Temporal Order of Alzheimer\u27s Disease-Related Cognitive Marker Changes in BLSA and WRAP Longitudinal Studies

Investigation of the temporal trajectories of currently used neuropsychological tests is critical to identifying earliest changing measures on the path to dementia due to Alzheimer\u27s disease (AD). We used the Progression Score (PS) method to characterize the temporal trajectories of measures of verbal memory, executive function, attention, processing speed, language, and mental state using data spanning normal cognition, mild cognitive impairment (MCI), and AD from 1661 participants with a total of 7839 visits (age at last visit 77.6 SD 9.2) in the Baltimore Longitudinal Study of Aging and 1542 participants with a total of 4467 visits (age at last visit 59.9 SD 7.3) in the Wisconsin Registry for Alzheimer\u27s Prevention. This method aligns individuals in time based on the similarity of their longitudinal measurements to reveal temporal trajectories. As a validation of our methodology, we explored the associations between the individualized cognitive progression scores (Cog‑PS) computed by our method and clinical diagnosis. Digit span tests were the first to show declines in both data sets, and were detected mainly among cognitively normal individuals. These were followed by tests of verbal memory, which were in turn followed by Trail Making Tests, Boston Naming Test, and Mini-Mental State Examination. Differences in Cog-PS across the clinical diagnosis groups were statistically significant, highlighting the potential use of Cog-PS as individualized indicators of disease progression. Identifying cognitive measures that are changing in preclinical AD can lead to the development of novel cognitive tests that are finely tuned to detecting earliest changes