Aaron Carroll talks with Dr. Bruce Lamb and Dr. Alan Palkowitz about Alzheimer’s disease. They discuss how they’re combining their different backgrounds and strengths – basic science in university research for Lamb and drug discovery in the pharmaceutical industry for Palkowitz – as they work to develop potential treatments for Alzheimer’s disease.
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IU School of Medicine is leading Indiana University’s first grand challenge, the Precision Health Initiative, with bold goals to cure multiple myeloma, triple negative breast cancer and childhood sarcoma and prevent type 2 diabetes and Alzheimer’s disease.
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Alzheimer’s disease is no stranger in the news cycle. The latest headlines are dedicated to a new study on how the brain keeps itself clean, a process which scientists have long suspected to be involved in the disease. Let’s take a look.
Congratulations, media! You succeeded. You even managed to panic my wife. Here’s the abstract (highlighting mine):
Background and Purpose—Sugar- and artificially-sweetened beverage intake have been linked to cardiometabolic risk factors, which increase the risk of cerebrovascular disease and dementia. We examined whether sugar- or artificially sweetened beverage consumption was associated with the prospective risks of incident stroke or dementia in the community-based Framingham Heart Study Offspring cohort.
Methods—We studied 2888 participants aged >45 years for incident stroke (mean age 62 [SD, 9] years; 45% men) and 1484 participants aged >60 years for incident dementia (mean age 69 [SD, 6] years; 46% men). Beverage intake was quantified using a food-frequency questionnaire at cohort examinations 5 (1991–1995), 6 (1995–1998), and 7 (1998–2001). We quantified recent consumption at examination 7 and cumulative consumption by averaging across examinations. Surveillance for incident events commenced at examination 7 and continued for 10 years. We observed 97 cases of incident stroke (82 ischemic) and 81 cases of incident dementia (63 consistent with Alzheimer’s disease).
This study used the Framingham Heart Study Offspring cohort, which began in 1971. The 10-year incidence of stroke and dementia began in 1998-2001. They excluded people with significant disease before the start of the monitoring period.
Did the participants differ by race or ethnicity? I have no idea. I do know, however, that the authors write about the “absence of ethnic minorities, which limits the generalizability of our findings to populations of non-European decent.” Was that in the coverage you read?
Did they differ by socioeconomic status? No idea. Did they abuse drugs? Work or retire? Live alone or with someone? Have a family history of disease? No idea.
Did they acknowledge that different artificial sweeteners are different molecules with likely different effects or implications? No.
Were there multiple comparisons, meaning some results might be due to chance? Yep. Did they rely on self-report, which might mean recall bias comes into play? Yep.
Was this an observational study? Of course.
Was all of that in the coverage you read?
The study reported the hazard ratios for the Model 2 (which adjusted for demographics, diet, physical activity, and smoking, but still missed a lot, noted above). There was a Model 3, which also accounted for various cardiometabolic factors, but the results weren’t as dramatic. Anyway, in Model 2, compared to drinking no diet soda at all, those who drank at least one a day had HR 2.96 for ischemic stroke and HR 2.89 Alzheimer’s dementia.
Reported in the small text under table 2 is that in Model 2, for this result, there were a total of 58 ischemic strokes in 2137 participants. So… it was rare. For Model 2, there were 47 diagnoses of Alzheimer’s Disease for 1087 participants. Again, pretty rare. (And that is if I’m reading it correctly. It says N/events, and I think they may have meant events/N).
I have pored through the paper and the data supplement, and I can’t find the actual rates of disease reported for each group. I don’t know how they differed.
This type of study, and any discussion of its meaning, would be full of caveats.
It’s an observational study, and it cannot show causation. It’s a well-known and limited dataset, which almost entirely lacks minority participation. They could control for some things, but many other (and important) factors couldn’t be accounted for. There were multiple measurements, and the analysis did not adjust for them. There are other studies which show different findings. The overall rates of dementia and stroke were low in this study, and therefore the scary relative differences aren’t likely as scary in terms of absolute differences. Those absolute rates weren’t clearly reported. There’s also no evidence that changing your behavior with respect to drinking diet soda will change any of these outcomes at all.
I dragged myself out of bed this morning for day 59 of P90X3, and when I got back upstairs, I found my wife in a panic. Evidently, she had seen stories like this on Facebook:
Popular sleep remedies and hayfever pills ‘increase risk of Alzheimer’s by more than 50%’
Sleep remedies, hayfever pills and anti-depressants are linked to dementia
The risk is greatest when high doses are taken over several years
Risk was 54 per cent higher for people taking the highest doses
Found a link between dementia and antihistamines Piriton and Benadryl
Link was found with sleep remedy Nytol and anti-depressant Doxepin
Also found with Nytol and Ditropan – treatment for an overactive bladder
Since she takes Benadryl regularly to help her sleep, she was now convinced that she was doomed to Alzheimer’s. My initial impulse was to roll my eyes, but I stopped because I want to remain married. Instead, I pulled up the study itself. It’s in JAMA Internal Medicine, “Cumulative Use of Strong Anticholinergics and Incident Dementia: A Prospective Cohort Study“:
Importance Many medications have anticholinergic effects. In general, anticholinergic-induced cognitive impairment is considered reversible on discontinuation of anticholinergic therapy. However, a few studies suggest that anticholinergics may be associated with an increased risk for dementia.
Objective To examine whether cumulative anticholinergic use is associated with a higher risk for incident dementia.
Design, Setting, and Participants Prospective population-based cohort study using data from the Adult Changes in Thought study in Group Health, an integrated health care delivery system in Seattle, Washington. We included 3434 participants 65 years or older with no dementia at study entry. Initial recruitment occurred from 1994 through 1996 and from 2000 through 2003. Beginning in 2004, continuous replacement for deaths occurred. All participants were followed up every 2 years. Data through September 30, 2012, were included in these analyses.
Exposures Computerized pharmacy dispensing data were used to ascertain cumulative anticholinergic exposure, which was defined as the total standardized daily doses (TSDDs) dispensed in the past 10 years. The most recent 12 months of use was excluded to avoid use related to prodromal symptoms. Cumulative exposure was updated as participants were followed up over time.
Main Outcomes and Measures Incident dementia and Alzheimer disease using standard diagnostic criteria. Statistical analysis used Cox proportional hazards regression models adjusted for demographic characteristics, health behaviors, and health status, including comorbidities.
Researchers followed more than 3400 participants who were 65 years of age or older for an average of 7 years. They were interested in seeing if the use of anticholinergic drugs, especially really chronic use, was associated with an increased risk of dementia or Alzheimer’s. The top line results were that those who used anticholinergic drugs had a significantly increased risk (hazard ratio 1.54) of dementia if they had at least 1095 standard daily doses of these drugs. That’s where the “more than 50% increased risk” comes from.
But let’s unpack. That’s a relative risk increase. What’s the actual increase? That’s hard to tease out, because they don’t report the actual rates of Alzheimer’s or dementia in the two groups, only the number of incidents per person years of follow up. For instance, you can tell from Table 3 that in the high users of these drugs, there were 184 cases of dementia for 4022 person years of follow up (or 0.46 cases per 10 person years) versus 136 cases per 5618 person years of follow-up in users who never used the drugs (or 0.24 cases per 10 person years). But that’s before adjustment.
These drugs are also all not the same. Here’s the full list of drugs:
There are a LOT of drugs there, and they’re not all the same. Some are for serious problems! In fact, more than half of the people in the trial who were high users of anticholinergics were on antidepressants (not benadryl).
This is also a cohort study. It’s possible that people who took the drugs needed them for issues that made them more predisposed to dementia than the drugs causing dementia. We can’t establish causality here.
You also can’t forget that these were all people over age 65. That’s a very different population than 40-year-old women, which is what my wife and many of her friends on Facebook were considering.
But that’s not even what I want to stress the most. There are tradeoffs here. I imagine that many of the people in this study were taking antidepressants because they were depressed. I hope they were receiving a benefit from it. Some are for bladder control issues. I imagine the drugs benefit those people, too. And a good discussion to have with a patient would be whether the benefits received from these drugs outweighs the potential small increase in risk of dementia over the next ten years. I imagine many would choose to take the drugs.
I was diagnosed with ulcerative colitis about 20 years ago. At various times in my life, it’s been absolutely terrible. The negative impact on my quality of life was massive. About 5-6 years ago, I began to take a new drug. New for me, at least – it’s old, generic, and dirt cheap. It also carries with it a potential small increase in the risk of bone marrow toxicity. When I started the drug, my wife was panicked about this, even though I tried to explain that the risk was very small. I have to have my blood drawn quarterly to monitor things.
Years later, and still on the drug, I’m in remission. You’d never know I have ulcerative colitis. Words cannot adequately describe the massive, huge increase in my quality of life that this has given me. I’d pay almost anything for this drug (which is worth another post), and there is absolutely, positively no question that – for me – the benefits I receive outweigh the risks.
But if you only focused on the potential harms, then you’d never consider therapy. And I’d have totally missed out.
We shouldn’t ignore harms. I bring them up all the time on this blog and elsewhere. But you shouldn’t ignore the benefits, either. Both are necessary to make informed medical decisions.
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11/09/2020
Tiffany Doherty
