Dementia is a growing public health concern with rising prevalence rates estimated to increase to 131 million within the next 3 decades. Accurate and early diagnosis of dementia is challenging with more than 50% of the cases undiagnosed. Dementia is associated with a wide spectrum of neurodegenerative diseases including Alzheimer's disease, Parkinson's disease dementia, vascular dementia and mild cognitive impairment. These dementias share clinical symptoms and several genetic, neurochemical and morphological factors making the distinction very challenging. Despite the genetic and clinical overlap, the specific mechanism(s) leading to the different dementia subtypes is poorly understood. Diagnosis of the different subtypes of dementia is important given differences in disease course, treatment and clinical management. There remains an urgent need to differentiate these dementias and understand the mechanisms underlying their pathogenesis. A major risk factor for dementia and neurodegeneration is diabetes, a chronic metabolic disorder characterized by insulin resistance and altered glucose metabolism. Currently, there are no disease-modifying therapies for dementia, however, increasing evidence from epidemiological studies suggest that certain nutrients that reduce the risk of diabetes may be neuroprotective. For example, consumption of fish, olive oil, fruits and green leafy vegetables commonly present in a Mediterranean diet may prevent the development of cognitive decline and dementia, however the mechanisms by which these nutrients promote brain health are not yet understood. In this study, gene expression microarray data will be analyzed using unbiased system-based pathway and network analyses, based on genetic and protein interactions, to identify common and unique mechanisms underlying the pathogenesis of dementia, determine if these mechanisms underlie the association between dementia and diabetes and determine if adherence to a Mediterranean diet may be neuroprotective.
The proposed research is expected to address the health crisis addressed by the National Alzheimer's Project Act, to prevent Alzheimer's disease and develop treatments, by increasing our understanding of the mechanisms underlying the pathogenesis of dementias. An integrative system-based approach using transcriptomic and network analysis will be used to unveil the molecular underpinnings of dementia subtypes (including Alzheimer's disease, Parkinson's disease dementia, mild cognitive impairment and vascular dementia) and type II diabetes, the largest risk factor for dementia. These studies are expected to unveil disease mechanisms associated with dementia, potential therapeutic targets and possible lifestyle choice that would reduce the risk of dementia.
