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Objective:To determine prevalence of dementia-related neuropathologic changes and examine their association with dementia risk and severity in centenarians, and compare findings with nonagenarians from the same cohort.Background:Centenarians worldwide are projected to increase 50-fold by 2100 with dementia incidence estimated ~40%. Brain autopsy studies in this population are highly limited.Design/Methods:Participants were individuals who agreed to autopsy from The 90+ Study, a longitudinal study of aging. Cognitive diagnoses were assigned during a multidisciplinary conference blinded to autopsy results. Using standardized protocols, dementia-related neuropathologic changes (NCs) were assessed blinded to clinical information and dichotomized for analyses: +Alzheimer’s disease (AD) neuropathologic change (ADNC;intermediate/high), +cerebral amyloid angiopathy (moderate/severe), +arteriosclerosis (moderate/severe), +Lewy body disease (limbic/neocortical), +TDP-43 (hippocampal/cortical), +age-related tau astrogliopathy (ARTAG;present), +microinfarcts (≥2), and +hippocampal sclerosis (present). Mini-Mental State Exam (MMSE) scores nearest to death were used to examine dementia severity. Prevalence and associated odds of dementia were determined for each NC and for the presence of multiple NCs.Results:388 participants (100 centenarians and 288 nonagenarians) with completed brain autopsies were included. In centenarians, ADNC was most prevalent (75%; vs. 71% in nonagenarians), followed by arteriosclerosis (69%; vs. 55% in nonagenarians) and ARTAG (66%; vs. 60% in nonagenarians). In centenarians, arteriosclerosis (69%) and TDP-43 (39%) were significantly more prevalent compared to nonagenarians (55% and 28% respectively; P=0.01 and P=0.05 respectively). 83% centenarians had 2+NCs and number of NCs was strongly associated with dementia risk. Odds ratio increased from 2.9 (95% Confidence interval (CI):0.49–16.9) for 2NCs, to 12.7 (95%CI:2.34–68.31) for 3, and 63.8 (95%CI:8.78–463.67) for 4NCs. Number of NCs was also associated with dementia severity.Conclusions:Prevalence of dementia-related NCs is exceptionally high in centenarians and greater for arteriosclerosis and TDP-43 compared to nonagenarians. Multiple NCs are typical in centenarians and strongly associated with cognitive impairment, with risk and severity increasing with higher numbers of NCs.Disclosure: Mr. Neuville has nothing to disclose. Ms. Ho has nothing to disclose. The institution of Dr. Sajjadi has received research support from NIH. Dr. Biswas has received research support from European Union's Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie Actions' fellowship (Grant agreement number 722046). The institution of Dr. Corrada has received research support from NIH. The institution of Dr. Kawas has received research support from NIH.

Background: Limbic predominant age related TDP-43encephalopathy (LATE) is a newly proposed term to denotethe contribution of transactive response DNA-binding pro-teinof 43 kDa (TDP-43) pathology to dementia at older age. Theaim of this work was to study the role of LATE in cognitiveimpairment and its risk factors in the oldest old (those ≥90years old).Methods: 240 participants of The 90+ Study with comprehensiveclinical, neuropsychology, and neuropathology datawere included. Dementia status, clinical syndrome, andimpaired cognitive domains were determined at multidisciplinarypost-mortem case conferences blind to autopsydata. Alzheimer’s disease neuropathology (ADNP) was definedas CERAD neuritic plaque score≥2 and Braak neuro-fibrillarytangle stage≥5. We defined LATE as those with at leastamygdala and hippocampal TDP-43 pathology (stage>2). Weexplored the association of LATE and of ADNP with cognitionmeasures by logistic regression ana-lyses adjusting for age, sex,and education. We separately explored the association betweenmedical histories (as potential risk factors) and LATE andADNP as outcomes adjusting for the above covariates.