APOE in the bullseye of neurodegenerative diseases: impact of the APOE genotype in Alzheimer’s disease pathology and brain diseases

Abstract

ApoE is the major lipid and cholesterol carrier in the CNS. There are three major human polymorphisms, apoE2, apoE3, and apoE4, and the genetic expression of APOE4 is one of the most influential risk factors for the development of late-onset Alzheimer's disease (AD). Neuroinflammation has become the third hallmark of AD, together with Amyloid-β plaques and neurofibrillary tangles of hyperphosphorylated aggregated tau protein. This review aims to broadly and extensively describe the differential aspects concerning apoE. Starting from the evolution of apoE to how APOE's single-nucleotide polymorphisms affect its structure, function, and involvement during health and disease. This review reflects on how APOE's polymorphisms impact critical aspects of AD pathology, such as the neuroinflammatory response, particularly the effect of APOE on astrocytic and microglial function and microglial dynamics, synaptic function, amyloid-β load, tau pathology, autophagy, and cell–cell communication. We discuss influential factors affecting AD pathology combined with the APOE genotype, such as sex, age, diet, physical exercise, current therapies and clinical trials in the AD field. The impact of the APOE genotype in other neurodegenerative diseases characterized by overt inflammation, e.g., alpha- synucleinopathies and Parkinson's disease, traumatic brain injury, stroke, amyotrophic lateral sclerosis, and multiple sclerosis, is also addressed. Therefore, this review gathers the most relevant findings related to the APOE genotype up to date and its implications on AD and CNS pathologies to provide a deeper understanding of the knowledge in the APOE field.

APOE effects on regional tau in preclinical Alzheimer’s disease

“…APOE4 is the strongest genetic predictor of sporadic Alzheimer's disease (AD) dementia [1][2][3][4] and is consistently associated with risk of abnormal amyloid during the stages preceding dementia onset [5][6][7]. APOE influences amyloid accumulation through interactions with production, fibrillization, and clearance mechanisms, as well as interactions between APOE, amyloid, tau, neuroinflammation, and neuronal structure and function [8][9][10]. On average, APOE4 carriers typically reach the threshold for abnormal amyloid (Aβ+) approximately 10-15 years before e3/3 carriers, whereas amyloid positivity is delayed by approximately 4 years in e2 carriers compared to e3/e3 carriers [11].…”

Structural Proteomic Profiling of Cerebrospinal Fluids to Reveal Novel Conformational Biomarkers for Alzheimer’s Disease

“…It is noted that ApoE is commonly found in amyloid deposits, and its interaction with Aβ peptide has been reported . The structural alteration of ApoE may have an amyloid-interfering property and association with amyloid-induced cytotoxicity . Similarly, most of the proteins displaying this trend in MCI also existed in the AD group, suggesting continuation and permanence of structure alteration during AD progression.…”

Pathway-specific polygenic risk scores correlate with clinical status and Alzheimer’s-related biomarkers

“…One approach to overcome this limitation has been to calculate PRS with the APOE region removed to demonstrate effects of the APOE gene and APOE-independent variants (17)(18)(19). In this light, AD risk genes identi ed through GWAS have been associated with a number of pathways, such as immune function, cholesterol transport, mitochondrial function, protein-lipid complex, and endocytosis (4,6,7,20,21), and the APOE gene itself impacts a variety of processes (22). Two individuals may therefore have similar scores on a global PRS with very different risk associated with the underlying pathways that are perturbed as a result.…”