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Caffeine protects Alzheimer's mice against cognitive impairment and reduces brain beta-amyloid production


Year of Publication:
Contact PI Name:
Gary W. Arendash
Contact PI Affiliation:
Memory and Aging Research Laboratory, University of South Florida, Tampa, Florida, USA
W. Schleif, K. Rezai-Zadeh, E.K. Jackson, L.C. Zacharia, J.R. Cracchiolo, D. Shippy, J. Tan
Primary Reference (PubMED ID):
Funding Source:
Johnnie B. Byrd Alzheimer’s Center and Research Institute
Study Goal and Principal Findings:

A recent epidemiological study suggested that higher caffeine intake over decades reduces the risk of Alzheimer’s disease (AD). The present study sought to determine any long-term protective effects of dietary caffeine intake in a controlled longitudinal study involving AD transgenic mice. Caffeine (an adenosine receptor antagonist) was added to the drinking water of amyloid precursor protein, Swedish mutation (APPsw) transgenic (Tg) mice between 4 and 9 months of age, with behavioral testing done during the final 6 weeks of treatment. The average daily intake of caffeine per mouse (1.5 mg) was the human equivalent of 500 mg caffeine, the amount typically found in five cups of coffee per day. Across multiple cognitive tasks of spatial learning/reference memory, working memory, and recognition/identification, Tg mice given caffeine performed significantly better than Tg control mice and similar to nontransgenic controls. In both behaviorally-tested and aged Tg mice, long-term caffeine administration resulted in lower hippocampal -amyloid (Aβ) levels. Expression of both Presenilin 1 (PS1) and β-secretase (BACE) was reduced in caffeine-treated Tg mice, indicating decreased Aβ production as a likely mechanism of caffeine’s cognitive protection. The ability of caffeine to reduce Aβ production was confirmed in SweAPP N2a neuronal cultures, wherein concentration-dependent decreases in both Aβ1– 40 and Aβ1– 42 were observed. Although adenosine A1 or A2A receptor densities in cortex or hippocampus were not affected by caffeine treatment, brain adenosine levels in Tg mice were restored back to normal by dietary caffeine and could be involved in the cognitive protection provided by caffeine. This data demonstrate that moderate daily intake of caffeine may delay or reduce the risk of AD. 

Therapeutic Agent

Therapeutic Information:
Therapy Type:
Natural Product
Therapeutic Agent:
Therapeutic Target:
Adenosine A2A Receptor
Therapeutic Target:
Adenosine A1 Receptor

Animal Model

Model Information:
Model Type:
Strain/Genetic Background:
Model Type:
Strain/Genetic Background:
Model Type:
Strain/Genetic Background:

Experimental Design

Is the following information reported in the study?:
Power/Sample Size Calculation
Randomized into Groups
Blinded for Treatment
Blinded for Outcome Measures
Pharmacokinetic Measures
Pharmacodynamic Measures
Toxicology Measures
ADME Measures
Route of Delivery
Duration of Treatment
Frequency of Administration
Age of Animal at the Beginning of Treatment
Age of Animal at the End of Treatment
Sex as a Biological Variable
Study Balanced for Sex as a Biological Variable
Number of Premature Deaths
Number of Excluded Animals
Statistical Plan
Genetic Background
Inclusion/Exclusion Criteria Included
Conflict of Interest


Outcome Measured
Outcome Parameters
Open Field Test
Y Maze
Elevated Plus Maze
Morris Water Maze
Circular Platform
Platform Recognition
Radial Arm Water Maze
Motor Function
Balance Beam Test
String Agility Test
Brain-Buffer Insoluble beta Amyloid Peptide 40
Brain-Buffer Insoluble beta Amyloid Peptide 42
Brain-Buffer Soluble beta Amyloid Peptide 40
Brain-Buffer Soluble beta Amyloid Peptide 42
Presenilin 1 (PS1)
beta-Site Amyloid Precursor Protein Cleaving Enzyme 1 (BACE1)
Adenosine Receptor Densities
Adenosine Receptor mRNA
Body Weight