Cross-Sectional and Longitudinal Comparisons of Biomarkers and Cognition Among Asymptomatic Middle-Aged Individuals with a Parental History of Either Autosomal Dominant or Late Onset Alzheimer Disease

Background: The comparison of autosomal dominant Alzheimer disease (ADAD) and late-onset Alzheimer disease (LOAD) is almost perfectly confounded by age, leading to a major challenge in the interpretation of results. We aim to compare biomarkers from the cerebrospinal fluid (CSF) and neuroimaging (magnetic resonance imaging (MRI); amyloid Positron Emission Tomography (PET)) between age-matched asymptomatic individuals at-risk for ADAD or LOAD. Methods: Cross-sectional and longitudinal biomarker and cognitive data from asymptomatic participants of 42 to 65 years in the Dominantly Inherited Alzheimer Network (DIAN) and the Washington University Adult Children Study (ACS) of LOAD were analyzed across 4 groups: DIAN mutation carriers (MC, n=33) and non-carriers (NON-MC, n=58), and ACS participants with a positive (FH+, n=176) and negative family history (FH-, n=120) of LOAD. Findings: Baseline age had the strongest effect on β-amyloid load (via Pittsburgh Compound B (PIB) PET) in DIAN MC, and was significantly associated with cortical thickness for all except for DIAN NON-MC. At the mean baseline age, DIAN MC had the lowest levels of CSF Aβ42, the highest levels of CSF total Tau, phosphorylated Tau (pTau181), and PIB PET uptake. Longitudinally, DIAN NON-MC showed no significant changes in any markers, whereas DIAN MC showed significant changes in all but CSF markers. ACS FH+ and FH- both showed significant changes in CSF Aβ42 and PIB uptake. DIAN MC had similar rate of increase in PIB PET uptake to ACS FH+, drastically faster rate of decline in hippocampal volume than others, and was the only group showing significant cognitive decline. Interpretation: Preclinical ADAD and LOAD appear to share many biomarker signatures, but significant differences between preclinical ADAD and ACS FH+ were found at baseline, and on the longitudinal changes in hippocampal volume and cognition, likely due to the later preclinical stage of ADAD at the similar ages. Funding: This study was supported by National Institute on Aging (NIA) grant R01 AG053550 (Dr. Xiong) and NIA grants P50 AG005681, P01AG026276, and P01 AG0399131 (Dr. Morris), and UF1AG032438 (Dr. Bateman). Image processing was supported in part by the Neuroimaging Informatics and Analysis Center (1P30NS098577) and R01 EB009352 (Benzinger). Data collection and sharing for this project was partly supported by The Dominantly Inherited Alzheimer’s Network (DIAN, UF1AG032438) funded by the National Institute on Aging (NIA), the German Center for Neurodegenerative Diseases (DZNE), Raul Carrea Institute for Neurological Research (FLENI), Partial support by Japan Agency for Medical Research and Development (AMED) JP21dk0207049 (Dr. Ikeuchi), and the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI) Declaration of Interest: All the authors declare no competing interest. Ethical Approval: The WU Human Research Protection Office approved both the ACS and the DIAN, the Institutional Review Boards/Independent Ethics Committees approved the DIAN protocol at all DIAN sites, and all participants gave written informed consent.