INTRODUCTION: Accurately assessing temporal order of cognitive decline across multiple domains is critical in Alzheimer's disease (AD). Existing literature presented controversial conclusions likely due to the use of a single cohort and different analytical strategies. METHODS: Harmonized composite cognitive measures in memory, language and executive functions from 13 cohorts in the ADSP-PHC data are used. A novel double anchoring events-based sigmoidal mixed model was developed using time to the incident of AD diagnosis as the time scale. RESULTS: Decline in memory occurred before decline in language which was followed by the decline in executive function. Throughout the entire AD continuum, APOE-ε4 non-carriers and non-Hispanic Whites showed better memory performance, respectively, in all three cognitive domains. DISCUSSION: Using harmonized data across multiple cohorts is the key to accurately characterizing the temporal order of AD biomarkers. Time to incident AD diagnosis should be used as the time scale for reproducibility purposes.

Dr. Dumitrescu reported grants from NIH during the study. Dr. Mez reported grants from NIH during the study and grants from the Department of Defense outside the submitted work. Dr. Saykin reported grants from NIH to Indiana University and support from multiple NIH grants during the conduct of the study as well as support from Avid Radiopharmaceuticals, a subsidiary of Eli Lilly (in-kind contribution of PET tracer precursor); Bayer Oncology (scientific advisory board); Eisai (scientific advisory board); Siemens Medical Solutions USA (dementia advisory board); National Heart, Lung, and Blood Institute (MESA observational study monitoring board); and Springer-Nature Publishing (editorial office support as editor-in-chief for Brain Imaging and Behavior) outside the submitted work. Dr. Hohman reported grants from NIH during the study and is a member of a scientific advisory board for Vivid Genomics outside the submitted work. Dr. Liu reported grants from NIH during the study. No other disclosures were reported.

This research was supported by U24-AG074855 (Timothy Hohman, Michael Cuccaro, A. Toga, MPI). Dr. Hohman was also supported by R01-AG079142. Dr. Dumitrescu was supported by R01-AG073439. Dr. Mukherjee was supported by R01-AG082730. Dr. Mez was supported by R01-AG061028. Dr. Saykin was supported by P30-AG010133 and R01-AG019771. Dr. Gifford was supported by R01-AG062826. Dr. Buckley was supported by R01-AG079142. Dr. Crane was supported by U01-AG0006781, U19-AG066567, and R01-AG029672.

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All contributing studies included in this work received ethical oversight from their respective institutions. This study constitutes secondary research, utilizing de-identified data obtained from primary data repositories. In accordance with NIH policy, this research does not qualify as human subject research, and therefore, obtaining consent from individual participants is not required.

I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.

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I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.

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This secondary research work utilizes de-identified data obtained from primary data repositories. The data used in this study may be available upon reasonable request to the principal investigators of ADSP-PHC or the respective contributing studies.