All logistic regression models were adjusted for age at death, gender and education. strongly associated with the presence of dementia, as was Braak staging but semi-quantitative plaque scores were not. Notably, TDP-43 pathology also correlated with dementia, while -synuclein distribution did not. In addition, hippocampal sclerosis was specific to participants with dementia and correlated with the presence of limbic TDP-43. In contrast to previous reports, we found that tau and amyloid- continue to be robust pathological correlates of dementia, even in the oldest-old. While individuals with no dementia had limited hippocampal tau and neocortical amyloid- pathology, dementia associated with an expansion in pathology, including increased neocortical tau and hippocampal amyloid- plaques, more abundant neocortical amyloid- deposition and hippocampal sclerosis with its attendant TDP-43 pathology. Keywords:Alzheimer’s, tau, amyloid, dementia, oldest-old == Introduction == Current models of Alzheimer’s disease suggest that dementia results when a neuropathological threshold is usually crossed (Vemuriet al., 2011). Several recent studies have suggested that this threshold between cognitively normal and individuals with Alzheimer’s disease narrows with age, especially the oldest-old, those aged 8590 years (Giannakopouloset al., 1994;Rileyet al., 2002;Imhofet al., 2007;Haroutunianet al., 2008;Savvaet al., 2009). As the extensive pathological build up of tau and amyloid- may precede the emergence of clinical Alzheimer’s disease by decades (Braak and Braak, 1997;Sperlinget al., 2011), the threshold of neuropathology that defines Alzheimer’s disease is usually challenging to define due to the differential effects of age, individual resilience or plasticity and other unknown factors. Since by 2050, the US populace of oldest-old living with Alzheimer’s disease is usually expected to outnumber the total number of patients with Alzheimer’s disease today (Hebertet al., Ginsenoside F3 2003), there is an urgent need to better understand the pathological correlates of dementia in the oldest-old. For these reasons, the study described here characterized the topographical spread and severity of Alzheimer’s disease and related neurodegenerative disease pathology in the 90+ Study (Kawas, 2008), a prospective longitudinal population-based study of ageing and dementia. Briefly, we show that dementia in the 90+ Study cohort associated with neocortical tau, hippocampal amyloid- plaques, more abundant neocortical amyloid- deposition and hippocampal sclerosis with TDP-43 pathology. == Materials and methods == == Study subjects == Study participants were the first 108 individuals to Rabbit Polyclonal to ANKRD1 come to autopsy from the 90+ Study, a longitudinal study of ageing and dementia in people aged 90 years. Although it is not standardized to the whole US populace, the 90+ Study is a population-based study because its cohort is composed of survivors of a study conducted in the early 1980s in a geographically defined area (The Leisure World Retirement Community). In addition, recruited participants lived at home as well as institutions, lived across the country, represent the full spectrum of health and cognitive abilities, and are representative of the oldest-old populace in Orange County, Califonia (Corradaet al., 2011). All 90+ Study participants agreed to neurological examinations by a trained physician or nurse practitioner every 6 months, including a full neuropsychological battery that incorporated the Mini-Mental State Examination. Relevant medical history, medication use and brain imaging evaluations were obtained from the participant’s physicians. Cognitive and functional abilities Ginsenoside F3 were obtained from informants in frequent contact with the participants using the Dementia Questionnaire (Kawaset al., 1994). After death, the Dementia Questionnaire was repeated to inquire about the participant’s condition after the last evaluation. The Institutional Review Board of the University of California, Irvine, approved all procedures and all participants or their surrogates gave written informed consent. After a participant’s death, all information available was reviewed and discussed during Ginsenoside F3 a multidisciplinary consensus diagnostic conference led by the 90+ Study principal investigator (C.K.). Participants were classified as either dementia or no dementia. Dementia diagnosis was established using Ginsenoside F3 Diagnostic and Statistical Manual of Mental Disorders 4th edition criteria (American Psychiatric Association, 1994). Participants with no dementia included individuals with a mild cognitive or functional impairment not severe enough for dementia. If a participant met dementia criteria, the primary and secondary aetiologies of dementia were specified using standard criteria. All cognitive.