A Novel Therapy for the Treatment of Dementia

Risk of Alzheimer's diease (AD) is linked to a prior history of type 2 diabetes mellitus (T2DM). The biological mechanism underlying this link is not known, although metabolic disease is linked to mid-life obesity. Cerebrovascular pathology is a major contributor to age-related dementia. Although most individuals with AD have some degree of comorbid cerebrovascular pathology, individuals with a history of obesity and T2DM have substantial amounts of this pathology. In fact, the amount of hallmark AD pathology is essentially unchanged in these cases, while cerebrovascular pathology increases. As our population demographics shift towards an older average age, the potential confluence of obesity, T2DM and age-related neurological dysfunction could be a public health disaster. To investigate this problem, we created a line of knock-in mice that become rapidly obese and diabetic, and develop amyloid pathology with increasing age. The most remarkable feature of this unique mouse model (db/AD) is that it develops a striking phenotype of cerebrovascular pathology, including aneurysms and strokes, and displays a profound cognitive impairment. We believe that we have created a unique model of AD with significant cerebrovascular disease, an understudied variant with limited treatment options. The central question of this proposal is: can we take advantage of this novel model for preclinical therapeutic development? We propose to tap into our knowledge of biological processes that lie at the conflux of cerebovascular disease, obesity, and metabolic dysfunction, and take advantage of an already approved, clinically useful drug that, in theory, might alter the disease course. We hypothesize that this drug will prevent or reverse the age-related cerebrovascular pathology and cognitive dysfunction in db/AD mice. The impact of this proposal is its potential for making progress towards a therapeutic for AD with significant cerebrovascular comorbity, a neurologic disorder that is both poorly understood and with limited treatment options. By using a drug that is already approved for human use, we are closer to a clinically viable treatment strategy than if we were attempting a purely theoretical approach. A major innovative feature of this proposal is the use of a novel mouse model with unique features, combining obesity and AD, and exhibiting significant age-related cerebrovascular pathology and cognitive dysfunction. This project not only has clear implications for the prevention and treatment of age-related cerebrovascular disease, but also has the potential to advance our understanding of the major underlying causes of cerebrovascular disease as a comorbidity in the AD brain.