1 Introduction

Alzheimer’s disease (AD) is a neurodegenerative disease with progressive loss of neuronal functions, which in turn results in memory deficits,cognitive deterioration,and impaired motor coordination. The increase in the aging population has led to an increasing prevalence of AD. However,no existing treatment can effectively halt the progression or prevent the onset of AD. AD is characterized neuropathologically by two hallmarks: intra‐neuronal neurofibrillary tangles and amyloid plaques^[1]. The major factor associated with AD is aging,with family history playing an important secondary role. However, another common risk factor for AD is the ε4 allele of the apolipoprotein E (APOE) gene^{[2, 3, 4]}.

The APOE gene is localized on chromosome 19 and comprises three major alleles (ε2,ε3,and ε4). Of these alleles,ε4 has been identified as a genetic risk factor for AD^[5]. Carriers have a higher risk with two APOE ε4 alleles (ε4/ε4)^[6]. APOE ε4 is considered as a biomarker for the preclinical stage of AD^[7]. In 2002,Lange et al. found that the APOE genotype had little effect on the rate of memory decline^[8]. However,the results of most research studies tend to suggest that APOE ε4 is commonly associated with age‐related cognitive decline^{[9, 10]}. Although APOE ε4 is generally suggested to play a role in the onset of AD,the mechanism through which it exerts this effect remains unclear. Potential mechanisms include affecting amyloid‐beta (Aβ) deposition and clearance,or playing a probable regulatory role in tau phosphorylation^{[11, 12, 13]}. Furthermore, most studies on the association of APOE with memory impairment have demonstrated significantly greater decline in memory in APOE ε4 carriers to no APOE ε4 carriers. APOE ε4 carriers have exhibited particularly impaired verbal and visual memory^{[14, 15]}. However,APOE ε4 is not only related to the acceleration of Aβ deposition,but also to hippocampal atrophy and default mode network dysfunction^[1],and other processes may be affected as well.

AD risk factors have not been thoroughly studied in different ethnicities and populations. There is evidence that these risk factors may vary considerably among ethnic groups. Table 1 summarizes the results of APOE ε4‐related studies examining different racial populations^[29]. Studies in Finland^[14],the Netherlands^[16], United Kingdom^{[17, 18]},and Italy^[19] have found APOE ε4 to be associated with cognitive decline. The APOE ε4 allele is especially common among people of European ancestry^[20]. Several studies from the United States have reported similar conclusions^{[8, 15, 21, 22]}. More specifically,The APOE ε4 allele is also common among people of African ancestry^[23]. Some studies suggest that APOE ε4 has a weaker relationship with cognitive decline in this population^[23],whereas other studies have suggested the opposite^{[24, 25]}. Table 1 show that a lower number of studies were conducted in Asia. In Japan,population‐based studies of white and Japanese populations have found that the APOE ε4/ε4 genotype is associated with a significantly increased risk of AD^[26]. Few studies have investigated this relationship in the population of China.

Table 1 Studies examining APOE ε4 allele carriers from different racial backgrounds (adapted from Mohamad et al.^[29])

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In 2015,Yang et al. published the first analysis of the relationship between the APOE ε4 genotype and treatment responses in the patients with AD in Taiwan, reporting that APOE ε4‐positive (i.e.,having at least one APOE ε4 allele) patients with AD exhibited more rapid functional decline despite treatment^[27]. However, this study had some limitations,including a relatively small sample size. Our study expanded these findings. In order to have a more clear understanding of the association of the therapeutic response and APOE ε4 genotype,we have analyzed 78 more patients with AD in Taiwan of whom 26.3% had the APOE ε4‐positive gene,by using one‐way ANOVA (Table 2) and controlling other possible variables^[27]. The average age of patients was 75.4 years. The APOE ε4 gene carriers were younger than non‐carriers and had a higher education level (Table 2). Of these 78 patients,62.2% had hypertension. No significant difference in cognitive resilience was observed between patients with differing APOE ε4 status,age,sex,education level,or hypertension status.

Table 2 Potential predictors of cognitive resilience among Alzheimer’s disease in the APOE ε4 carriers in Taiwan (adapted from Yang CH et al.^[27])

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The heterogeneous results for the association of therapeutic outcomes and APOE ε4 genotype in published studies might be the result of differences in the study designs,psychometrics used,and races.

Although our study yielded nonsignificant results, above mentioned studies have been limited by various methodological problems including small sample size,corrected detection and analysis methods,and dichotomous measures of cognitive functioning. Furthermore,nongenetic differences,such as lifestyle and dietary factors,may also affect the results. The potential for cognitive resilience was not significant in the fully adjusted models. Considering the different results of the two studies in the population in Taiwan evaluating the therapeutic response of APOE ε4 genotype in patients with AD,the detailed mechanisms and other variables related to the therapeutic response should be clarified.

APOE testing warrants further research for the development of a screening method for the APOE gene across different races. APOE genotype could be a clinical biomarker similar to amyloid plaques and hyperphosphorylated tau proteins. Such studies on the racial differences in APOE could lead to interventions aimed at high‐risk groups. These studies can aid in developing ways to promote cognitive resilience among APOE ε4 carriers of different racial backgrounds.

The authors have no financial interest to disclose regarding the article.