Show 1451: Rethinking Dementia: Is What We Believed about Alzheimer’s Wrong?

For decades, neurologists and pharmaceutical firms have been focused on amyloid plaque building up in the brains as the cause of Alzheimer disease. Drug companies have developed compounds to remove that plaque, and they have been successful. There are medicines, notably lecanemab and donanemab, that reduce the amount of amyloid plaque visible on a scan. They may also slow the rate of cognitive decline somewhat.  But they may not make a substantial difference in problems patients and their families care most about–confusion, memory loss, difficulty making decisions. Is it time for us to start rethinking dementia?

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How Should We Be Rethinking Dementia?

America is aging. Baby boomers, who make up a disproportionately large segment of the population, will soon be turning 80. That could be bad news as we imagine an enormous number of people disabled by dementia. There is a silver lining to that cloud, though. Compared to individuals born in the 1920s and 1930s, those born in the 1940s and 1950s have a lower risk overall of Alzheimer disease and other types of dementia (JAMA, May 13, 2025). Are there steps we can all take to reduce our risk of dementia even further?

The Disappointing Results of Plaque-Removing Drugs:

As we mentioned above, the FDA approved lecanemab (Leqembi) and donanemab (Kisunla) to treat Alzheimer disease (AD) because they reduce plaque in the brain. Family members may have had high hopes, but the only impact these drugs have on cognition is a slight slowing of the inexorable decline. They are, moreover, quite pricey and the scans to monitor potentially serious side effects are also expensive. Some people on these meds experience brain swelling or hemorrhage. Over the long term, they may be associated with whole brain shrinkage, although they seem to spare the hippocampus, known as the memory center. None of those reactions is desirable

What Else Can We Do to Reduce Our Risk of AD?

One approach we might consider as we start rethinking dementia is low-dose lithium. Lithium has long been used to treat bipolar disorder, but the doses used are large and can trigger adverse consequences, especially for kidney function. New research has shown that people with mild cognitive impairment, a possible precursor to AD, have low levels of lithium in their brains (Nature, Sep. 2025).  Studies in mice show that low lithium levels seem to lead to amyloid plaque and tau accumulation. These are signatures of Alzheimer disease. Can we prevent or reverse this with low-dose lithium, using a nontoxic formulation? That remains to be tested in a randomized clinical trial. Dr. Doraiswamy emphasizes that no one should be taking lithium, even at low doses, outside the context of a controlled study. Don't try this at home.

Rethinking Dementia May Mean Vaccines:

An impressive body of epidemiological evidence links vaccination against influenza or shingles to a reduced risk for dementia. A natural experiment in Wales (Nature, May 2025) and another in Australia (JAMA, June 17, 2025) have confirmed the causal connection. Vaccination against shingles significantly reduces the chance of developing AD later. However, results from a trial of an antiviral medication were presented at a recent conference. Unfortunately, the medicine was not effective in preventing AD. Consequently, this strategy may not be as promising as we would like.

People who get multiple vaccinations against the flu get a measure of protection from dementia, however (Age and Ageing, July 1, 2025). Another natural experiment in East and West Germany demonstrated that the BCG vaccine against tuberculosis unexpectedly led to "lower incidence of lymphomas and acute lymphoblastic leukemia in cohorts immunized by BCG compared to those non-immunized by this vaccine" (Frontiers in Pediatrics, July 31, 2025). There is also tantalizing evidence that people treated with BCG for bladder cancer are less likely to develop AD (PLoS One, Nov. 7, 2019).

What Is Amyloid Plaque Doing in the Brain?

Right from the start in 1906, when Dr. Alois Alzheimer described the condition, he flagged amyloid plaque in the brain as a distinctive feature. No wonder people thought of it as the cause of the disease. More recently, though, scientists have been rethinking dementia. They have found that beta amyloid has antimicrobial activity. Might the buildup of plaque indicate an infectious process? We still don’t know for sure, but it seems possible.

Rethinking Dementia and Diet:

Until now, scientists studying AD have paid very little attention to specific components of diet. They did not have much evidence that what we eat affects our risk for cognitive decline. There have been only a few large randomized clinical trials of diet. A recent trial of the MIND diet (Mediterranean-DASH Intervention for Neurodegenerative Delay [MIND] diet) was disappointing. So far, none has lasted long enough to tell whether dietary changes in midlife might help prevent dementia. That said, Dr. Doraiswamy suggests that the Mediterranean diet has some supporting evidence. After all, what is good for the heart is also good for the brain.

Physical Activity and the Risk of Dementia:

There is some evidence that aerobic exercise can help reduce your chance of an AD diagnosis. Recent research shows that people who consistently rack up 5,000 to 7,500 steps a day are much less likely to develop dementia than those who are sedentary (Nature Medicine, Nov. 3, 2025). Likewise, those who habitually walk at least 15 minutes at a time during the day appear to be somewhat protected from cognitive decline. These results are from observational studies, however. Randomized clinical trials of movement to reduce the chance of dementia have not found benefits for memory. Executive function may improve, though. Dr. Doraiswamy cautions, in addition, that we should avoid sports that increase the risk for concussion or head trauma such as boxing, mixed martial arts, football or even soccer. He generally recommends walking for seniors because it offers aerobic physical activity with minimal risk of head injury.

In fact, he suggests a walking book club would be ideal. Not only do you get the body in motion, you engage the brain and practice social connection. All of these can be helpful in keeping our brains in shape. Dr. Doraiswamy's research shows solving crossword puzzles can improve their cognitive function over the course of more than a year (International Journal of Clinical Trials, April-June 2025). This could be an enjoyable approach to rethinking dementia and its prevention.

Are There Drugs We Should Avoid?

Certain medications work by interfering with acetylcholine, a crucial neurochemical. Such anticholinergic drugs, such as many urologists prescribe to treat overactive bladder, can impair cognition. One extremely common and potent anticholinergic is readily available without a prescription. Millions of seniors take it every night in the form of Tylenol PM, Advil PM or some other PM pain reliever. Diphenhydramine (Benadryl) makes people feel sleepy, so people often swallow it thinking that getting a good night's sleep will help them stay sharp. Everyone concerned about preventing dementia should check with prescribers and pharmacists about all the drugs they take, including OTC pills. Reducing the anticholinergic burden is an important step toward protecting the brain.

This Week's Guest:

Murali Doraiswamy, MBBS, FRCP, is Professor of Psychiatry and Behavioral Sciences. He is Director of the Neurocognitive Disorders Program in the Department of Psychiatry  and a Professor in Medicine at Duke University Medical School. He is a faculty network member of the Duke Institute for Brain Sciences.

[caption id="attachment_137503" align="alignnone" width="400"] P. Murali Doraiswamy, MBBS, FRCP, Duke University[/caption]