Cholinesterase Inhibitors Found to Slow Long-term Cognitive Decline

Cholinesterase inhibitors, a class of medicines used for treating Alzheimer’s disease, are linked to long-term reductions in cognitive decline and in the risk of death among patients, a recent study found.

In fact, the cognitive benefits and reduced mortality lasted for up to five years after diagnosis, the researchers said.

Among the three cholinesterase inhibitors evaluated, Razadyne(galantamine) had the strongest effect on cognitive decline — and was the only one that significantly reduced the risk of developing severe dementia among Alzheimer’s patients.

The study was among the first to investigate the effects of cholinesterase inhibitors on cognition and to evaluate the therapies’ overall long-term impact, according to investigators.

“Our results provide strong support for current recommendations to treat people with Alzheimer’s disease with cholinesterase inhibitors, but also shows that the therapeutic effect lasts for a long time,” Maria Eriksdotter, MD, PhD, the study’s lead investigator and a professor at the Karolinska Institutet, in Sweden, said in a press release.

The study, “Long Term Effects of Cholinesterase Inhibitors on Cognitive Decline and Mortality,” appeared in the journal Neurology.

Alzheimer’s patients have lower levels of acetylcholine, a chemical messenger — or neurotransmitter — that transmits signals between nerve cells in the brain. Acetylcholine also is involved in cognitive functions such as memory, attention, and concentration. Cholinesterase inhibitors boost acetylcholine levels by blocking the enzyme acetylcholinesterase that breaks down this neurotransmitter.

Razadyne, Aricept (donepezil), and Exelon (rivastigmine) are three cholinesterase inhibitors approved by the U.S. Food and Drug Administration. All three also are approved for use in many other countries, including in Sweden, the EU, Canada, and Japan.

Now, Eriksdotter and her colleagues sought to investigate the long-term effects of these cholinesterase inhibitors on cognitive decline, the development of severe dementia, and mortality. Their target population was patients with Alzheimer’s dementia or mixed Alzheimer’s dementia. For the study, the team used data from the Swedish Dementia Registry.

Cognitive function was evaluated using the Mini-Mental State Examination (MMSE), in which a score lower than 10, on a scale from 0 to 30, indicates severe dementia. Sores between 21 and 24 indicate mild dementia.

A total of 11,652 cholinesterase inhibitor users and 5,826 non-users were included in the analysis. These individuals had a mean age of 81.2 and 62% were female.

The cholinesterase inhibitor-treated patients began taking either Aricept (62%), Razadyne (21%), or Exelon (17%) no more than three months after their dementia diagnosis, with a median interval of two days between diagnosis and the start of treatment.

At baseline, or the study’s start, the mean MMSE score was 21.2 for all patients, 22 for cholinesterase inhibitor users, and 21.9 for non-users. During the average five-year follow-up period, cholinesterase inhibitor users were found to have better MMSE scores at any visit compared with non-users.

Treatment with cholinesterase inhibitors showed an association with higher cognition at follow-up, with Razadyne presenting the largest effect size (0.18 MMSE points change). There were no significant differences among different cholinesterase inhibitors’ effects on cognition.

Of the 17,478 patients in total in the analysis, 6,055 (35%) died during the follow-up period. Cholinesterase inhibitor users had 27% lower mortality than non-users. Razadyne users had the largest decrease (29%) in mortality compared with non-users, while those on Aricept had a 22% reduction, and those taking Exelon a 14% decrease.

Among 6,802 patients with at least two MMSE measurements, 255 developed severe dementia, including 4.0% of non-users and 3.7% of cholinesterase inhibitor users. When analyzed by individual cholinesterase inhibitor, Razadyne was the only treatment to significantly decrease the risk of severe dementia, by 31%.

“Of all three drugs, galantamine [Razadyne] had the strongest effect on cognition, which may be due to its effect on nicotine receptors and its inhibiting effect on the enzyme acetylcholinesterase,”  said Hong Xu, MD, PhD, the study’s first author and a postdoctoral researcher at the Karolinska Institutet.

The researchers noted several study limitations, among them its observational nature, the assumption that patients’ treatment statuses remained consistent throughout the follow-up period, and the inclusion of patients with early and later diagnosed dementia. Other limitations were the possibility that mixed Alzheimer’s dementia patients had different treatment responses, and inconsistencies in the number of MMSE scores patients received.

Nonetheless, they believe that these data provide evidence that cholinesterase inhibitors “decrease long-term cognitive decline and risk of death and that galantamine [Razadyne] decreases the risk of severe dementia,” in Alzheimer’s patients.