In Thai Nationals, the ApoE4 Allele Affects Multiple Domains of Neuropsychological, Biobehavioral, and Social Functioning Thereby Contributing to Alzheimer’s Disorder, while the ApoE3 Allele Protects Against Neuropsychiatric Symptoms and Psychosocial Deficits

Abstract

The apolipoprotein E epsilon 4 (ApoE4) allele is the strongest genetic risk factor for Alzheimer's disorder (AD) and is associated with semantic and episodic memory deficits. The aim of this study was to examine the associations between ApoE alleles (E2, E3, E4) and genotypes and neuropsychological tests, behavioral functions, and dementia symptoms as assessed using Consortium to Establish a Registry for Alzheimer's Disease (CERAD). This study included 60 patients with Alzheimer's disorder (AD), 60 with mild cognitive disorder (MCI), and 62 normal volunteers. ApoE4 carriers and individuals with E3/E4 and E4/E4 genotypes show an increased incidence of AD, but not MCI. ApoE4 carriers and especially E4/E4 homozygotes show a worse outcome on the CERAD total score, Blessed Dementia Scale, and Short Blessed Test and lower scores on the Verbal Fluency Test, Boston Naming Test, Constructional Praxis Recall, and Word List Memory, Recall, and Recognition. ApoE4 carriers and E4/E3 heterozygotes show higher scores on the Clock Drawing Test. ApoE4 carriers show a worse outcome on the CERAD clinical history scores of memory, language, personality, ADL, orientation, and social skills, while allele AopE3 carriers show better scores on activities of daily living (ADL) and social skills. ApoE3 carriers show lower total weighted, irritability/aggression, and behavioral dysregulation scores on the Behavior Rating Scale for Dementia. The results show that in Thai individuals, the presence of ApoE4 allele is accompanied by a multifarious decline in neurocognitive functions and behavioral features and that ApoE3 may convey protection against neuropsychiatric symptoms and a decline in social skills. ApoE4 and especially the E4/E4 genotype may affect multiple domains of cognitive, biobehavioral, and social functioning thereby contributing to AD phenomenology.

Impact of Apolipoprotein E gene polymorphism during normal and pathological conditions of the brain across the lifespan

“…Some recent studies [300,301] show that the default-mode network in APOE 4 subjects differs from non- APOE 4 in a way that APOE 4 seems to establish the functional communications across different brain regions (connectomics), which could predispose to some cognitive disadvantage across the entire lifespan. Moreover, some investigations pointed out that there is indeed an association between cognition measurements and personality traits [302,303]. If these links are also based, influenced, or modulated by a specific genotype, such APOE 4 vs. APOE 2 is under investigation.…”

Apolipoprotein E ε4 Specifically Modulates the Hippocampus Functional Connectivity Network in Patients With Amnestic Mild Cognitive Impairment

“…Also, APOE ε4 carriers have been demonstrated to experience an earlier onset of memory decline and to have greater rates of disease progression than non-APOE ε4 carriers (Ungar et al, 2014 ). Neuropsychological studies have revealed that APOE ε4 has a significant effect on general cognitive function (Tangwongchai et al, 2018 ), especially episodic memory (Rajah et al, 2017 ). Neuropathological studies in human and animal models have proved that APOE ε4 has a physical interaction with Aβ, which has a strong influence on memory deficit in probable preclinical AD (Holtzman et al, 2012 ).…”

Mild Cognitive Impairment is not a Valid Concept and Should be Replaced by a More Restrictive, Biologically Validated Class, Named Mild Cognitive Dysfunctions (MCD): A Nomothetic Network Approach

“…The early phases of AD are characterized by a gradual decline in neurocognitive functions including impairments in episodic and semantic memory and word fluency [5,6]. In the later stages of AD, patients suffer from deficits in memory, language and naming, orientation, executive functions, perceptual-motor functions, attention, and social skills including communication and judgement [6,7]. At that stage, difficulties to perform activities of daily living (ADL) and neuropsychiatric symptoms, such as behavioral dysregulation, irritability and aggression, inertia, and depressive, vegetative and psychotic symptoms, may be evident [7].…”

“…In the later stages of AD, patients suffer from deficits in memory, language and naming, orientation, executive functions, perceptual-motor functions, attention, and social skills including communication and judgement [6,7]. At that stage, difficulties to perform activities of daily living (ADL) and neuropsychiatric symptoms, such as behavioral dysregulation, irritability and aggression, inertia, and depressive, vegetative and psychotic symptoms, may be evident [7]. The pathophysiology of AD comprises neuroinflammation with astrogliosis, neurofibrillary tangles, accumulation of amyloid plaques, dystrophic neurites with tau protein, and synaptic, neuronal and neuropil loss [2,3,8,9].…”

“…Aging and genetic factors are the most important unmodifiable risk factors for AD and the apolipoprotein E epsilon 4 (ApoE4) allele is the most widely replicated genetic risk factor of AD [7,10]. Around 40% of AD patients carry the ApoE4 allele and risk of AD is increased in E2/E4 (Odds Ratio=2.6), E3/E4 (Odd Ratio=3.2), and especially in E4/E4 (Odds ratio=14.9) carriers [10].…”