“If you ask people whether Alzheimer’s is a brain disease, the intuitive answer would be, of course, ‘Yes,’” César Cunha, a doctoral student at the University of Copenhagen, said. “After all, the final pathology we see is indeed in the brain. But a disease can appear in one place and begin somewhere else.”
In February, Cunha and his colleagues published a large study (still in preprint stage and awaiting peer review at the time of publication) that does not claim that Alzheimer’s is not a brain disease, but rather raises an intriguing possibility: At least in some patients, the pathological process leading to the disease begins entirely outside the brain.
Other researchers agree that the subject needs to be viewed through a broader lens.
“As neuroscientists, we tend to be very brain-centric, but this study really shines a spotlight on the fact that the brain is not disconnected from the rest of the body, and when changes happen in the rest of the body, it affects how the brain functions,” Donna Wilcock, professor of neurology at Indiana University and editor-in-chief of Alzheimer’s and Dementia, told New Scientist.
“Even though Alzheimer’s is a brain disease, we need to think about the whole body when we think about how it begins,” she said.
This debate matters because it goes far beyond terminology. Alzheimer’s disease is a progressive condition that gradually damages nerve cells in the brain, and it is the most common cause of dementia. In its early stages, it primarily affects memory, but as it progresses, it can impair orientation, language, judgment, and the ability to carry out daily tasks.
The brains of Alzheimer’s patients typically display two key hallmarks: beta-amyloid—sticky protein fragments that clump together and form deposits between nerve cells—and tangles of another protein, tau, inside the cells. Because these changes are found in the brain—and because the disease was first identified in 1906 by German physician and researcher Alois Alzheimer during a post-mortem examination—most research in the field over the past century has focused on what happens inside the skull.
This perspective gained strong support in 1992, when John Hardy and Gerald Higgins proposed the “amyloid cascade hypothesis.” Based on the hypothesis, the accumulation of beta-amyloid is the initiating event in Alzheimer’s disease, with “plaques” forming between the nerve cells; next, tau proteins accumulate inside the cells; and then communication between neurons is disrupted, leading to cell death and cognitive decline.
Ever since, the majority of drug-development efforts for Alzheimer’s have targeted the removal of amyloid deposits from the brain. However, even when these drugs effectively reduce the plagues, the clinical improvement in patients remains very limited. At best, they only slow the rate of decline—they don’t halt the progression of the disease, and are certainly not a cure.
This is why more and more researchers are looking beyond the brain and asking what sets this pathological chain in motion in the first place.
A Genetic Clue from Obesity and Diabetes
When Cunha began his research on Alzheimer’s disease, he did not expect his work to challenge long-held assumptions about the condition. In his initial study, he sought to understand what occurs long before any symptoms appear—that preclinical period when the disease is not yet diagnosed but the processes leading to it may already be underway.
César Cunha, a doctoral student at the University of Copenhagen, researches factors other than the brain in Alzheimer's disease. (Courtesy of César Cunha)
He chose to focus on obesity and type 2 diabetes for a simple reason: A growing body of evidence had already linked these conditions, along with high blood pressure and cardiovascular disease, to an elevated risk of dementia. So he and his colleagues posed a genetic question: Could they identify regions of the genome associated with higher risks of obesity and diabetes as well as Alzheimer’s disease? If so, these regions might point to a shared biological mechanism that kicks in early, well before the disease manifests in the brain.
In this study, they did not try to map the entire genetics of Alzheimer’s. Instead, they focused specifically on the overlap: genomic regions associated with both Alzheimer’s and obesity or diabetes. They identified 35 candidate genes across seven shared genomic regions.
The next step was to examine where in the body those genes are active. If these genes were primarily active in the brain, it would reinforce the conventional view. But if they turned out to be active in other organs, it would suggest the disease may originate along a broader pathway.
This is where Cunha encountered the surprising graph. “When I checked where the genes were active,” he recalled, “I kept looking at one graph and saying to myself: This doesn’t make sense—the expression of these genes in the brain is extremely low.” At first, he thought this might be unique to the small subset of genes that overlapped with Alzheimer’s, obesity, and diabetes. But the deeper he dug, the clearer it became that the pattern was more widespread.
To date, more than 90 genomic regions associated with Alzheimer’s risk have been identified. Cunha’s first study dealt with only a small subset—those that also overlapped with obesity and diabetes—but as he looked further, he found the same pattern held more broadly: for many of the genes linked to Alzheimer’s, the strongest expression signals appeared not in the brain, but in other tissues throughout the body.
With this finding, Cunha set out to explore in which tissues and immune cells the genetic risk signals for the disease actually appear.
What the New Study Found
The new study drew on an exceptionally large dataset from the European Alzheimer and Dementia Biobank, encompassing nearly 86,000 Alzheimer’s patients and close to half a million control subjects. Cunha and his colleagues combined this genetic data with maps showing where different genes are active across tissues and specific cell types.“What interested us was not only which regions of the genome are linked to the disease, but where in the body those signals are activated,” he said. To explore this, the team applied several independent computational methods, each tackling the task from a different angle. They later validated their findings with yet an additional tool that produced similar results.
The study analyzed genetic data from nearly 86,000 Alzheimer’s patients and almost 500,000 control subjects in the European Alzheimer and Dementia Biobank. Shutterstock
For Cunha and his team, it was important to conduct research without assuming the disease starts in the brain. “It’s like working with a clean slate,” he said. It was also important to base the work on human data, rather than on mice. “Mice are a limited model for Alzheimer’s,” he said, in part because they do not naturally develop the disease as it appears in humans.
And, focusing on genetics has a distinct advantage. “If you examine the brains of people who died from the disease, you see only the final stage of the disease,” he explained. “But when you look at genetics—it’s there from birth. So if you want to understand what might precede the disease and perhaps even drive it, genes can be a better window than looking at a brain that has already been severely damaged at the final stage.”
The main findings were consistent across analyses. Within the brain, the problematic genes were active primarily in microglia—the brain’s local immune cells. Far stronger signals, however, were detected outside the brain: in the lungs, the digestive system, white blood cells, bone marrow, pancreas, and liver.
This is a key takeaway. For years, microglia have been a major focus in Alzheimer’s research, but when Cunha compared them to immune cells elsewhere in the body, he found that the strongest signals appear in those peripheral cells.
In other words, while the brain is still part of the story, the genetic risk map—if we look at it as a clue to where the disease may originate—points primarily to the body’s boundaries with the outside world. Cunha repeatedly uses the term “barrier tissues”—tissues that are in constant contact with the external environment and filter what enters the body.
The lungs, for example, constantly encounter air, particles, viruses, and bacteria. “The lungs are the first immunological barrier these viruses encounter when they enter the body,” he said. Similarly, the gut encounters food, toxins, and gut bacteria. The skin, too, is a first line of defense against the external world.
These are all areas where the immune system must be particularly alert. If they are where Alzheimer’s risk signals are active, one plausible explanation is that the Alzheimer’s process begins with persistent disruption in immune and inflammatory responses that eventually reach the brain.
“Beyond the barrier tissues, we found these genes active in the pancreas and liver as well, in immune system cells in the blood, and in the bone marrow, where white blood cells—the immune cells in the blood—are produced,” Cunha said.
The researchers also identified an interesting age-related pattern. When they examined gene activities in blood immune cells and other tissues over the course of a lifetime, they noticed a peak around ages 55–60. While this doesn’t prove that the disease begins at that exact time, it does spotlight a compelling window—one that overlaps with the onset of mild cognitive impairment in some people and, as explained below, the weakening of the blood-brain barrier.
How the Body ‘Talks’ to the Brain
But how exactly does inflammation in the lungs, gut, or blood end up causing memory damage in the brain? Here, Cunha was more cautious, noting that this is precisely the part that science still does not fully understand.
Exactly how inflammation in the lungs, gut, or blood potentially leads to memory damage in the brain remains unclear. Shutterstock
His central hypothesis concerns the blood-brain barrier—a protective mechanism that filters what passes from the bloodstream into brain tissue. This barrier makes it very difficult for immune cells, pathogens, and other large particles to penetrate the brain.
With aging, however, the barrier tends to weaken and may become more permeable. When that happens, chronic inflammation or overactivity of immune cells may no longer remain a “body-only” problem and can begin to affect the brain as well.
“Normally, the role of immune cells is to respond only when there is a virus or bacterium that needs to be cleared,” Cunha said. “But perhaps the genes that increase the risk of Alzheimer’s cause these immune cells to act even when they shouldn’t. And if such immune cells reach the brain after the blood-brain barrier has weakened, that could be a mechanism through which the immune system in the body causes deterioration in the brain.”
He used a simple analogy to illustrate the idea: A well-functioning home alarm system should be able to distinguish between a burglar and a cat wandering by, while a faulty alarm goes off at every little movement. Some of the genes linked to Alzheimer’s might operate in a similar way, he suggested. While they do not directly “cause” the disease, they make the immune system overly sensitive, overly activated, and overly inflammatory. When this persists for years and the blood-brain barrier weakens with age, the brain may end up paying the price.
This does not mean Alzheimer’s is an autoimmune disease, in which the immune system attacks the body’s own tissues. Cunha was wary of this definition. In his view, while the immune system undoubtedly plays an important role in the development of the disease, currently there is insufficient evidence to prove that it is an autoimmune disease such as multiple sclerosis, where the immune attack is typically faster and more aggressive.
“To call Alzheimer’s an autoimmune disease would be too far a step at this stage,” he said.
Not the First Clue
The idea that Alzheimer’s disease may not originate solely in the brain did not begin with Cunha. As early as 2002, a 25-year follow-up study of more than a thousand Japanese American men in Hawaii found that participants with lower levels of hs-CRP—a blood protein that signals inflammation—at midlife were at reduced risk of developing dementia later on.In simple terms, inflammation levels measured many years before symptoms appear were linked to future dementia risk.
Subsequent studies have shown similar associations, though they stopped short of proving direct causality. For example, a 2020 study linked bacterial markers of periodontal disease to higher risk of Alzheimer’s, particularly in older age. Periodontal disease is a common disease that can cause bad breath, bleeding gums, gum recession, and, in severe cases, tooth loss.
Another 2023 study explored the connection between gut bacteria and Alzheimer’s. Researchers identified 10 types of bacteria associated with the risk of the disease, with some linked to elevated risks and others to lower risks. In January, a major review of about 200 studies concluded that 16 different diseases—including periodontal disease, liver disease, kidney disease, and type 2 diabetes—collectively account for approximately one-third of the global burden of dementia.
Ruth Itzhaki, a renowned molecular neurobiologist and emerita professor at the University of Manchester, has been studying for decades the possible role of herpes viruses in Alzheimer’s. Itzhaki found that HSV-1—the herpes simplex virus and the same virus that causes cold sores—does not disappear from the body after the initial infection and often remains dormant for years, sometimes decades. Later in life, it may reach the brain or reactivate there, triggering inflammation and cumulative damage over time.
An illustration of Epstein-Barr virus, a member of the herpes virus family. Kateryna Kon/Shutterstock
Supporting evidence also comes from Rudolph Tanzi, a pioneering neuroscientist at Harvard Medical School. In a 2018 study, he and his colleagues showed that infecting cultured human neurons with herpes viruses was sufficient to induce rapid accumulation of amyloid-beta.
“They infected neurons with those infectious viruses, and showed that this alone was enough for the pathology seen in Alzheimer’s to develop. Nothing else is needed,” Cunha said. For him, this suggests that amyloid may not be a mere byproduct of the disease, but also part of the brain’s response to infection.
These findings align with the “microbial protection hypothesis” advanced over the past decade. It proposes that amyloid-beta may originally have been generated to help trap invaders such as viruses and bacteria, but becomes problematic when the response gets out of control and leads to excessive accumulation.
Rethinking Early Intervention
If this is true—even partially—the therapeutic implications could be profound. For decades, one of the greatest challenges in brain medicine has been the blood-brain barrier itself: The difficulty of getting drugs into brain tissue. If part of the process driving Alzheimer’s occurs “upstream,” in the immune system in the blood and in barrier tissues, we may not always have to target the brain directly in order to intervene.In Cunha’s opinion, this represents one of the most important insights from his research. Instead of concentrating exclusively on attempts to clear the disease’s end-products from the brain, it could be possible to intervene at an earlier stage: reducing unnecessary inflammatory activation of the immune system, better safeguarding the blood-brain barrier, and identifying individuals who are entering the window of vulnerability before visible brain damage appears.
This idea gains extra relevance in light of emerging vaccine studies. In February 2026, researchers at Kaiser Permanente Southern California reported that among those age 65 and older who had received two doses of vaccine to prevent shingles—a painful condition triggered by reactivation of the chickenpox virus—the cumulative risk of dementia was significantly lower than in unvaccinated patients. Over the follow-up period, dementia risk stood at 5.67 percent in the vaccinated group, compared with 10.64 percent in the control group.
Cunha urges caution here—the vaccine is not a treatment for Alzheimer’s, and the study does not prove that any single virus is the sole cause of the disease. Furthermore, even though vaccine studies, infection research, and genetic findings are increasingly pointing in the same direction, it doesn’t mean we should abandon all prior knowledge about Alzheimer’s.
The brain remains central to the disease. The ultimate damage—memory loss, impaired language, and loss of independence—all occurs in the brain. Cunha’s research does not establish direct causality, nor does it yet identify the pathological pathway, such as which cells cross the blood-brain barrier or which brain regions are impacted first.
Nevertheless, it serves a vital function: It has the potential to change the lens through which we view the disease.
“There is still a great deal we do not understand about the processes that lead to the disease, but I see our paper as a foundation that can encourage other researchers to examine these mechanisms and understand how they really work,” he said.
“It may even contribute to a paradigm shift—when researchers read it and say to themselves that there is already solid evidence pointing to the fact that the disease may not begin in the brain.”
This article was originally published by Epoch Magazine Israel.
