PROJECT SUMMARY/ABSTRACT This is a K23 career development award application for Dr. Neal Parikh, a neurologist and junior investigator pursuing patient-oriented research on the contribution of liver fibrosis to cognitive impairment and dementia. Dr. Parikh seeks to develop expertise in two key content areas: 1) cognitive impairment and Alzheimer’s disease and related dementias (ADRD), with a focus on neuroimaging correlates of ADRD and mechanisms of cognitive impairment, and 2) chronic liver disease hepatology with a focus on liver fibrosis and biomarkers. He also seeks to develop advanced skills in study design and statistical methods specific to the study of ADRD. Dr. Parikh has assembled a mentoring team led by Dr. Costantino Iadecola, a neurologist with expertise in the links between systemic factors and cognition, in addition to three co-mentors: Dr. David E. Cohen, a hepatologist with expertise in chronic liver disease and liver metabolism, Dr. Mony de Leon, an investigator with expertise in ADRD neuroimaging, and Dr. Rebecca Gottesman, a neurologist with expertise in ADRD epidemiology. Based on emerging evidence and his preliminary data, Dr. Parikh’s central hypothesis is that liver fibrosis is independently associated with cognitive impairment, dementia, and related neuroimaging markers. Dr. Parikh will test this hypothesis in three specific aims. Specific Aim 1 will test the hypothesis that liver fibrosis is associated with cognitive impairment, incident dementia risk, and related imaging markers at the population level among 500,000 participants in the United Kingdom Biobank prospective cohort study. Specific Aim 2 will test the hypothesis that liver fibrosis is associated with cortical β-amyloid deposition on florbetapir position emission tomography (PET) imaging in a diverse, multi-center cohort of 346 nondemented participants in an Atherosclerosis Risk in Communities-PET ancillary study. Specific Aim 3 will characterize the prevalence, causes, and impact of subclinical liver fibrosis in a prospectively enrolled cohort of 120 patients with cognitive impairment and dementia. The proposed aims will use multiple liver fibrosis markers and complementary cognitive endpoints, spanning neuropsychological testing, adjudicated incident dementia outcomes, and neuroimaging markers including white matter hyperintensity volume and cortical β-amyloid burden. The proposed research is significant because it seeks to establish a novel risk factor for cognitive impairment and dementia, thus raising the possibility of new liver-targeted preventive and therapeutic strategies in ADRD and cognitive impairment broadly. The proposed research is innovative because it seeks to expand the paradigm of multi-etiology cognitive impairment and dementia by establishing a role for liver fibrosis in cognition beyond hepatic encephalopathy. Further, this work will bridge hepatology and neurology to address the burden of neurological disease by adapting contemporary an...