Polygenic effects on the risk of Alzheimer's disease in the Japanese population

Abstract

Background: Polygenic effects have been proposed to account for some disease phenotypes; these effects are calculated as a polygenic risk score (PRS). This score is correlated with Alzheimer's disease (AD)-related phenotypes, such as biomarker abnormalities and brain atrophy, and is associated with conversion from mild cognitive impairment (MCI) to AD. However, the AD PRS has been examined mainly in Europeans, and owing to differences in genetic structure and lifestyle, it is unclear whether the same relationships between the PRS and AD-related phenotypes exist in non-European populations. In this study, we calculated and evaluated the AD PRS in Japanese individuals using genome-wide association study (GWAS) statistics from Europeans.

Methods: In this study, we calculated the AD PRS in 504 Japanese participants (145 cognitively unimpaired (CU) participants, 220 participants with late mild cognitive impairment (MCI), and 139 patients with mild AD dementia) enrolled in the Japanese Alzheimer's Disease Neuroimaging Initiative (J-ADNI) project. In order to evaluate the clinical value of this score, we (1) determined the polygenic effects on AD in the J-ADNI and validated it using two independent cohorts (a Japanese neuropathology (NP) cohort (n = 565) and the North American ADNI (NA-ADNI) cohort (n = 617)), (2) examined the AD-related phenotypes associated with the PRS, and (3) tested whether the PRS helps predict the conversion of MCI to AD.

Results: The PRS using 131 SNPs had an effect independent of APOE. The PRS differentiated between CU participants and AD patients with an area under the curve (AUC) of 0.755 when combined with the APOE variants. Similar AUC was obtained when PRS calculated by the NP and NA-ADNI cohorts was applied. In MCI patients, the PRS was associated with cerebrospinal fluid phosphorylated-tau levels (β estimate = 0.235, p value = 0.026). MCI with a high PRS showed a significantly increased conversion to AD in APOE ε4 noncarriers with a hazard rate of 2.22. In addition, we also developed a PRS model adjusted for LD and observed similar results.

Conclusions: We showed that the AD PRS is useful in the Japanese population, whose genetic structure is different from that of the European population. These findings suggest that the polygenicity of AD is partially common across ethnic differences.

Keywords: Alzheimer’s disease; Mild cognitive impairment; Polygenic risk score.

Fig. 1

The PRS.noAPOE in the ADD group was significantly higher than those in the CU and MCI groups. The PRS.noAPOEs (A) or PRS.adjLD (B) in each group were represented by violin plots (CU, n = 145; MCI, n = 220; ADD, n = 139). Each violin plot includes the kernel probability density of the data at different values and the box plots with the median value and the interquartile range. Tukey’s HSD test was used to perform multiple comparisons of PRSs among each group. We normalized the PRS distribution to have a mean of 0 and an SD of 1. CN = cognitively normal; MCI = mild cognitive impairment; ADD = Alzheimer’s disease dementia

Fig. 2

The PRS.noAPOE and PRS.adjLD correlated with CSF Tau/Aβ42 ratios in the MCI. CSF tTau/Aβ42 (A, C) and pTau/Aβ42 (B, D) ratios by decile of PRS are shown in each diagnostic group. The participants were divided into ten groups based on the PRS.noAPOE, ranging from the lowest group (1st decile) to the highest group (10th decile). CN = cognitively normal; MCI = mild cognitive impairment; ADD = Alzheimer’s disease dementia

Fig. 3

The high-PRS group was more likely to convert to AD than the low-PRS group in the APOE ε4 non-carrier individuals with MCI. Kaplan–Meier survival curves for conversion rates of MCI to AD in the low-PRS group (1st tertile) and the high-PRS group (3rd tertile). The shaded area represents the 95% confidence interval