October 11, 2019
Treatment with an oral anticoagulant delays memory decline and the conversion to Alzheimer disease (AD) in mice. The finding should spark future studies to see whether use of direct oral anticoagulants has therapeutic value in AD, investigators say.
Prior studies have shown that patients with AD tend to have poor cerebral circulation, and there is increasing evidence that AD is associated with a chronic procoagulant state.
In the new study, long-term anticoagulation therapy with dabigatran (Pradaxa, Boehringer Ingelheim) inhibited thrombin and abnormal deposition of fibrin in a mouse model of AD.
After receiving dabigatran for 1 year, the mice had no memory loss, and there was no reduction in cerebral circulation. Dabigatran also reduced typical AD symptoms, including cerebral inflammation, blood vessel injury, and amyloid protein plaques.
"Dr Alois Alzheimer already more than a century ago said that this disease was a disease of the blood vessels of the brain, and this was forgotten over many years," co–senior investigator Valentin Fuster, MD, PhD, director of Mount Sinai Heart in New York City, told Medscape Medical News. "We began to study this with the most modern technology in a mouse model of Alzheimer's that is very similar to humans."
The study was published online October 7 in the Journal of the American College of Cardiology.
Fuster's co–senior investigator is Marta Cortes-Canteli, PhD, Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain. Together with colleagues at the Rockefeller University in New York City and other centers, they tested the effects of dabigatran (60 mg/kg body weight over 24 hours on average) vs placebo on AD pathogenesis in a transgenic mouse model of AD (TgCRND8 AD mice) and their wild-type litter mates. The mice received dabigatran in their chow.
Treatment with dabigatran for 12 months prevented memory decline, cerebral hypoperfusion, and toxic fibrin deposition in the mice.
Dabigatran treatment also significantly reduced the extent of amyloid plaques, oligomers, phagocytic microglia, and the infiltration of T cells by 24%, 52%, 31%, and 32%, respectively. The drug also had beneficial effects on blood-brain barrier integrity.
"Frankly, it's a very fascinating finding" and may help "redirect" research into the vascular aspect of AD, said Fuster.
"Therapeutics aimed at normalizing the prothrombotic environment present in AD, in combination with other disease-modifying compounds, might be instrumental in improving AD pathogenesis," the researchers write.
"Of course, there is a significant distance between an animal model and a human, but the disease appears to be the same," Fuster said. "The next step is to begin to understand this in humans through all the new technology that we have to assess the vessels of the brain and maybe to begin already to do some studies with anticoagulation in humans. We are meeting already to discuss it," he added.
Many Unanswered Questions
Commenting on the findings for Medscape Medical News, Maria Carrillo, PhD, chief science officer for the Alzheimer's Association, said there are many unanswered questions about the use of anticoagulants as a treatment for AD and that "it has possibilities and should be explored further.
"In the bigger picture, it is exciting to see a wide variety of new avenues for Alzheimer's treatment being investigated more thoroughly," Carrillo said.
One of the limitations of the use of anticoagulation for treating AD is the increased incidence of intracranial bleeding, which the authors acknowledge, Carrillo said. "While not evident in this study, not all anticoagulant drugs are the same. Plus, we know very little about the effect of long-term anticoagulation in a frail, aging, Alzheimer's population," she noted.
"At the same time, repurposing an already-approved drug like the one tested in this study ? where we already know something about safe doses and side effects ? can mean that it moves more quickly through the testing and approval process," said Carrillo.
The study was funded in part by a proof-of-concept award from the Robertson Therapeutic Development Fund of the Rockefeller University and through grants from the National Institutes of Health. The authors and Carillo have disclosed no relevant financial relationships.