Analysis of ApoE4’s role in influencing the cognitive status of patients via microglia signaling in Alzheimer’s disease

Abstract

Alzheimer’s disease (AD) is a neurodegenerative disease affecting individuals of age 60+ years. A combination of genetic and environmental factors are responsible for the disease. The major pathophysiology associated with the disease is accumulation of Amyloid beta plaques and neurofibrillary tangles (tauopathy). Several genes through Genome wide sequencing studies (GWAS) have been found to be a risk factor in the disease progression. One such gene is ApoE whose allelic variant ApoE4 has a high risk of disease development. Glial cells play a central role in the disease pathophysiology. The focus of this study is to analyze the relationship between the Apoe4 allele and tauopathy in glial cells in AD patients at different Braak staging and cognition levels. For this, the study was divided into three parts. The first analysis was based on the Aging, Dementia and Traumatic Brain Injury (TBI) Project from the Adult Changes in Thought (ACT) study. The study spanned across three anatomical brain sections- Temporal cortex, Hippocampus and Parietal cortex. For the second part of analysis, the data was accessed from the same ACT study at the University of Washington Alzheimer’s Disease Research Center (ADRC) without any history of TBI. This data was further segregated into dementia and non dementia patient cohorts. In both the studies, microglial markers IBA1, tauopathy markers AT8 and NeuN markers were studied to produce a numerical expression value for statistical analysis. In the first part of the study, it was observed that the presence of ApoE4 did not directly influence tauopathy in a cohort of traumatic brain injury (TBI) patients. However, tauopathy increased when progressing from Braak stage 0-2 to Braak stage 5-6, but there was no significant effect on microglia levels, as indicated by constant IBA1 levels in three brain tissues (hippocampus, parietal cortex, and temporal cortex) that are commonly affected in Alzheimer's disease (AD).In the second part of the study, ApoE4 was found to influence microgliosis in dementia patients with the allele, and its absence also had an impact on the pathophysiology of cognitively resilient non-dementia patients. In ApoE4-positive dementia patients, ApoE4 was associated with increased tauopathy compared to non-dementia patients with the allele. In the absence of ApoE4, cognitively resilient patients showed increased microgliosis, which was found to be protective rather than toxic, unlike in the presence of ApoE4. This increased microgliosis could potentially explain the cognitive resilience observed in ApoE4-negative patients, as it may lead to an increased population of neuroprotective microglial cells. However, ApoE4 had no significant effect on astrocytic cells, as indicated by no significant change in GFAP process area in cognitively resilient non-dementia patients.