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-43 encephalopathy (LATE) is a newly proposed term to denote the contribution of transactive response DNA-binding pro-tein of 43 kDa (TDP-43) pathology to dementia at older age. The aim of this work was to study the role of LATE in cognitive impairment and its risk factors in the oldest old (those ≥ 90years old). Methods: 240 participants of The 90+ Study with comprehensive clinical, neuropsychology, and neuropathology data were included. Dementia status, clinical syndrome, and impaired cognitive domains were determined at multidisciplinary post-mortem case conferences blind to autopsy data. Alzheimer’s disease neuropathology (ADNP) was defined as CERAD neuritic plaque score≥2 and Braak neuro-fibrillary tangle stage≥5. We defined LATE as those with at least amygdala and hippocampal TDP-43 pathology (stage>2). We explored the association of LATE and of ADNP with cognition measures by logistic regression ana-lyses adjusting for age, sex, and education. We separately explored the association between medical histories (as potential risk factors) and LATE and ADNP as outcomes adjusting for the above covariates.

Introduction

The association between neuropathological changes and dementia among centenarians and nonagenarians remains unclear.

Methods

We examined brain tissue from 100 centenarians and 297 nonagenarians from The 90+ Study, a community-based longitudinal study of aging. We determined the prevalence of 10 neuropathological changes and compared their associations with dementia and cognitive performance between centenarians and nonagenarians.

Results

A total of 59% of centenarians and 47% of nonagenarians had at least four neuropathological changes. In centenarians, neuropathological changes were associated with higher odds of dementia and, compared to nonagenarians, the odds were not attenuated. For each additional neuropathological change, the Mini-Mental State Examination score was lower by 2 points for both groups.

Discussion

Neuropathological changes continue to be strongly related to dementia in centenarians, highlighting the importance of slowing or preventing the development of multiple neuropathological changes in the aging brain to maintain cognitive health.

Highlights

Individual and multiple neuropathological changes are frequent in centenarians. These neuropathological changes are strongly associated with dementia. There is no attenuation of this association with age.