Opposing effects of SARS-CoV-2/COVID-19 infection and recombinant zoster vaccination on the risk of late-onset Alzheimer disease

ImportanceMore than half a decade since the emergence of SAR-CoV-2, its broader sequelae are still poorly understood. Initial data indicate viral infections such as SARS-CoV-2 and herpes zoster negatively impact cognition, but studies examining their independent or synergistic impact on late-onset Alzheimer disease (LOAD) risk among older adults are lacking. ObjectiveTo test the hypothesis that SARS-CoV-2/COVID-19 infection and recombinant zoster vaccination are independently associated with higher and lower risk of LOAD, respectively, among older ([&ge;]65 years of age) individuals. Design, Setting, and ParticipantsA retrospective cohort of 1,480,535 patients from the US National Clinical Cohort Collaborative (N3C) COVID-19 Enclave with no diagnosis of LOAD on January 20, 2020. The follow-up period ended May 16, 2025. ExposureRecorded SARS-CoV-2 infection/COVID-19 and recombinant zoster (Shingrix) vaccination. Main Outcomes and MeasuresLate-onset Alzheimer disease incidence within the five-year follow-up period. ResultsCox proportional hazard models adjusted for age at baseline, sex, and race found that COVID-19 infection was associated with a 12% increased hazard of LOAD (HR=1.12, 95% CI: 1.09-1.15, p<0.0001). Having a Shingrix vaccine did not significantly change the hazard estimate of LOAD (HR=1.13, 95% CI: 1.10-1.16, p<0.0001). Recombinant zoster vaccination was associated with reduced hazard of LOAD in both COVID-19-absent and COVID-19-positive individuals, though the protective effect was attenuated among those with COVID-19 infection. Specifically, among individuals without documented COVID-19 infection, adjusted for age at baseline, sex, and race, Shingrix vaccination was associated with a 37% reduced hazard of LOAD (HR=0.63, 95% CI: 0.60-0.65, p<0.0001), while among COVID-19 patients, the reduction was 23% (HR=0.77, 95% CI: 0.73-0.81, p<0.0001), suggesting a significant interaction between COVID-19 infection and vaccination status on LOAD risk. Conclusions and RelevanceSARS-CoV-2/COVID-19 infection and recombinant zoster vaccination are modifiable risk factors for LOAD among older individuals, with a modestly significant interaction between the two. Recombinant zoster vaccination reduced LOAD risk regardless of sex and race, though the protection is greater in those without documented COVID-19 infection. Recombinant zoster vaccination and reduced exposure to COVID-19 infection in the later decades of life reduce the risk of developing Alzheimer disease over at least a five-year period. Key Points QuestionIs SARS-CoV-2/COVID-19 infection among older individuals associated with late-onset Alzheimer disease (LOAD), and is this risk modified by recombinant zoster vaccination? FindingsRetrospective cohort analysis of older individuals (age [&ge;]65 between January 20, 2020 and May 16, 2025; n[~]1.5 million) indicates that those with [&ge;]1 reported COVID-19 infection were at increased LOAD risk compared with those with no reported infection. Recombinant zoster vaccinated patients had decreased LOAD risk, and among those with a COVID-19 infection, the vaccination mitigated the elevated LOAD risk. MeaningRecombinant zoster vaccination reduces LOAD risk among older individuals and mitigates the COVID-19-associated LOAD risk.