Allergic Disease Linked to Increased Risk of Dementia in Largest Study to Date

Perspective from Independent Experts

“This study makes an important contribution to our understanding of the relationship between allergic diseases and dementia in midlife and older age groups,” said Zoe Arvanitakis, MD, MS, FAAN, professor of neurological sciences at Rush Medical College of Rush University and the medical director of the Rush Memory Clinic at the Rush Alzheimer’s Disease Center.

“Prior to this study, the data on this relationship have been far less convincing because of smaller sample sizes and less robust study design,” said Dr. Arvanitakis, who was not involved with the study.

“The fact that these investigators had such an enormous sample size allowed them not only to study three important allergic diseases—including asthma, which is becoming more common—but [also] to break down the risk associated with each of these three diseases, as well as separating out outcomes of Alzheimer’s disease and vascular dementia separately.”

“The sample size also allowed them to do stratified analysis to consider the effect of potentially important cofounders, such as age,” she continued. “In general, the authors used a very comprehensive approach in their analyses with sensitivity analyses and otherwise, which lends even further confidence in the validity of their results.”

Keenan Walker, PhD, director of the Multimodal Imaging of Neurodegenerative Disease Unit within the laboratory of behavioral neuroscience at the National Institute on Aging, whose research focuses on abnormal immune function and inflammation in Alzheimer’s disease and late-life cognitive decline, called the paper “the seminal study on this topic to date.”

“Given what we have seen in other epidemiological studies associating autoimmune and general inflammatory conditions with dementia risk, this has been a question that many people have been wondering about,” he said. “I study inflammation, and I often have people ask me if their allergies put them at higher risk for dementia, but I was unable to give them a good answer because of the lack of robust evidence. Since allergies and allergic conditions are likelier weaker risk factors, you need a larger population to assess the association, which is one of the key strengths of this study. And the findings seem very consistent across subgroups.”

Another strength of the study, Dr. Walker noted, is its ability to separate AD and vascular dementia into different subgroups.

“The causes of these two forms of dementia do have many similarities, but they are distinct in many ways, and this study does suggest that some of the allergic conditions may be more relevant for AD than vascular dementia, for example. This suggests the possibility that allergic conditions might be interacting with some of the molecular factors that are specific to AD, such as amyloid-beta and tau.”

There are limitations, of course.

“One important factor is that the study was done in Korea, and so we don’t know whether these results apply to other populations in the world and how well it would apply in the US population, which has different genetic composition and different environmental exposures,” Dr. Arvanitakis said. “It isn’t the kind of very large study that we could easily do in the United States because of the differences in our health care systems. We do have large population-based studies, for example, research using the Medicare claims system, but that involves people who are 65 years and older.”

One strength of the Korean study, she noted, is is that at baseline, people involved were younger (in their 40s).

What Lies Behind the Association?

The study raises many more questions, said Tharick Pascoal, MD, PhD, assistant professor of psychiatry and neurology at the University of Pittsburgh. “At the end of the day, these are phenomenological findings,” he said. “What are the mechanisms behind this association?”

He suggested three possible explanations for the association between allergic disease and dementia.

“First, it is possible that peripheral inflammation associated with a condition such as asthma or allergies can activate microglia and increase inflammation in the brain, leading to dementia,” he said.

A second possible etiology is the effects of medications. “Some studies have suggested that medications associated with these allergic diseases, such as anticholinergic medications, may also play a role in dementia,” Dr. Pascoal said. “And it’s interesting to note that the second-generation medications, which cross the blood-brain barrier less, appeared to be associated with less risk of dementia than the first-generation medications.”

Finally, Dr. Pascoal speculated that allergic diseases and dementia may have a shared underlying pathology, rather than one disease playing a role in causing another.

“What is an allergy at the end of the day but a hyper-reaction in the immune system to something that is otherwise not harmful?” he asked. “It’s also hypothesized that dysregulation in the immune system in the brain plays a key role in AD, so perhaps both of these conditions are the result of a hypersensitive immune system.”

Each of these possible mechanistic explanations has different implications for prevention and management, he said.

“If inflammation from allergic diseases activates inflammation of the brain, then this could be a modifiable risk factor, and maybe we should treat allergic disease more aggressively to mitigate the risk of dementia in the future,” Dr. Pascoal pointed out. “But if the association is a result of the medications, then you may be increasing the risk of dementia with more aggressive treatment. And if the association results from a shared feature of the immune system, then this is not modifiable—at least not with treating the allergies. This is a very good paper to suggest the right questions to ask next, but now we need more mechanistic studies, including animal model research.”

Dr. Arvanitakis noted that other studies have looked at ways in which inflammation may affect the brain more indirectly as well.

“For example, there has been some interesting research done on the relationship between chronic dental conditions, such gum inflammation, over many years and how that could be associated with dementia, and there are questions about whether that’s due to the inflammatory processes themselves or the infectious processes, because other research also suggests that chronic infections like HIV could be associated with dementia,” she said. “More recently, we have seen that other infectious etiologies, such as the virus causing COVID, may have indirect inflammatory effects on the brain as well.”

In the meantime, Dr. Walker cautioned against alarming patients about the association.

“This study is great in terms of hypothesis generation and suggesting more avenues of research, but it’s very early on in terms of connecting the dots,” he said. “Since allergies are so prevalent, we don’t want these findings to put fear in some 20 percent of the population. It should be noted that the effect sizes, though statistically significant, are small, on the order of a 10- to 20-percent increase in dementia risk. That is a meaningful finding because these diseases are so prevalent, but on an individual level, the increased risk is very small.”