Dear Editor,

Alzheimer's disease (AD) is characterized by a decline in cognition and brain volume, and there is growing evidence that COVID-19 can lead to impaired cognitive function and even dementia [1]. As such, it is important to determine whether there is a causal relationship between COVID-19 and AD.

Mendelian randomization (MR) is a powerful tool for assessing the causal relationship of exposure factors on the outcome using single nucleotide polymorphisms (SNPs) as instrumental variables (IVs) [2]. Previous MR studies have examined the relationship between COVID-19 and AD using e genome-wide association study (GWAS) datasets, but their results have been inconsistent. The study by Zhang et al. showed susceptibility and hospitalization of COVID-19 (R5, January 18, 2021) were associated with a higher risk of AD [2]. Baranova et al. found genetic liabilities to hospitalized COVID-19 and critical COVID-19 (R6, June 15, 2021) were associated with an increased risk for AD [3]. Here, we aimed to reassess the causal association between COVID-19 phenotype and AD risk via an updated MR study.

The study utilized the most up-to-date summary-level data for the COVID-19 phenotype, sourced from the COVID-19 Host Genetics Initiative (version R7, updated as of April 8, 2022). The data was divided into three sections, namely COVID-19 susceptibility (consisting of 159,840 cases compared to 2,782,977 controls), COVID-19 hospitalization (44,986 cases vs. 2,356,386 controls), and COVID-19 severity (18,152 cases vs. 1,145,546 controls) [4]. We obtained summary data for AD and AD-by-proxy from a large genome-wide meta-analysis on European populations, involving 71,880 cases and 383,378 controls [5].

SNPs strongly associated with the COVID-19 phenotype were extracted (P < 5E-8, cut-off R2 < 0.001, clumping window = 10,000 kb). We used proxy SNPs (minimum LD R2 value 0.8) and excluded palindromic SNPs and those with an F-statistic < 10. Random-effects inverse-variance weighted (IVW) was used as the main result of MR analysis, and MR-Egger, weighted median, simple mode, and weighted mode methods were used as supplements to MR estimation. Cochran’s Q test, MR-Egger intercept test and MR-PRESSO methods were used to detect heterogeneity and horizontal pleiotropy. We used the PhenoScanner tool to screen for secondary phenotypes associated with risk factors and outcomes to reduce pleiotropy. The significance threshold for Bonferroni measures was corrected to P < 0.02 (0.05/3), and P values between 0.02 and 0.05 were considered nominally relevant. All analyses were performed using the TwoSampleMR package (version 0.5.6) of R software (version 4.2.1).

As illustrated in Fig. 1 and Table S1, our MR analysis did not reveal a significant causal association between COVID-19 susceptibility and AD risk (IVW: OR = 1.0252; 95% CI: 0.9948–1.0565; PIVW = 0.105). There was no evidence of heterogeneity or pleiotropy for this analysis. We observed a causal association between COVID-19 hospitalization and increased risk of AD using the IVW method (IVW: OR = 1.0163; 95% CI: 1.0045–1.0282, PIVW = 0.007; PWeighted median = 0.035; PWeighted mode = 0.039). Cochran’s Q test suggested heterogeneity (P = 0.006). Notably, random-effects IVW allowed for heterogeneity. Interestingly, no outliers were found for MR-PRESSO (P = 0.774). The causal effect between severe COVID-19 and increased risk of AD was clarified by the IVW approach (IVW: OR = 1.0092; 95% CI: 1.0014–1.0171, PIVW = 0.020; PMR Egger = 0.042; PWeighted median = 0.046). Although Cochran’s Q test demonstrated heterogeneity (P = 0.033), MR reanalysis after the removal of 2 outliers by MR-PRESSO was consistent with previous results (IVW: OR = 1.0096; 95% CI: 1.0031–1.0161; PIVW = 0.003). No potential horizontal pleiotropy was revealed by MR-Egger intercept test in any of the MR analyses, consolidating the stability and consistency of our MR estimates.

Fig. 1
figure 1

MR estimation of the COVID-19 phenotypes for AD. AD, Alzheimer’s disease; IVW, inverse-variance weighted method

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In conclusion, our study has revealed compelling evidence supporting a causal association between COVID-19 hospitalization and severity and increased risk of AD. However, there was no significant causal association between COVID-19 susceptibility and AD risk. These findings carry significant implications for preventing and managing AD in COVID-19 patients, underscoring the need for further research to better understand the mechanisms behind this correlation.