Evaluation of Apolipoprotein e4 allele as Susceptible Factor for Neurodegenerative Diseases among Eastern Indians

Research Article

Austin Alzheimers J Parkinsons Dis. 2023; 6(2): 1040.

Evaluation of Apolipoprotein e4 allele as Susceptible Factor for Neurodegenerative Diseases among Eastern Indians

Dipanwita Sadhukhan¹; Smriti Mishra¹; Priyanka Mukherjee¹; Atanu Biswas²; Subhra Prakash Hui³; Tapas Kumar Banerjee¹; Arindam Biswas¹

¹Molecular Biology & Clinical Neuroscience Division, National Neurosciences Centre, Calcutta, Kolkata, India

²Institute of Post graduate of Medical Education & Research and Bangur Institute of Neurosciences, Kolkata, India

³S.N Pradhan Centre for Neurosciences, University of Calcutta, Kolkata, India

*Corresponding author: Arindam Biswas Molecular Biology & Clinical Neuroscience Division, National Neurosciences Centre, Calcutta, Peerless Hospital (2nd floor) 360, Panchasayar, Kolkata 700094, India. Email: thisisarindam@gmail.com

Received: October 18, 2023 Accepted: November 20, 2023 Published: November 27, 2023

Abstract

Background & Objectives: Apolipoprotein E (ApoE) and age have been identified as the major risk factors for several neurodegenerative disorders. Among the three major isoforms (ApoE2, ApoE3 & ApoE4) of APOE, ApoE4 often shows ethnicity dependent association with neurodegenerative diseases. In the present study, we aim to determine the e4 allele/genotype frequency among the different neurodegenerative disorders and their correlation with several demographic and clinical parameters from eastern India.

Methods: A total of 826 individuals were recruited for this study which includes 128 PD-MCI, 144 PDD, 90 DLB, 114 FTD, 94 AD and 256 unrelated neurologically controls from eastern India. Subjects were analysed for APOE genotype (E2, E3 and E4) by PCR-RFLP techniques and Sanger sequencing.

Results: The APOE4 allele was significantly associated with each of the disease subtypes, selected for the study (P=0.016 to 0.000), while e3 allele was predominant among controls. Further stratification of subjects identified significant overrepresentation of (a) positive family history for FTD (P=0.0414) & AD (P=0.029) and (b) early age at onset of for PDD (P=0.0316) and FTD (P=0.0034) among the e4 allele carriers. Furthermore, lowering of BMSE score was also observed among the e4 allele carriers of AD subjects (P=0.0324).

Conclusion: There is a significant association of APOE4 allele with different neurodegenerative diseases influencing lowering of age at onset, BMSE score and positive family history among ethnic Bengali population of eastern India.

Keywords: APOE; Neurodegenerative diseases; Indians

Introduction

The Apolipoprotein E (ApoE) protein has a crucial role in lipid and cholesterol flux in the central nervous system [1]. Among its three major human isoforms, ApoE2, ApoE3, and ApoE4, APOE4 is considered as one of the most potent risk factors for the development of neurological disorders. The presence of two arginine at the 112th and 158th positions in the APOE4 protein provides it with an enhanced lipid binding property with reduced stability rendering pathogeniecity than other isoforms.

Neuronal death in neurodegenerative diseases is often associated with abnormal protein accumulation, immune system activation, neuroinflammation and blood-brain barrier disruption. In Alzheimer’s Disease (AD) pathology, APOE polymorphisms with the combined effect of sex, age, diet, and physical exercise, have a major effect on astrocytic and microglial function and microglial dynamics, synaptic function, amyloid-β load, tau pathology, autophagy, and cell–cell communication [2]. As a result, APOE4 carriers often show a greater Aβ deposition both in quantity and density compared to non-APOE4 carriers. Similarly, in Parkinson’s Disease (PD), an increase in alpha-synuclein aggregate formation is found to be influenced by the APOE4 genotype [3]. However, studies showed incongruities in this regard suggesting that APOE polymorphisms may result in a higher risk of cognitive impairment than motor deterioration. In Lewy body dementia, it also has distinct roles in microglia-associated alpha-synuclein clearance in the midbrain [4]. A number of genetic association studies also highlighted increased disease risk for e4 alleles in frontotemporal dementia [5].

Although APOE plays a significant role in several central nervous system pathologies which are mostly complex in nature, the genetic association data often appear to be inconsistent due to differences in APOE allele frequencies across ethnic populations. In India, a number of genetic studies have been performed in neurodegenerative disorders considering either one or few disease types at a time. However, the results are conflicting and may be influenced by with limited number of study subjects and mutiethnicity. Therefore, the present study aims to evaluate the frequency of APOE isoforms in several neurodegenerative diseases in a relatively larger sample representing the ethnic Bengali population of Eastern India.

Materials and Methods

Study Subjects

A total of 570 patients clinically diagnosed with neurodegenerative disorders [128 Parkinson’s disease with mild cognitive impairment (PD-MCI), 144 Parkinson’s Disease with Dementia (PDD), 90 Dementia with Lewy body (DLB), 114 Frontotemporal Dementia (FTD) and 94 Alzheimer’s Disease (AD)] by clinicians were recruited from Eastern India in this study with their written informed consent as per guidelines of Indian Council of Medical Research (ICMR). Patients were diagnosed following standard diagnosis criteria. In addition, 256 age and ethnicity matched unrelated healthy individuals with no personal or family history of neurodegenerative diseases and/ or any other neurological symptoms were also recruited as controls in the present study from Kolkata. Bengali version of Mini Mental State Examination (BMSE) scale was used for primary tool during evaluation [6]. The diagnostic labelling was done by trained neurologists (AB and TKB). Diagnosis was performed using standard diagnostic criteria (MDS task force criteria for PD-MCI [7] and PDD [8], FTD by FTD Consortium criteria [9], DLB by DLB consortium criterion – fourth consensus [10] and AD by NIA-AA criteria [11]. The demographic details of patients are described in Table 1.