The APOE ε4 Allele Affects Cognitive Functions Differently in Carriers of APP Mutations Compared to Carriers of PSEN1 Mutations in Autosomal-Dominant Alzheimer's Disease.

Ove Almkvist,Caroline Graff

doi:10.3390/genes12121954

Ove Almkvist, Caroline Graff

Open Access

https://doi.org/10.3390/genes12121954

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Abstract

Mounting evidence shows that the APOE ε4 allele interferes with cognition in sporadic Alzheimer’s disease. Less is known about APOE in autosomal-dominant Alzheimer’s disease (adAD). The present study explored the effects on cognition associated with the gene–gene interactions between the APOE gene and the APP and PSEN1 genes in adAD. This study includes mutation carriers (MC) and non-carriers (NC) from adAD families with mutations in APP (n = 28 and n = 25; MC and NC, respectively) and PSEN1 (n = 12 and n = 15; MC and NC, respectively) that represent the complete spectrum of disease: AD dementia (n = 8) and mild cognitive impairment (MCI, n = 15 and presymptomatic AD, n = 17). NC represented unimpaired normal aging. There was no significant difference in the distribution of APOE ε4 (absence vs. presence) between the APP vs. PSEN1 adAD genes and mutation status (MC vs. NC). However, episodic memory was significantly affected by the interaction between APOE and the APP vs. PSEN1 genes in MC. This was explained by favorable performance in the absence of APOE ε4 in PSEN1 compared to APP MC. Similar trends were seen in other cognitive functions. No significant associations between APOE ε4 and cognitive performance were obtained in NC. In conclusion, cognitive effects of APOE–adAD gene interaction were differentiated between the PSEN1 and APP mutation carriers, indicating epistasis.

Highlights

Alzheimer’s disease (AD) is defined at autopsy by extracellular deposits of β-amyloid accumulated in plaques and neurofibrillary tangles of intracellular phosphorylated tau [1]
The APOE ε4 allele has a deleterious effect on disease onset in sporadic Alzheimer’s disease that is related to the number of APOE ε4 alleles [2]
The aim of the present study was to investigate the possible interaction between the APOE gene and the APP and PSEN1 genes in autosomaldominant AD (adAD) as observed on various cognitive functions

Summary

Introduction

Alzheimer’s disease (AD) is defined at autopsy by extracellular deposits of β-amyloid accumulated in plaques and neurofibrillary tangles of intracellular phosphorylated tau [1]. The APOE ε4 allele has a deleterious effect on disease onset in sporadic Alzheimer’s disease (sAD) that is related to the number of APOE ε4 alleles [2]. APOE ε4 influences lipid metabolism in the brain, β-amyloid and tau processing, synaptogenesis, glucose metabolism, mitochondrial function, vascular integrity, and neuroimmune modulation [3,4]. In this way, sAD as well as normal aging is affected by various APOE-related functions. Less is known about the relationship between APOE and possible effects in autosomaldominant AD (adAD). The YECO–APOE ε4 interaction did not add any power to the time-related cognitive changes in adAD. In a cohort of the specific Colombian PSEN1 mutation, no significant effect was found in association with APOE ε4 [7]

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