Is Dementia an Infectious Disease?

Pauline Anderson

March 28, 2013

New data from the Northern Manhattan Study (NOMAS) has linked exposure to viral or bacterial infections to cognitive decline.

The study used an infectious burden (IB) index that has been associated with vascular risk, suggesting that there might be some "common ground" between vascular disease and dementia, said lead author Mira Katan, MD, a research fellow at Columbia University in New York City.

"If we can prove that this is causal, which we don't do in this study, then if we can eradicate these pathogens, we might be able to reduce the risk not only for dementia but also for stroke, and that would be big," said Dr. Katan. "You would have an impact on 2 major public health burdens."

The research is published in the March 26 issue of Neurology.

Infectious Burden

NOMAS, a large, multiethnic cross-sectional study, included 1625 stroke-free participants enrolled between 1993 and 2001 (mean age, 69 years; 65% women and 58% Hispanic).

Researchers assessed cognitive status at baseline using the 30-point Mini-Mental State Examination (MMSE) score and annually using the modified Telephone Interview for Cognitive Status (TICS-m).

They also used an infectious burden (IB) index, a composite serologic measure of exposure to common pathogens. The index included measurements of bacteria (Chlamydia pneumoniae, Helicobacter pylori) and viruses (cytomegalovirus [CMV] and herpes simplex virus [HSV] types 1 and 2).

Dr. Mira Katan

The study linked a higher IB index with lower scores on the MMSE. The index was associated with greater odds of having an MMSE score of 24 or less compared with a score of more than 24 (unadjusted odds ratio [OR] per standard-deviation [SD] IB, 1.58; 95% confidence interval, 1.36 - 1.82). The association persisted after adjustment for demographic and risk factors.

In a subgroup analysis of 984 participants with available data, the researchers found that the association between the IB index and MMSE did not change after adjustment for APOE genotype.

Cognition Over Time

The study did not find an association of IB index with changes in cognition over time. "We didn't see that the higher the infectious burden the more you declined afterwards," said Dr. Katan. "There was an association with your current cognitive impairment, but we couldn't see an effect over time."

It might be that a longer follow-up — for example, 15 years — could uncover an effect, she added.

The analysis indicated that the viruses that were studied — CMV and HSV-1 and -2 — alone affect cognition, said Dr. Katan. The viral serologies burden (VSB) index was associated with an MMSE score of 24 or less compared with a score greater than 24 (adjusted OR per SD of VIB index, 1.22; P = .04) and with the TICS-m.

It's impossible to determine which of the viruses might play a more important role because the IB index is a cumulative weighted index. There could be an interaction between the viruses, said Dr. Katan.

It's also not known exactly how a virus might damage the brain, although Dr. Katan surmised that infections might trigger chronic inflammation in blood vessels, which could lead to vascular dementia. Also, a virus could have a direct neurotoxic effect; she said. However, she stressed that more basic research is needed to determine the mechanism.

In general, the study showed that the magnitude of effects of IB were greater among women, those with lower socioeconomic status, and the physically inactive. The association was most prominently modified by participant's physical activity levels.

"Your exposure to infectious burden is still there, but the effect it has in the long run might be modified by exercising," said Dr. Katan.

Evidence from other studies shows that physical activity affects inflammation, she added. "If you have a higher infectious burden or have accumulated infections during your lifetime, but were exercising, it might be that you can counter this type of inflammation. So behavior could interact with your vulnerability."

She emphasized that her study does not prove a causal link and that intervention studies are needed for this.

"Revolutionize" the Field?

That's exactly what the authors of an accompanying editorial suggest. Timo E. Strandberg, MD, PhD, Department of Medicine, Geriatric Clinic, University of Helsinki, and Allison E. Aiello, PhD, Department of Epidemiology, Center for Social Epidemiology and Population Health, University of Michigan School of Public Health, Ann Arbor, said they hoped the current study might spur a randomized controlled trial of valacyclovir in patients with Alzheimer's disease (AD).

Demonstrating that old-age cognitive decline, including AD, reflects slowly progressing diseases of viral etiology "would revolutionize the dementia research field (and be Nobel Prize worthy)," Dr. Strandberg and Dr. Aiello write. "However, great challenges remain."

Most of the studies to date have been cross-sectional and associative, and conflicting evidence supports different viral types in association with dementia. They also point to previous enthusiasm in the cardiac community about C pneumoniae infection as a possible cause of atherosclerosis that did not pan out in large clinical trials of antibiotics. Promising results with valacyclovir in schizophrenia, for example, suggest a trial of this drug might be in order, despite differences in these populations, they write.

"One has to start somewhere. A first step might be a randomized controlled trial in patients with AD using valacyclovir with an adequate dose (possibly 3 g) and duration (6 months or longer) to cover reactivations of herpesviridae and with careful selection of sensitive study endpoints (such as the Alzheimer Disease Assessment Scale–cognitive subscale)," they suggest.

"Currently, no antimicrobial studies in AD can be found in trial registries," they conclude. "Such a study is nevertheless worth doing, and the editorialists hope that the study by Katan et al., along with earlier pioneering work by other groups that have examined specific infectious etiologies of cognition and AD, will stimulate this endeavor."

Dr. Katan sees benefits and drawbacks to such a study. On the one hand, it might be worthwhile because valacyclovir is a well-known medication and physicians have had a lot of experience using it, "so the risks would be very low and you might have some benefit," she said.

On the other hand, testing the drug in patients who are already demented could be too late, said Dr. Katan. "If you don't see an effect, it would prompt the conclusions that there is no association, but I think you couldn't make that conclusion from such a trial because it might be that you missed it because the damage is already done."

Dr. Katan has received within the last 3 years research grants from BRAHMS Thermo Fisher Scientific, the Swiss National Sciences Foundation and the Foundation Leducq. Dr. Strandberg received grant support from the King Gustav V and Queen Victoria Foundation, the University Hospital of Oulu and the University Central Hospital of Helsinki and serves on the executive board of the European Union Geriatric Medicine Society. He has received a grant from the University Central Hospital of Helsinki for an antiviral trial. He has had various cooperation (consultations and educational) with several companies (including Astellas, Novartis, Orion, and Pfizer) in healthcare. Dr. Aiello receives support as principal investigator of several National Institutes of Health grants.

Neurology. 2013;80:1209-1215, 182-183 Abstract Editorial