S5‐02‐04: Relationships of cerebrovascular atherosclerosis with amyloid, tau, α‐synuclein and TDP‐43 pathologies in neurodegenerative disease dementias

not available. S5-02-04 RELATIONSHIPS OF CEREBROVASCULAR ATHEROSCLEROSIS WITH AMYLOID, TAU, a-SYNUCLEIN AND TDP-43 PATHOLOGIES IN NEURODEGENERATIVE DISEASE DEMENTIAS Mark Yarchoan, Sharon X. Xie, Mitchel A. Kling, Juan B. Toledo, David A. Wolk, Edward B. Lee, Vivianna M. Van Deerlin, M.Y. Lee Virginia, John Q. Trojanowski, Steven E. Arnold, University of Pennsylvania, Philadelphia, Pennsylvania, United States. Background: Accumulating epidemiological data link atherosclerosis with Alzheimer’s disease (AD) and possibly other neurodegenerative diseases. Risk factors that are common among these include age, APOE-ε4 polymorphism, smoking, inflammation, obesity and the metabolic syndrome. Yet the nature and specificity of atherosclerotic vascular contributions to AD or other neurodegenerative diseases remain unclear. To address this, we investigated the frequency and grades of atherosclerotic plaques in the circle of Willis in AD and multiple other neurodegenerative diseases and we correlated severity ratings with the molecular pathological lesions of these diseases. Methods: Semi-quantitative data from gross and microscopic neuropathological exams in 1000 cases from the University of Pennsylvania’s Alzheimer’s Disease Center and Center for Neurodegenerative Disease Research were analyzed, including 410 with a primary diagnosis of AD, 230 with synucleinopathies (Parkinson’s disease with and without dementia, dementia with Lewy bodies, multiple system atrophies), 157 with TDP-43 proteinopathies (frontotemporal dementias, amyotrophic lateral sclerosis), 144 with tauopathies (Pick’s disease, progressive supranclear palsy, corticobasal degeneration and others), and 59 with normal aging. ANOVA, logistic and linear regression models assessed the relationships of circle of Willis atherosclerosis ratings with diagnoses and histological ratings of neurodegenerative disease lesions labeled with thioflavin-S and antibodies directed at PHFtau, a-synuclein and TDP43 in multiple cortical and subcortical brain regions. Results: Over 77% of AD subjects had grossly apparent circle of Willis atherosclerosis, a percentage that was significantly higher than normal (47%), or other neurodegenerative diseases (43-67%). Age and sex adjusted atherosclerosis ratings were highly correlated with neuritic plaque (P <0.0001) and PHFtau neurofibrillary tangle (P <0.0001) ratings in the whole sample and within individual groups. We found no such associations between atherosclerosis ratings and a-synuclein or TDP-43 lesion ratings either in the whole sample or in individual disease categories. Conclusions: These results provide further confirmation that atherosclerotic vascular disease in the circle of Willis and AD are interrelated. We also find that this association is relatively specific to AD and is not observed with other major neurodegenerative diseases or disease lesions. Our findings are consistent with a hypothesis that common etiologic or reciprocally synergistic pathophysiological mechanisms promote both atherosclerotic vascular pathology and plaque and tangle pathology. Featured Research Sessions: F5-01: Applications of Electrophysiological Methods in the Field of Alzheimer’s Disease (PIA: Electrophysiology) P725