Summary: A new study finds that long-term, low-dose caffeine intake may worsen neuropsychiatric symptoms linked to Alzheimer’s disease. In mouse models, caffeine increased neophobia and anxiety-like behaviors and reduced cognitive flexibility, while offering minimal benefits to learning and memory.
Source: UAB.
While memory loss is the best-known symptom of Alzheimer’s disease, neuropsychiatric symptoms often appear early and cause substantial distress for patients and caregivers. These symptoms—collectively called Behavioral and Psychological Symptoms of Dementia (BPSD)—include anxiety, apathy, depression, hallucinations, and paranoia, and they vary widely between individuals.
Caffeine has been proposed as a potential preventive strategy against dementia because it blocks adenosine receptors, which are implicated in age-related dysfunction. Some epidemiological and experimental work has suggested protective cognitive effects of caffeine in aging and Alzheimer’s contexts. However, evidence also indicates that once cognitive impairment and neuropsychiatric symptoms are present, caffeine may have adverse effects.
To explore this, researchers tested long-term, low-dose caffeine in both normal aging mice and a familial Alzheimer’s disease model (3xTg-AD). “These mice reproduce many features of early-onset Alzheimer’s in humans: they exhibit cognitive deficits as well as a range of BPSD-like behaviors, making them a valuable model to study how caffeine influences both cognitive and neuropsychiatric symptoms,” says Raquel Baeta-Corral, first author of the study.
The team simulated chronic oral intake of a low caffeine dose (0.3 mg/mL in drinking water), roughly equivalent to three cups of coffee for a human, administered from adulthood (6 months) until middle age (13 months). “We previously identified the adenosine A1 receptor as a mediator of some adverse caffeine effects. This study examines long-term, low-level exposure across disease onset and progression in both Alzheimer’s-model and healthy, age-matched mice,” explains Dr. Björn Johansson of Karolinska Institutet and Karolinska University Hospital.
The study found that chronic low-dose caffeine significantly altered behavior across most variables measured. The strongest effects were seen for neophobia (fear or avoidance of novel stimuli), anxiety-related behaviors, emotional reactivity, and cognitive flexibility. In 3xTg-AD mice, these changes aggravated their existing BPSD-like profile. Increased neophobia and anxiety made tasks that depend on exploration and adaptive behavior more difficult for Alzheimer’s-model mice.
Learning and memory in the 3xTg-AD mice showed little overall improvement from caffeine; any modest benefits only emerged after detailed analysis of specific navigation and search strategies. In other words, caffeine did not meaningfully counteract the cognitive deficits when it simultaneously heightened anxiety and behavioral rigidity. In non-transgenic (NTg) aging mice, caffeine also produced a worsened pattern in some measures, which reduced differences between the two groups in certain behavioral tests.
Additional findings included genotype-specific effects on circadian motor activity that were amplified by caffeine, and selective modulation of emotional and risk-assessment behaviors in NTg mice. Caffeine also normalized splenomegaly observed in 3xTg-AD animals—a sign of altered peripheral immune status—and tended to raise corticosterone levels, suggesting physiological stress responses may be affected by chronic caffeine intake.
“Our observations of adverse caffeine effects in an Alzheimer’s disease model, together with prior clinical reports, indicate that caffeine can exacerbate BPSD-like symptoms and thereby interfere with any potential cognitive benefits,” says Dr. Lydia Giménez-Llort, lead researcher and Director of the Medical Psychology Unit at the UAB Institute of Neuroscience. “These findings are important to consider when evaluating coffee-derived treatments or recommending caffeine use for people at risk of, or living with, dementia.”
This research is part of the PhD work of Raquel Baeta-Corral and was led by Lydia Giménez-Llort (Medical Psychology Unit, Department of Psychiatry and Legal Medicine; UAB Institute of Neuroscience) in collaboration with Dr. Björn Johansson (Department of Molecular Medicine and Surgery and Department of Geriatrics, Karolinska Institutet and Karolinska University Hospital). The project was carried out within the framework of a Health Research Fund initiative from the Institute of Health Carlos III.
Source: Lydia Giménez-Llort – UAB
Publisher: NeuroscienceNews
Image Source: NeuroscienceNews.com image is in the public domain.
Original Research: “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” by Raquel Baeta-Corral, Björn Johansson, and Lydia Giménez-Llort, published in Frontiers in Pharmacology (2018).
UAB. “Long-Term Caffeine Use Worsens Alzheimer’s Symptoms.” NeuroscienceNews, April 1, 2018.
Abstract
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
Objective: To evaluate long-term behavioral effects of a low caffeine dose in male 3xTg-AD mice and age-matched non-transgenic (NTg) mice, assessing both cognitive function and Behavioral and Psychological Symptoms of Dementia (BPSD)-like behaviors.
Methods: Animals received caffeine (0.3 mg/mL in drinking water) or plain water from 6 to 13 months of age, covering the onset and progression of cognitive impairment in the 3xTg-AD model. This dosing produces plasma caffeine levels in mice comparable to those found in human coffee drinkers.
Results: Caffeine produced significant effects on most behavioral measures, particularly neophobia, anxiety-like behaviors, emotionality, and cognitive flexibility. The 3xTg-AD and NTg mice responded differently to caffeine: in 3xTg-AD mice, increased neophobia and anxiety exacerbated their BPSD-like profile and limited cognitive benefits. Caffeine also affected circadian motor activity, modulated emotional and risk-assessment behaviors in NTg mice, normalized splenomegaly in 3xTg-AD animals, and tended to elevate corticosterone.
Conclusion: Long-term low-dose caffeine exacerbates neuropsychiatric-like symptoms in an Alzheimer’s disease mouse model and alters behavior in normally aging mice. These adverse effects may counteract potential cognitive benefits and should be considered when investigating caffeine-based approaches for dementia prevention or treatment.