High Degree of Heterogeneity in Alzheimer's Disease Progression Patterns

There have been several reports on the varying rates of progression among Alzheimer's Disease (AD) patients; however, there has been no quantitative study of the amount of heterogeneity in AD. Obtaining a reliable quantitative measure of AD progression rates and their variances among the patients for each stage of AD is essential for evaluating results of any clinical study. The Global Deterioration Scale (GDS) and Functional Assessment Staging procedure (FAST) characterize seven stages in the course of AD from normal aging to severe dementia. Each GDS/FAST stage has a published mean duration, but the variance is unknown. We use statistical analysis to reconstruct GDS/FAST stage durations in a cohort of 648 AD patients with an average follow-up time of 4.78 years. Calculations for GDS/FAST stages 4–6 reveal that the standard deviations for stage durations are comparable with their mean values, indicating the presence of large variations in the AD progression among patients. Such amount of heterogeneity in the course of progression of AD is consistent with the existence of several sub-groups of AD patients, which differ by their patterns of decline. Author Summary: In recent decades, our understanding of Alzheimer's disease (AD) has increased; however, some basic questions still remain unresolved. One of them is: how homogeneous is AD? Is the course of progression more or less the same for most patients, or are there large variations? Our paper studies a large cohort of AD patients which comes from a 23-year-long study, and performs a statistical analysis of progression speed. We quantify the amount of spread in GDS/FAST stage durations (a staging system widely used by clinicians). We arrive at an astonishing conclusion that the mean length of AD stages is comparable with their standard deviation! This means that individual courses of AD progression may differ very much from each other, and from the textbook mean values. This has implications both for clinical trials (how do we assess if a new drug is effective, if the amount of natural spread is so large in untreated patients?), and for our understanding of this disease, which appears to be comprised of sub-diseases with different patterns of decline.