Identification of clusters of rapid and slow decliners among subjects at risk for Alzheimer's disease

Abstract

The heterogeneity of Alzheimer's disease contributes to the high failure rate of prior clinical trials. We analyzed 5-year longitudinal outcomes and biomarker data from 562 subjects with mild cognitive impairment (MCI) from two national studies (ADNI) using a novel multilayer clustering algorithm. The algorithm identified homogenous clusters of MCI subjects with markedly different prognostic cognitive trajectories. A cluster of 240 rapid decliners had 2-fold greater atrophy and progressed to dementia at almost 5 times the rate of a cluster of 184 slow decliners. A classifier for identifying rapid decliners in one study showed high sensitivity and specificity in the second study. Characterizing subgroups of at risk subjects, with diverse prognostic outcomes, may provide novel mechanistic insights and facilitate clinical trials of drugs to delay the onset of AD.

Figure 1

Correlation Network between clinical and biomarker variables in all MCI subjects. The network Baseline descriptors are denoted by squares while circles are used to denote longitudinal rate of change (slope) descriptors. Green color depicts cognitive and functional variables with squares depicting baseline values and circles depicting rate of change values. Yellow squares depict baseline MRI volumetric measures while yellow circles depict slope of MRI volumetric changes over time. Orange squares represent baseline brain FDG-PET and AV45PET data while red squares represent baseline spinal fluid amyloid-beta, total-tau and phosphorylated-tau data. See Methods for details of the measurements. The length of the edges is inversely proportional to the strength of the correlation. Only Spearman’s correlations rho > 0.5 are shown as edges. Slopes are denoted with the prefix alphabet “S” in front of the test name. FAQ = Functional Activities Questionnaire; ADAS11 and ADAS13 reflect the 11-item and 13-item versions of this test. MOCA = Montreal Cognitive Assessment Scale; Other details are described in the Methods.

Figure 2

Clustering of the total (N = 562) MCI sample into Rapid and Slow decliners.

Figure 3

X-axis depicts duration of follow up. Y-axis depicts ADAS-Cog-13 total scores and higher scores depict greater worsening of cognition (due to more cognitive errors). The slopes depict the markedly different cognitive baseline and endpoint for slow versus rapid declining subpopulations of MCI subjects.

Figure 4

X-axis depicts duration of follow up. Y-axis depicts ADAS-Cog-13 total scores and higher scores depict greater worsening of cognition (due to more cognitive errors). The slopes depict sex-specific cognitive baseline and endpoint scores for slow versus rapid declining subpopulations of MCI subjects.