Avoiding a severe bout of flu in middle age may protect a person’s future brain health, according to a large population-based study. In the January 19 Neuron, researchers led by Mike Nalls at the National Institutes of Health, Bethesda, Maryland, reported that, among 450,000 people in Finland and the U.K., 12 common viral illnesses increased a person’s risk of developing any of six neurodegenerative diseases over 15 years. Pneumonia caused by the flu associated with five diseases, while viral encephalitis or meningitis posed the greatest risk for Alzheimer’s disease. The scientists suggest that vaccination against these viral illnesses might protect against neurodegenerative diseases.
- Flu-related pneumonia associated with higher risk of five neurodegenerative diseases.
- Viral encephalitis increased the risk of Alzheimer’s by 30-fold.
- Risk abated over 15 years.
“This is a very interesting and important paper that strongly supports the link posited for over 33 years … between infections, herpes simplex virus 1 (HSV1) in particular, and AD,” wrote Ruth Itzhaki of the U.K.’s University of Manchester. Oliver Goldhardt, Technical University of Munich, Germany, was in agreement. “Because of the growing evidence, the link between viruses and NDDs, in my opinion, cannot be dismissed,” he wrote (comments below).
Previous research suggested that having cold sores or genital lesions, both caused by HSV, increases a person’s risk of developing AD (Feb 2021 news; Apr 2021 conference news). Likewise, someone who caught Epstein-Barr virus (EBV), which causes mononucleosis, is a whopping 32-fold more likely to develop MS (Bjornevik et al., 2022). While the impact of COVID on NDD risk is still unknown because data are scarce and the length of follow-up short, researchers have seen that severe COVID can worsen existing neurological problems and speed cognitive decline in the year after infection (Apr 2021 conference news; Mar 2022 news). However, nobody has systematically looked for links between NDDs and all common viral infections.
Now, co-first authors Kristin Levine and Hampton Leonard have analyzed medical records from 344,000 people from the Finnish nationwide biobank, FinnGen, and 106,000 in the U.K. Biobank. All participants were of European ancestry and older than 60 at baseline. About 405,500 were healthy, while 44,500 had been diagnosed with an NDD: 11,650 with AD, 2,750 with vascular dementia, 18,700 with all-cause dementia, 7,200 with Parkinson’s disease, 840 with amyotrophic lateral sclerosis, and 3,500 with multiple sclerosis.
Levine and Leonard compared NDD diagnosis to prior hospitalization with 32 common viral illnesses, including flu, pneumonia, viral warts, chickenpox/shingles, viral encephalitis, and meningitis. Viral exposure was based on hospital billing codes, so the researchers could not say whether it was the infection or something else that sent a person to the hospital. Any one of 12 of the illnesses correlated with a higher incidence of any of the six NDDs in both databanks. Notably, most of these viral illnesses are caused by neurotropic viruses—those that are able to get into the CNS and into neurons. These include influenza viruses, HSV, the herpes zoster virus that causes chickenpox/shingles, various enteroviruses that cause meningitis, and EBV.
Which viral illness posed the greatest NDD risk? People who had had viral encephalitis were 31 times more likely to develop AD and 40 times likelier to have dementia of any kind than were people not hospitalized for infection. Likewise, AD risk jumped a whopping 62-fold after meningitis. Nalls told Alzforum that he was surprised by the strength of these associations. People who were infected with EBV were four times more likely to get MS, an eightfold lower risk than previously reported. Nalls attributes the difference to the hospital billing codes used here, versus blood testing for the virus in prior studies. “What struck us is that our results produced a similar finding even though we mined a very different type of data,” he told Alzforum.
And it was not just infections of the brain. People hospitalized for a viral intestinal infection had three to five times the risk of developing AD or vascular dementia. Viral hepatitis tripled PD risk, while herpes zoster boosted the likelihood of developing vascular dementia and MS two- to sixfold.
Of all the infections studied, flu or flu-induced pneumonia were tied to the most NDDs. People from both cohorts who had been hospitalized for flu, with or without pneumonia, were two- to sevenfold more likely to have AD, all-cause dementia, vascular dementia, PD, or ALS.
Since infections are typically acute and neurodegenerative disease can advance slowly over years or decades, the authors wondered if the risk for NDDs wanes after infection. Levine and Leonard found that it was highest the first year, then fell over 15 years. For example, hazard ratios for all-cause dementia slid from 83 within a year of viral encephalitis to 24 over the next four years, then to five by year 15 (see image below). That’s riskier than having an ApoE4 allele or a TREM2 R47H mutation. “We were surprised to see any associations after that long,” said Leonard.
Risk versus Time. After a viral infection causing warts (blue), an unspecified illness (mustard), encephalitis (lavender), pneumonia (green), flu (crimson), or flu-induced pneumonia (light blue), hazard ratios for developing all-cause dementia are highest within the first year and drop over 15 years. [Courtesy of Levine et al., Neuron, 2023.]
What does this all mean for middle-aged folks? Hugo Lövheim of Umeå University, Sweden, noted that all these cases were in people who had severe symptoms. Therefore, they didn’t represent people who rode out the flu or shingles at home. Preventing severe viral illness by getting vaccinated against the flu, pneumonia, or shingles may partially protect someone from getting an NDD, the authors suggest. Indeed, a previous analysis concluded that people who got flu or pneumonia shots were less likely to get AD than the unvaccinated (July 2020 conference news).
As for what’s next, Levine said they are running similar unbiased analyses on links between NDDs and bacterial infections, specific types of intestinal infections, and sleep disorders. Nalls said they are also looking for enough data on COVID infection and NDD diagnosis to be able to analyze.
Lavinia Alberi Auber of the Swiss Integrative Center for Human Health, Fribourg, and others have proposed a worldwide consortium to study causative links between infectious agents and NDDs in a standardized way. “We need to study the human pathobiome as seriously as we do the human genome,” Alberi Auber wrote (comment below). “We are exposed to many pathogens every day, and what makes one individual more susceptible to developing a severe or chronic infection is the host-pathogen interaction.” The researchers are seeking funding for the consortium.—Chelsea Weidman Burke
- Herpes Update—Virus Increases Dementia Risk in Sweden
- More Data on Herpes and Alzheimer’s Disease
- COVID-19 Worsens Neurological Problems, Delirium
- Mild COVID Infection Can Shrink Brain, Speed Cognitive Decline
- Could Common Vaccines Protect Against Alzheimer’s Disease?
- Bjornevik K, Cortese M, Healy BC, Kuhle J, Mina MJ, Leng Y, Elledge SJ, Niebuhr DW, Scher AI, Munger KL, Ascherio A. Longitudinal analysis reveals high prevalence of Epstein-Barr virus associated with multiple sclerosis. Science. 2022 Jan 21;375(6578):296-301. Epub 2022 Jan 13 PubMed.
- Levine KS, Leonard HL, Blauwendraat C, Iwaki H, Johnson N, Bandres-Ciga S, Ferrucci L, Faghri F, Singleton AB, Nalls MA. Virus exposure and neurodegenerative disease risk across national biobanks. Neuron. 2023 Apr 5;111(7):1086-1093.e2. Epub 2023 Jan 19 PubMed.