Towards a clinical timeline of Alzheimer’s disease; a multivariate cognitive perspective

Abstract

AbstractBackgroundAlzheimer’s disease (AD) is a multifactorial disease characterised by a long period of neuronal loss which manifests clinically as cognitive decline and ultimately dementia. Understanding the nature and magnitude of cognitive decline prior to dementia is critical to understanding the disease course. Here we quantify change in six cognitive composite scores to compare their temporal sequence and rates of change early in the AD disease course.MethodAmyloid‐beta positive (Aβ+) cognitively unimpaired (CU), MCI and AD participants from the Australian Imaging, Biomarkers and Lifestyle (AIBL) study of ageing with ≥three study visits (N = 857), were used to derive composite scores for executive function, language, attention and processing, recognition, visuospatial, and a general composite used in clinical trials (AIBL‐PACC). A multivariate method for combining cognitive change trajectory curves was used to place each composite score trajectory in a common numerical space. Using the mean AIBL‐PACC scores for the prodromal group (MCI‐Aβ+) as a reference, change over a three‐year period for each composite was estimated. Given the AIBL requirement for a minimum 1.5 SD change in two or more cognitive domains to justify progression to MCI/AD, disease time was set with the zero point at a ‐1.5 AIBL‐PACC score, representing a 1.5 SD decline in AIBL‐PACC from the mean CU Ab‐ population at baseline.ResultThe AIBL‐PACC, language and visuospatial functioning scores showed the steepest trajectories indicating AD related decline in these scores was fastest (Figure 1). AIBL‐PACC reached the ‐1.5 point on the y‐axis first followed closely by memory recognition, with steeper trajectory of decline for the AIBL‐PACC across the age range. Focusing on AIBL‐PACC, it took 2.15 years to transition from ‐1.5 to the mean of the prodromal group (‐1.87). At five years past the start of the prodromal stage, the data suggests a drop in the AIBL‐PACC to ‐2.54, an approximate decline of ∼0.22 points per year.ConclusionThis is the first presentation of a novel multivariate disease trajectory method examining expected change across the AD continuum among Aβ+ persons. A 3‐year change in the PACC composite demonstrated here will be relevant to measure disease progression during clinical trials.