CROSS-SECTIONAL AND LONGITUDINAL COMPARISONS OF COGNITION AND BIOMARKERS AMONG COGNITIVELY NORMAL INDIVIDUALS AGED 42 TO 65 YEARS WITH A FAMILY HISTORY OF EITHER AUTOSOMAL DOMINANT AD (ADAD) OR LATE-ONSET AD (LOAD)

Abstract

The comparison of ADAD and LOAD is almost perfectly confounded by age, leading to a major challenge in the interpretation of results. We focused on an age window (42y to 65 y) shared by the Dominantly Inherited Alzheimer Network(DIAN) and the Washington University Adult Children Study(ACS) of LOAD. General linear mixed models were used to compare cognition and biomarkers across 4 groups: DIAN mutation carriers(MC) in the PSEN1 or PSEN2 or APP genes and non-carriers(NON-MC), and ACS participants with a positive and negative family history(FH+, FH-) of LOAD. Of 349 asymptomatic individuals aged 42y to 65y at baseline: 37 were DIAN MCs, 59 were DIAN NON-MCs; 146 were ACS FH+, and 107 were ACS FH-. Age had a stronger effect on baseline mean cortical b-amyloid load (via Pittsburgh Compound B positron emission tomography [PIB PET]) in DIAN MCs than in any other groups. After adjusting for age, DIAN MCs had the lowest CSF Ab42 and the highest cortical PET PIB value at baseline, and ACS FH+ participants had lower CSF Ab42 level than DIAN NON-MCs. Longitudinal rate of increase in PET PIB uptake was similar between DIAN MCs and ACS FH+, but all were significantly faster than that in DIAN NON-MCs and ACS FH-. Older age was associated with lower normalized cortical thickness at baseline for all groups except for DIAN NON-MCs in which the direction was reversed. Longitudinally, the rate of change in cortical thickness for DIAN MCs was different from that for ACS FH+. No difference was found on baseline normalized hippocampal volume across the 4 groups after adjusting for age. However, the longitudinal rate of decline in hippocampal volume was the fastest in DIAN MCs. Finally, after adjusting for age and education, no differences were found between DIAN MCs and ACS participants (FH+ or FH-) on either the baseline level or the rate of longitudinal changes on cognitive tests of semantic memory, processing speed, and executive function. Baseline and longitudinal differences on CSF and imaging biomarkers, but not on cognition, between participants with a family history of ADAD or LOAD, were found.