Towards personalized vaccine repurposing for Alzheimer’s prevention: genotype-specific protective association of the shingles vaccine with odds of Alzheimer’s disease in participants of two large cohort studies

Our earlier study found that adult vaccination against shingles (herpes zoster infection caused by the reactivation of the varicella-zoster virus) was associated with significantly reduced risk of Alzheimer's disease (AD) later in life. Here, we investigated genotype-specific associations between the shingles vaccine and the odds of AD using data from the Health and Retirement Study (HRS) and the UK Biobank (UKB). This prospective case–control study included genotyped participants from the HRS (N = 9,188) and UKB (N = 66,748) cohorts, who survived beyond age 75. Multivariable logistic regression models were applied to assess associations between vaccination against shingles and later onset of AD. Vaccination status was defined as having received at least one live attenuated herpes zoster vaccine between ages 65 and 75. The outcome was AD onset after age 75. The analysis was stratified by carrier status of minor allele (A) of the SNP rs6859, a risk factor for AD located in NECTIN2 gene, which is involved in vulnerability to viral infections. Observed covariates included education, smoking, APOE4 allele counts, and (when not stratified) race and sex. Receiving the shingles vaccine between ages 65 and 75 was associated with significantly lower odds of AD onset later in life (OR = 0.55, p-value = 0.021) in an unstratified HRS sample. After stratification, the AD-protective association became stronger in carriers of the rs6859 (A) allele (OR = 0.43, p-value = 0.016), especially in females (OR = 0.28, p-value = 0.018). In non-carriers of (A) allele, the association between the shingles vaccine and AD became non-significant. Similar associations were observed in the UKB (OR = 0.53, p-value < 0.001 in an unstratified sample; OR = 0.51, p-value = 0.001 in rs6859 (A) carriers; and non-significant results in non-carriers). Vaccination against shingles received between ages 65 and 75 is associated with significantly lower odds of AD onset later in life in both HRS and UKB cohorts, especially in female carriers of the rs6859 (A) allele, a genetic risk factor for AD in NECTIN2 gene. Our results support personalized repurposing of the shingles vaccine for AD prevention.