When patients tell me they’re afraid of getting dementia, I don’t hand them a book of crossword puzzles and wish them luck. I ask three questions. What are you willing to do? What risks will you accept? How much not-knowing can you live with?
For the man who watched his father stop recognizing his own children, surrogate endpoints are not an academic debate. He wants to know what to do Monday morning.
Medicine’s official answer is to wait for the randomized trials. I believe in randomized trials. But I also think patients deserve a straighter conversation about the imperfect options we have while we wait.
In October, University College London announced AD-SMART, an adaptive trial that plans to enroll about 1,200 people with symptomatic Alzheimer’s disease. It starts with two cheap generics: metformin, the diabetes workhorse, and atomoxetine (Strattera), an ADHD drug. Each is tested on its own against a shared placebo group. Nobody is mixing a cocktail. Drugs that fail get dropped, and new candidates get added. Investigators will follow cognition, daily function, and neuropsychiatric symptoms for 18 months, with the first drugs expected to be evaluated around 2030.
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That announcement deserved more attention than it got. After decades of pouring money and talent into amyloid, someone is finally asking whether metabolism and norepinephrine matter at the bedside. Metformin goes after cellular energy and insulin pathways. Atomoxetine works on the locus coeruleus, norepinephrine, and possibly neuroinflammation. Neither drug has to win for the trial to be worth running. It’s just good to see the field look up from its favorite target.
The early data are hints, not answers. In a randomized pilot of 80 overweight adults with amnestic mild cognitive impairment, metformin beat placebo on one verbal-recall test after a year, but not on the broader ADAS-Cog. Long-term follow-up of the Diabetes Prevention Program found roughly 60 percent lower adjusted odds of dementia in people originally randomized to metformin. But there weren’t many dementia cases, the confidence intervals were wide, and the overall pattern of cognitive impairment didn’t differ significantly between groups.
Atomoxetine’s pilot was smaller still: 39 people with biomarker-positive mild cognitive impairment. Spinal fluid tau markers moved in the right direction. Cognition didn’t budge. Nobody can give you a reliable absolute risk reduction or number needed to treat for preventing dementia with either drug. And AD-SMART is a treatment trial in people who already have symptoms. It is not a prevention trial in healthy adults.
So what do I actually tell people?
The unglamorous stuff comes first. Move. Control your blood pressure. Deal with diabetes and smoking. Get your hearing and vision fixed. Stay connected to other people. Eat like a reasonable adult. Have a reason to get out of bed. I’ve come to believe that purpose is a health behavior, even if it’s annoyingly hard to randomize.
That advice has more behind it than good intentions. In the U.S. POINTER trial, published in 2025, 2,111 older adults at risk for decline were randomized to a structured or a self-guided lifestyle program. Both groups improved on cognitive testing. The structured group did slightly better, by about 0.03 standard deviations per year. That’s small, and it isn’t proof of fewer dementia diagnoses. But it’s a real randomized signal for something patients can start today.
Then we talk about infection. Herpes simplex and varicella-zoster live in our nerves for decades and wake up from time to time. Could repeated reactivation, and the immune response it stirs up, speed neurodegeneration in vulnerable brains? The biology is serious. The proof of cause isn’t there yet.
The shingles vaccine data are the most tantalizing. In Wales, eligibility for the old live shingles vaccine hinged on a sharp birthday cutoff, which handed researchers a natural experiment. They estimated 3.5 percentage points fewer new dementia diagnoses over seven years among the vaccinated, a conditional number needed to treat of about 29. That’s a big effect. But it wasn’t a randomized dementia-prevention trial. Later analyses have questioned how plausible and consistent the effect sizes are across natural experiments. And the Welsh study looked at Zostavax, not the recombinant Shingrix we use now.
I recommend Shingrix to eligible patients because it prevents shingles and its complications. Full stop. If it also delays dementia, wonderful, but that’s a possible bonus, not an indication and not a promise I make. Observational studies of Shingrix look encouraging, but they can’t give us a trustworthy number needed to treat for dementia.
Now for the part that’s uncomfortable for me.
For patients who are especially concerned about dementia, I have prescribed valacyclovir off-label after walking them through the viral hypothesis. I understand the urge to act now instead of waiting decades for certainty. But if I’m going to write about the cutting edge, I owe readers the evidence that cuts against my own practice.
In the VALAD trial, 120 adults with early symptomatic Alzheimer’s or biomarker-positive mild cognitive impairment, all seropositive for herpes simplex, were randomized to valacyclovir (target dose 4 grams a day) or placebo. At 78 weeks, cognition was worse on valacyclovir: a 3.93-point difference on the 11-item ADAS-Cog, P = .01. Daily function didn’t improve. Neither did Alzheimer imaging measures.
Does that settle whether a lower dose started before symptoms could prevent disease? No. Different patients, different stage, different question. But it means I can’t call valacyclovir proven neuroprotection. There’s no established preventive dose, no demonstrated absolute benefit, and no defensible number needed to treat. Long-term use also carries real risks, including kidney injury and neurotoxicity, especially as kidney function declines.
Being willing to take a risk doesn’t make a hunch work. If I offer something unproven, the patient needs to hear about the negative trial, the uncertain upside, the known toxicities, and the perfectly reasonable choice of not taking it at all. Better yet, we should be steering motivated patients into well-designed prevention trials.
Let me be clear about what I’m not saying. I’m not saying start atomoxetine on every sixty-five-year-old with a family history of dementia. I’m not saying put people with normal metabolism on metformin. And a positive HSV antibody is not a dementia risk test or a reason for antiviral prophylaxis. Plenty of people have one. For dementia prevention, these drugs are experimental.
What I am saying is that doctors should stop treating uncertainty as the end of the conversation. Tell patients what’s proven for its intended use, what has a modest randomized signal on cognition, what’s still a hypothesis, and what could go wrong. Ask what they’re hoping to change. Revisit the decision as the evidence comes in.
The next real advance in Alzheimer’s might be a biologic, a generic pill, a vaccine, some combination, or something nobody is studying yet. The universe hasn’t shown its hand. Until it does, here is the most honest thing I know how to say to a patient who asks me what to do: There are things worth doing now. There are promising ideas that may not pan out. I’ll help you tell the difference.
Larry Kaskel is an internist and “lipidologist in recovery” who has been practicing medicine for more than thirty-five years. He runs a concierge practice in the Chicago area and serves on the teaching faculty at the Northwestern University Feinberg School of Medicine. He is also affiliated with Northwestern Lake Forest Hospital.
Before podcasts were even a thing, Dr. Kaskel hosted Lipid Luminations on ReachMD, building a library of more than four hundred shows featuring thought leaders in cardiology, lipidology, and preventive medicine.
He is the author of Dr. Kaskel’s Living in Wellness, Volume One: Let Food Be Thy Medicine, a book that blends evidence-based medicine with practical strategies for a longer healthspan. His current work focuses on rethinking the cholesterol hypothesis and exploring the infectious roots of atherosclerosis. More information is available at larrykaskel.com.
