Alzheimer’s disease is the leading cause of dementia and a major contributor to disability and mortality in older adults. More than 50 million people currently live with dementia, and this number may triple by 2050 due to population aging.
Genetic factors – particularly the apolipoprotein E ε4 allele – strongly influence disease risk. However, disease progression is not determined solely by genetics: environmental and potentially modifiable factors also play a role. Studies indicate that vascular health, metabolic disorders, education level, and lifestyle can influence the likelihood of developing Alzheimer’s disease.
Β-amyloid accumulation, pathological tau changes, synaptic dysfunction, and progressive neuronal loss characterize Alzheimer’s disease. Increasing evidence suggests that neuroinflammation interacts with these processes. Chronic activation of innate immunity – particularly via microglia – may link diverse forms of damage to neurodegeneration. In this context, infections can amplify inflammatory processes in the brain.
Vaccination against varicella may reduce the risk of dementia. Although causality has not been established, potential explanations include enhancement of antiviral immune responses, suppression of viral reactivation, and immune training – all of which may influence long-term neuroinflammatory processes.
Certain microorganisms may also contribute to neurodegenerative diseases, including Porphyromonas gingivalis and some herpesviruses. Latent infections are of particular interest, as they persist long-term and may periodically reactivate, sustaining chronic inflammation.
Toxoplasma gondii is a parasite that can persist in brain tissue. Infection has been linked to neuropsychiatric disorders, including schizophrenia, as well as cognitive impairment and dementia. However, the mechanisms underlying these associations remain unclear. It is also unknown whether antimicrobial treatments targeting latent infections affect the risk of neurodegeneration.
To identify drugs associated with reduced Alzheimer’s risk, Israeli researchers analyzed electronic medical records from more than 9,000 patients with Alzheimer’s disease and over 18,000 controls. Key findings were validated using data from the large U.S. clinical database TriNetX.
Laboratory Findings in Alzheimer’s Disease
Patients with Alzheimer’s disease more frequently exhibited several laboratory abnormalities:
- low free T3 levels – below 3.5 pmol/L;
- severe vitamin D deficiency – below 10 ng/mL;
- folic acid levels that were either low – below 2.8 ng/mL – or elevated – above 17 ng/mL;
- very low ALT levels – below 8 U/L.
Association of Medications and Vaccination with Alzheimer’s Risk
Two varicella vaccines showed a strong association with reduced Alzheimer’s risk:
- recombinant vaccine – reduced risk by 84%;
- live attenuated vaccine – reduced risk by 63%.
A significant reduction was also observed in patients receiving atovaquone/proguanil, an antiprotozoal drug used for malaria prevention. This drug inhibits mitochondrial function in protozoa and disrupts folate metabolism. Alzheimer’s risk was reduced by 64%.
Validation in the TriNetX Database
Toxoplasma gondii infection was associated with a higher incidence of dementia, with a 2.43-fold increase in risk.
Independent analysis using TriNetX confirmed the initial findings: atovaquone/proguanil use was associated with reduced Alzheimer’s risk across all age groups:
- 50–59 years – 63% reduction;
- 60–69 years – 51% reduction;
- 70–79 years – 48% reduction.
The protective effects of varicella vaccination and atovaquone/proguanil did not add up. Atovaquone/proguanil was associated with reduced dementia risk only in unvaccinated individuals, whereas no effect was observed in vaccinated individuals. Conversely, varicella vaccination reduced dementia risk only in those who had not received atovaquone/proguanil.
The protective effects persisted for up to 10 years.
The interaction between latent T. gondii infection and herpesvirus reactivation may explain these findings. After primary infection, T. gondii persists in neurons in a latent state. Reactivation of viruses, including herpesviruses, may impair immune control of latent protozoal infections in the central nervous system, enhance inflammation, increase blood–brain barrier permeability, and facilitate parasite spread – ultimately contributing to neurodegeneration.
