Alzheimer’s disease (AD) is the leading cause of dementia in elderly individuals (Alzheimers Dement, 2020). Polymorphism in the apolipoprotein E (APOE) gene is a major risk determinant of late-onset AD (Farrer et al., 1997; Liu et al., 2013). Of the three major APOE allelic variants, epsilon (ε) 2, ε3 and ε4, APOE ε4 is associated with an increased risk, while APOE ε2 has been reported as having a protective effect over the risk of AD (Saunders et al., 1993; Corder et al., 1994; Farrer et al., 1997; Liu et al., 2013). Having a single APOE ε4 allele increases the risk of AD onset 2–4 fold and having two APOE ε4 alleles increases the risk about 8–12 fold (Farrer et al., 1997). Increasing evidence suggests that the effect of APOE ε4 on AD risk is exerted through inhibition of amyloid-β (Aβ) clearance and promotion of Aβ aggregation (Liu et al., 2013; Yamazaki et al., 2019). APOE ε4 also contributes to AD pathogenesis by impairing microglial responsiveness, lipid transport, synaptic integrity and plasticity, glucose metabolism, and cerebrovascular integrity and function (Liu et al., 2013; Yamazaki et al., 2019).

The risk conferred by APOE ε4 varies by age and sex, and these differences in AD risk have important implications for treatment trials, diagnostics, and therapeutics (Ungar et al., 2014). APOE ε4 exerts its maximal effect on AD risk by the early 70’s, with a reduction in risk after age 85 in both sexes (Jarvik et al., 1995; Farrer et al., 1997). Evidence indicates that the APOE ε4 risk for AD is greater in women than men (Payami et al., 1994; Farrer et al., 1997; Altmann et al., 2014; Buckley et al., 2018). Whereas Neu et al. (2017) found that men and women with the APOE ε4 genotype did not show a difference in AD risk across the age span of 55–85 years, but women had an increased risk between the ages of 65 and 75 (Neu et al., 2017).

The effect of ethnic background on the APOE association with AD risk has long been known, with African American and Hispanic APOE ε4 carriers having a lower risk than Caucasian APOE ε4 carriers, and Japanese carriers having the highest odd ratios (ORs) (Farrer et al., 1997; Tang et al., 1998). China has the largest population of patients with dementia in the world (Jia et al., 2020). The associations between APOE genotype and AD risk in the Chinese population were reported (Liu et al., 2014; Wu et al., 2015; Chen et al., 2022), however, the effect of age and sex on APOE ε4 risk in Chinese population is still unknown. In addition, data on this in the Taiwan Chinese population remains limited due to small sample sizes in previous studies (Hong et al., 1996; Liu et al., 1999; Hu et al., 2000; Huang et al., 2002; Lai et al., 2003). Therefore, we conducted the current study to evaluate the association between APOE genotype and AD in a Taiwan Chinese population, and to explore if the association varies by age and sex.

We have demonstrated that the APOE ε4 allele represents a major risk factor for AD in the Taiwanese Chinese population, although its effect is weaker when compared to Caucasian populations. Although the difference did not reach a level of statistical significance, the risk appears to be higher in younger age groups. APOE ε4 carrier women and men did not show a significant difference in AD risk but APOE ε4 carrier men appear to have a higher risk at older age, while APOE ε4 carrier women had an increased risk at a younger age. While the impact of age and sex on the association between APOE genotype and AD is well-established in Caucasians, to the best of our knowledge, this is the first study in the Taiwan Chinese population.

Apolipoprotein E ε4 allele frequency in AD patients and the related risk for AD are different in people of different ethnicities. A previous study showed that APOE ε4 allele frequency in AD patients was highest in Caucasian (36.7%) followed by African American (32.2%), Japanese (27.8%) and Hispanic (19.2%) individuals (Farrer et al., 1997). Although APOE ε4 is considered the most important risk factor for AD, the APOE ε4 allele frequency in AD patients is lower in Taiwanese (17.9%) which was in line with previous studies (Liu et al., 1999; Huang et al., 2002). According to the study conducted by Farrer et al. (1997), the association between APOE ε4 and AD in Japanese people (ε3/ε4: OR 5.6, 95% CI = 3.9–8.0, ε4/ε4: OR 33.1, 95% CI = 13.6–80.5 relative to ε3/ε3) was higher than in Caucasian people (ε3/ε4: OR 2.7, 95% CI = 2.2–3.2, ε4/ε4: OR 12.5, 95% CI = 8.8–17.7), while the association was lower among African Americans (ε3/ε4: OR 1.1, 95% CI = 0.7–1.8, ε4/ε4: OR 5.7, 95% CI = 2.3–14.1) and Hispanics (ε3/ε4: OR 2.2, 95% CI = 1.3–3.4, ε4/ε4: OR 2.2, 95% CI = 0.7–6.7) (Farrer et al., 1997). Our study reports the APOE ε4 related risk for AD in a Taiwan Chinese population (ε3/ε4: OR 2.24, 95% CI = 1.76–2.84, ε4/ε4: OR 7.21, 95% CI = 3.11–16.76). When including our findings, the risk of having AD in APOE ε4 carriers was highest in Japanese, followed by Caucasian, Taiwan Chinese, African Americans and Hispanics. The comparison of APOE ε4 allele frequency in AD patients and the related risk for AD among different ethnicities is summarized in Table 6. This should be verified by more studies in the future.

Unlike previous studies (Payami et al., 1994; Farrer et al., 1997; Altmann et al., 2014), APOE ε4 carrier women and men did not show a significant difference in AD risk. This finding is consistent with a previous study that men and women with one copy of APOE ε4 have nearly the same odds of developing AD across the age span of 55–85 years (Neu et al., 2017). APOEε4 homozygous women appear to have a increased risk compared to homozygous men, which aligns with the study conducted by Farrer et al. (1997). Their study showed that the OR for APOE ε4/ε4 leaps to 10 and above for men and women, but even among the homozygotes there appears to be a slightly greater effect in women (Farrer et al., 1997). However, it is important to interpret the result cautiously due to the limited number of APOE ε4 homozygotes in our study participants.

Our observation of a stronger effect of APOE ε4 in individuals under the age of 75 is consistent with previous reports that APOE ε4 exerts its maximal effect on AD risk by the early 70’s, with a reduction in risk after the age of 85 (Jarvik et al., 1995; Farrer et al., 1997). This finding is in line with epidemiological evidence that APOE ε4 is not only associated with an increased risk of the development of AD but also a lower age of onset (Corder et al., 1993; Rebeck et al., 1993; Farrer et al., 1997; Liu et al., 2013). The mean age of clinical onset is 68 years in ε4 homozygotes, 76 years in ε4 heterozygotes, and 84 years in ε4 non-carriers, indicating that APOE ε4 dramatically increases the risk of AD development with an earlier age of onset in a gene dose-dependent manner (Corder et al., 1993; Rebeck et al., 1993).

In our study, APOE ε4 carrier men showed a non-significant higher risk after the age of 75, whereas APOE ε4 carrier women exhibited an increase in risk before the age of 75. The increased risk of AD in women before the age of 75 years may be associated with the events that occur 15–20 years earlier, possibly coinciding with the period of menopause (Dubal and Rogine, 2017), which on average begins at 51 years of age, and during which physiological changes and estrogen loss occurs (McKinlay et al., 1992). A possible explanation for the higher AD risk in APOE ε4 carrier men at an older age is that the age-adjusted period of prevalence for cardiovascular disease (CVD) related to APOE genotype is higher in men than in women (18.6% in the ε4 group for men and 9.9% for ε4 women) (Lahoz et al., 2001). The prevalence of CVD has also been shown to increase with age (Yazdanyar and Newman, 2009; North and Sinclair, 2012), and individuals with CVD are at a higher risk for AD especially if they carry the APOE4 allele (Stampfer, 2006; Eriksson et al., 2010; de Bruijn and Ikram, 2014). Therefore, older men with APOE ε4 may have a higher risk of AD. This hypothesis needs further validation. It is also important to carefully exclude cognitive impairments caused by stroke or cerebrovascular diseases, as the comorbidity of CVD and AD is high in the elderly.

There were some limitations to the current study. First, we did not adjust for known AD risk factors, such as the number of years of education, family history of AD and vascular risk factors (Barnes and Yaffe, 2011), as they are all known risk factors for developing AD, in addition to APOE ε4. Second, no participants with APOE ε2/ε4 genotyping were recruited in our study. Therefore, whether the protective effect of the ε2 allele overcomes the risk brought on by the ε4 allele is unknown. Third, these findings are based on a population from hospital outpatient clinics and may not be generalized to the general population. Fourth, we did not report the prevalence of CVD in the recruited subjects; future studies with information on the prevalence of CVD are warranted to better understand the association between APOE genotype, CVD, dementia and AD, especially in older men. Even so, our findings warrant further investigation as it is likely a complex set of risk factors associated with AD development, and consideration should be given to age and sex-specific treatments for cognitive decline and AD. For example, if women are at an increased risk of AD at a younger age, it is plausible that treatments for women, especially those who carry an APOE ε4 allele, may need to be initiated earlier. Additionally, it is important to vigorously control modifiable cardiovascular risk factors, particularly in men who are APOE ε4 carriers, due to their higher risks of AD and CVD at an older age.

In conclusion, we reported the association between APOE genotype and AD in a Taiwan Chinese population. At older age (≥75 years), APOE ε4 carrier men have a higher risk of AD, while APOE ε4 carrier women have an increased risk at a younger age. This is important to consider for individual patients in terms of diagnostics, treatment, and genetic counseling.

The original contributions presented in this study are included in the article/supplementary material, further inquiries can be directed to the corresponding author.

The studies involving humans were approved by the Kaohsiung Medical University Hospital Institutional Review Board [KMUHIRB-SV(II)-20190059, KMUHIRB-SV(II)-20200034, KMUHIRB-E(II)-20220263, and KMUHIRB-SV(I)-20230025]. The studies were conducted in accordance with the local legislation and institutional requirements. Written informed consent for participation in this study was provided by the participants’ legal guardians/next of kin.

L-CH and Y-HY contributed to the study conception and design. M-YL, C-FC, Y-PC, K-YL, and Y-HY contributed to the acquisition of data. L-CH, C-FC, Y-PC, and Y-HY analyzed and interpreted the data. L-CH and Y-HY conducted the statistical analyses and involved in writing the initial draft of the manuscript. All authors reviewed and revised the manuscript and approved the submitted version.