

“…Still, the molecular mechanisms involved in the etiology and progression of AD are not fully understood. Recent publications have revealed a role for multiple pathways in AD, based on brain proteomics and transcriptomic analyses [2,3]. These pathways are relevant not only to neurons but also to cells regulating response to inflammation [4], such as microglia [5].…”

“…Liu et al [8] identified a novel brain-enriched RING finger E3 ligase, RNF182, which shows elevated expression in AD brains and may play a role in controlling neurotransmitter release. Pathways involved with filament-based processes, cellular detoxification, and wound healing have also been involved [2,3]. A decline in sensory function, including taste has also been reported with aging and AD [9].…”