Chronic Exposure to Caffeine Worsened Symptoms in Alzheimer’s Mouse Model

Long-term exposure to caffeine worsens Alzheimer’s disease symptoms, a new mouse study shows.

The study “Long-term Treatment with Low-Dose Caffeine Worsens BPSD-Like Profile in 3xTg-AD Mice Model of Alzheimer’s Disease and Affects Mice with Normal Aging” was published in the journal Frontiers in Pharmacology.

Alzheimer’s disease is characterized by memory problems, but also by neuropsychiatric symptoms, collectively known as Behavioral and Psychological Symptoms of Dementia (BPSD). Those symptoms may include depression, apathy, hallucinations, delusions, agitation, aggression, and sleep disturbances.

Consumption of coffee/caffeine recently has been suggested as a preventive strategy for dementia in Alzheimer’s disease and aging-related decay due to its inhibitory activity over adenosine A2A receptors, which show an abnormal expression and function in aging and related diseases.

In fact, according to researchers, “at the experimental level, long-term caffeine treatment has been demonstrated to ameliorate [improve] cognitive impairment in animal models of Alzheimer disease.”

However, recent research suggests that once the neuropsychiatric symptoms are set, caffeine may have the opposite effect.

“The mice develop Alzheimer’s disease in a very close manner to the human patients with early-onset form of the disease. They not only exhibit the typical cognitive problems but also a number of BPSD-like symptoms, so it is a valuable model to address whether the benefits of caffeine will be able to compensate its putative [presumed] negative effects”, Raquel Baeta-Corral, PhD, in a press release. Baeta-Corral, of the  Universitat Autònoma de Barcelona, is the study’s first author

“We had previously demonstrated the importance of the adenosine A1 receptor as the cause of some of caffeine’s adverse effects,” said Björn Johansson, researcher and physician at the Karolinska University Hospital.

“Now, we simulated a long oral treatment with a very low dose of caffeine (0.3 mg/mL) equivalent to three cups for a human coffee-drinker to answer a question which is relevant for patients with Alzheimer’s, but also for the aging population in general, and that in humans would take years to be solved since we should wait until the patients were aged,” he said.

Mice had a long-term (seven months) chronic exposure to low levels of caffeine starting in adulthood until middle age; these ages correspond to the onset and advanced stages of the disease, respectively. The experiments were conducted in an Alzheimer’s disease mouse model and in healthy age-matched mice.

“The low caffeine dosing used (0.3 mg/ml) was previously found to give a plasma concentration profile in mice roughly equivalent to that of a human coffee drinker,” researchers wrote.

The results showed that caffeine altered the behavior of healthy mice and worsened the neuropsychiatric symptoms, especially those related to neophobia (fear of everything new) and other anxiety-like behaviors, in mice with Alzheimer’s disease.

Learning and memory, both influenced by anxiety, showed little benefits from caffeine.

“Our observations of adverse caffeine effects in an Alzheimer´s disease model together with previous clinical observations suggest that an exacerbation of BPSD-like symptoms may partly interfere with the beneficial cognitive effects of caffeine,” researchers wrote.

“Some ways to deal with these multi-effects are to optimize the dose, to use active substances in coffee other than caffeine, and to use synthetic drugs modeled after caffeine, such as subtype-selective adenosine receptor antagonists, rather caffeine itself,” they concluded.