More Evidence Anticholinergics Increase
MCI Risk

Michael Vlessides

October 13, 2020

Common anticholinergics, both over-the-counter and prescription, are tied to a significantly increased risk for mild cognitive impairment (MCI) and cognitive decline in elderly individuals with otherwise normal cognitive function, new research confirms.  

In a study of more than 700 individuals, investigators found the drugs, which include some antihypertensives, allergy medications, and antidepressants, were associated with a 47% increased risk for MCI in otherwise healthy older adults.

"What is most stunning to me is that we found these very compelling associations in a pretty healthy patient sample," study investigator Lisa Delano-Wood, PhD, told Medscape Medical News.

"Many studies have shown similar effects, but we could never be sure whether those samples were biased because participants were older and already pretty far down the road in terms of cognitive loss," added Delano-Wood, codirector of the Memory, Aging & Resilience Clinic at the University of California San Diego School of Medicine.

"Our study adds quite a bit to these previous findings because we show these negative effects in people who were generally younger and cognitively normal at baseline, but then who progressed to mild cognitive impairment, which is an important risk factor for Alzheimer's disease. We also showed that certain folks at genetic risk for Alzheimer's disease appear to be more vulnerable to the effects of these medications," she added.

The study was published online September 2 in Neurology.

Underappreciated Risk

Given the increasing prevalence of Alzheimer's disease (AD) worldwide, studies examining risk factors that may accelerate cognitive impairment in older adults are growing in importance.  

Although anticholinergics may represent one such risk factor, the long-term cognitive changes associated with their use—- particularly among older adults with no cognitive impairment — is often underappreciated by clinicians, the investigators note.

Nevertheless, data regarding the interaction between anticholinergics and cognitive impairment are beginning to emerge. Previous animal studies have demonstrated that cholinergic deprivation can promote neurodegeneration in brain regions vulnerable to AD.

As previously reported by Medscape Medical News, an observational case-control study found that use of strong anticholinergics for 3 years or more in middle-aged and older people was associated with an almost 50% increased dementia risk.

Delano-Wood had her own experience with the drugs. "Over the years, I've noticed polypharmacy in many of my cognitive dysfunction patients, and often the same medications would come up in their charts," she said.

Given these associations, as well as the premise that anticholinergics may damage vulnerable brain regions and contribute to cognitive decline, the researchers examined potential mechanisms to determine whether individuals with AD risk factors may benefit from reduced anticholinergic use.

For the longitudinal analysis, they used a series of sensitive neuropsychological diagnostics to help assess the effects of anticholinergic medications and the drugs' interaction with genetic and cerebrospinal fluid AD risk factors on the progression to mild cognitive impairment among individuals with unimpaired cognitive profiles.

The study included 688 cognitively normal participants (mean age 73.5 years; 49.6% female) from the Alzheimer's Disease Neuroimaging Initiative (ADNI). Information from the database was used to identify anticholinergic use at each participant's baseline visit.

The investigators assessed what they called anticholinergic burden using both a dichotomous score and a novel cumulative metric they developed. The cumulative burden score was based on the number, dosage, and strength of anticholinergics consumed by participants.

A series of clinical variables including depressive symptoms, vascular risk, APOE carrier status, and cerebrospinal fluid AD pathology, were assessed. The incidence of MCI was determined via neuropsychological testing.

Finally, the effects of anticholinergics on domain-specific cognitive decline were assessed using data from a battery of neuropsychological tests comprising language, attention/executive function, and memory.

The researchers used regression analyses to examine the risk for progression to MCI over 10 years, while linear mixed effects models examined 3-year rates of decline in memory, executive function, and language as a function of anticholinergic use.

Not Always a Case of Overprescribing

Results showed that 230 of the 688 participants (33%) were taking anticholinergic drugs, with an average of 4.7 anticholinergic drugs taken per person. Metoprolol, atenolol, loratadine, and bupropion were the most common.

Of the 230 individuals taking anticholinergics, 117 (51%) subsequently developed MCI, compared with 192 of the 458 who were not taking the drugs (42%). Overall, individuals taking anticholinergics demonstrated a 47% increased risk for incident MCI over a 10-year period (hazard ratio, 1.47; P =.01).

Not surprisingly, the researchers' assessment of cumulative anticholinergic burden scores revealed that greater burden was associated with an increased risk for incident MCI.

With respect to genetic risk, results showed that patients who took anticholinergics and had the APOE ε4 allele were more than twice as likely to develop incident MCI than their counterparts who took the drugs but did not have the APOE ε4 allele (HR, 2.69; P < .001).

Cerebrospinal fluid risk-interaction effects yielded similar findings. Individuals who took anticholinergics and were positive for cerebrospinal fluid biomarkers of AD pathology demonstrated a relative risk that was almost five times greater than those who consumed the drugs but did not have such biomarkers (HR, 4.89; P < .001).

Given these findings, it came as little surprise to the researchers that linear mixed effects models showed anticholinergic consumption predicted a steeper slope of decline in both memory (P = .02) and language (P = .02). Such effects, they note, were exacerbated in those with AD risk factors.

Interestingly, the researchers also found that participants were taking anticholinergic drugs at dosages much higher than the lowest effective dose recommended for older adults. Indeed, 57% of participants consumed twice the recommended dosage, while 18% were taking at least four times the recommended dosage.

"This is important because there needs to be a balance between optimizing drugs and decreasing toxicity and overall anticholinergic burden," Delano-Wood said. "What makes it even harder is that many of these anticholinergic medications can be found over-the-counter.

"So it's not always the case that physicians are overprescribing — you also have patients taking more of the drugs than is prescribed to them."

In addressing the study's limitations, Delano-Wood acknowledged that only one third of the study participants were taking anticholinergic medications, far less than the up to 70% reported in similar studies.

The study findings not only cement the link between anticholinergic consumption and progression to MCI, but also demonstrate that the cumulative burden of anticholinergic consumption may play an important role.

Delano-Wood said the study also suggests that reducing the use of anticholinergic drugs before people develop cognitive problems may be an important way to mitigate the negative consequences of these agents, particularly among those with an elevated risk of developing Alzheimer's disease.

"In my memory clinic, all patients see our geriatrician for what we call a medication reconciliation," she noted. "The geriatrician looks at all their medications, and will work with them to try other classes of medications that do not have anticholinergic effects. So it becomes a relationship with the physician to minimize anticholinergic burden."

Important but Not Novel

Commenting on the findings for Medscape Medical News, Ronald C. Petersen, MD, PhD, from the Mayo Clinic in Rochester, Minnesota, who was not involved in the study, said that while the findings are important, they do not seem particularly novel.

"The effect of anticholinergics on memory has been known for decades," said Petersen, who is a member of the American Academy of Neurology.

"Nevertheless, it's important for patients and clinicians to know that drugs with anticholinergic properties can have a deleterious effect on memory," he continued. "So if you've got a patient with a tendency for dementia and you give them a nickel's worth of an anticholinergic drug, they might become significantly impaired."

"That said, it's too early to say that these drugs actually cause dementia," Petersen added. "I'm not sure of that at all."

Delano-Wood noted that future studies are needed to determine whether stopping anticholinergic use leads to a reduced risk for MCI and AD.

"There are several de-prescribing studies ongoing right now that I think are really exciting," she said. "The idea is to see if people get better when we actually take them off these medications."

Delano-Wood and Petersen have disclosed no relevant financial relationships. The study was supported by the National Science Foundation, National Institutes of Health, Alzheimer's Disease Neuroimaging Initiative, and US Department of Defense.

Neurology. Published online September 2, 2020. Abstract

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