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We recently demonstrated that the frequencies of biomarker groups defined by the presence or absence of both amyloidosis (A ) and neurodegeneration (N ) changed dramatically by age in cognitively non-impaired subjects. Our present objectives were to assess the consequences of defining neurodegeneration in five different ways on the frequency of subjects classified as N , on the demographic associations with N , and on amyloidosis and neurodegeneration (A/N) biomarker group frequencies by age. This was a largely cross-sectional observational study of 1331 cognitively non-impaired subjects aged 50-89 drawn from a population-based study of cognitive ageing. We assessed demographic associations with N , and A/N biomarker group frequencies by age where A was defined by amyloid PET and N was defined in five different ways: (i) abnormal adjusted hippocampal volume alone; (ii) abnormal Alzheimer's disease signature cortical thickness alone; (iii) abnormal fluorodeoxyglucose positron emission tomography alone; (iv) abnormal adjusted hippocampal volume or abnormal fluorodeoxyglucose positron emission tomography; and (v) abnormal Alzheimer's disease signature cortical thickness or abnormal fluorodeoxyglucose positron emission tomography. For each N definition, participants were assigned to one of four biomarker groups; A-N-, A N-, A-N , or A N . The three continuous individual neurodegeneration measures were moderately correlated (rs = 0.42 to 0.54) but when classified as normal or abnormal had only weak agreement ([kappa] = 0.20 to 0.29). The adjusted hippocampal volume alone definition classified the fewest subjects as N while the Alzheimer's disease signature cortical thickness or abnormal fluorodeoxyglucose positron emission tomography definition classified the most as N . Across all N definitions, N subjects tended to be older, more often male and APOE4 carriers, and performed less well on functional status and learning and memory than N- subjects. For all definitions of neurodegeneration, (i) the frequency of A-N- was 100% at age 50 and declined monotonically thereafter; (ii) the frequency of A N- increased from age 50 to a maximum in the mid-70s and declined thereafter; and3 (iii) the frequency of A-N (suspected non-Alzheimer's pathophysiology) and of A N increased monotonically beginning in the mid-50s and mid-60s, respectively. Overall, different neurodegeneration measures provide similar but not completely redundant information. Despite quantitative differences, the overall qualitative pattern of the A-N-, A N-, A-N , and A N biomarker group frequency curves by age were similar across the five different definitions of neurodegeneration. We conclude that grouping subjects by amyloidosis and neurodegeneration status (normal/abnormal) is robust to different imaging definitions of neurodegeneration and thus is a useful way for investigators throughout the field to communicate in a common classification framework.

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