EVALUATING THE ASSOCIATION BETWEEN MITOCHONDRIAL DYSFUNCTION AND COGNITIVE DECLINE IN ALZHEIMER'S DISEASE

Introduction Alzheimer's Disease (AD) is the 6th leading cause of death in the United States, with the current number of 5.8?million affected individuals anticipated to increase to 13.8?million by 2050 (Alzheimer's Association, 2019). As the number of older adults living with Alzheimer's rapidly increases, research continues to probe the complexities of the disease's progression. AD was originally identified by the presence of amyloid plaques and neurofibrillary tangles in brain, and most research has focused on these elements. However, targeting amyloid cascade and tau phosphorylation has not resulted in the development of drugs that have halted or reversed the cognitive decline associated with AD (Du, Wang, & Geng, 2018). AD has multiple determinants, and, in most cases, plaques and tangles may not be secondary to other underlying processes. The focus of our research is investigating the role of cellular energy dysfunction in the etiology and progression of AD. Preliminary findings from our group, Sonntag and colleagues (2017), revealed changes in energy metabolism (or bioenergetics) in the fibroblasts of 10 patients with late-onset Alzheimer's Disease, the most common form of AD, compared to 20 age-matched controls, with implications of impaired mitochondrial metabolic potential as a possible contributor to the pathophysiology of AD. The present study builds on the prior work of Sonntag et al, aiming to confirm previous findings with additional samples of fibroblasts and lymphocytes from older adults with mild to moderate Alzheimer's Disease. The cells gathered are being converted to brain cells, neurons and glia, to determine whether the abnormalities seen in peripheral lines are also seen in the brain. In collaboration with the Geriatric Psychiatry Research Program at McLean, data obtained from the collected samples will be analyzed alongside the results from brain imaging data (specifically, MRI and amyloid PET scan) and clinical measures of the participants as supporting evidence in the link between mitochondrial dysfunction and cognitive decline in AD. Methods This study aims to enroll a total of 40 subjects (ages 65 to 89): 20 control subjects and 20 subjects diagnosed with mild to moderate Alzheimer's Disease. Enrolled subjects will undergo the following scales to assess for comorbid psychiatric disorders and their severity: Montgomery-Asberg Depression Rating Scale (MADRS),Young Mania Rating Scale (YMRS), Geriatric Depression Scale (GDS) and the Mini-International Neuropsychiatric Interview (MINI). The Montreal Cognitive Assessment (MOCA) is also performed to determine study suitability. Once inclusion criteria are met for both populations, samples of skin and blood will be collected and subsequently processed to grow cell lines of fibroblasts and lymphocytes. These cells are reprogrammed to induced pluripotent stem cell lines (iPSC) and then to neuronal and glial lines. Results Though ongoing, we anticipate similar results to Sonntag et al. (2017), as genetic determinants are shared among peripheral and CNS cells. In culture, both genetic and exogenous risk factors can be studied. As a secondary result, a correlation is anticipated between the bioenergetic abnormalities observed in the cells and in the brain imaging data and clinical measures of the participants. These findings may support the association between mitochondrial dysfunction and the cognitive decline in Alzheimer's Disease among a larger sample size. Conclusions Identifying the mitochondrial dysfunction in Alzheimer's Disease not only contributes a new explanation for its complex pathophysiology, complementary to other hypotheses, but provides a new direction for the development of novel treatments to effectively target the devastating effects of cognitive decline in AD. This research was funded by: This study is funded by the Program for Neuropsychiatric Research at McLean Hospital