Data-driven identification of endophenotypes of Alzheimer’s disease progression: implications for clinical trials and therapeutic interventions
AffiliationUniv Arizona, Coll Med, Dept Pharmacol
Univ Arizona, Coll Med, Dept Neurol
Latent class mixed models
MetadataShow full item record
PublisherBIOMED CENTRAL LTD
CitationData-driven identification of endophenotypes of Alzheimer’s disease progression: implications for clinical trials and therapeutic interventions 2018, 10 (1) Alzheimer's Research & Therapy
JournalAlzheimer's Research & Therapy
Rights© The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License.
Collection InformationThis item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at firstname.lastname@example.org.
AbstractBackground: Given the complex and progressive nature of Alzheimer's disease (AD), a precision medicine approach for diagnosis and treatment requires the identification of patient subgroups with biomedically distinct and actionable phenotype definitions. Methods: Longitudinal patient-level data for 1160 AD patients receiving placebo or no treatment with a follow-up of up to 18 months were extracted from an integrated clinical trials dataset. We used latent class mixed modelling (LCMM) to identify patient subgroups demonstrating distinct patterns of change over time in disease severity, as measured by the Alzheimer's Disease Assessment Scale-cognitive subscale score. The optimal number of subgroups (classes) was selected by the model which had the lowest Bayesian Information Criterion. Other patient-level variables were used to define these subgroups' distinguishing characteristics and to investigate the interactions between patient characteristics and patterns of disease progression. Results: The LCMM resulted in three distinct subgroups of patients, with 10.3% in Class 1, 76.5% in Class 2 and 13.2% in Class 3. While all classes demonstrated some degree of cognitive decline, each demonstrated a different pattern of change in cognitive scores, potentially reflecting different subtypes of AD patients. Class 1 represents rapid decliners with a steep decline in cognition over time, and who tended to be younger and better educated. Class 2 represents slow decliners, while Class 3 represents severely impaired slow decliners: patients with a similar rate of decline to Class 2 but with worse baseline cognitive scores. Class 2 demonstrated a significantly higher proportion of patients with a history of statins use; Class 3 showed lower levels of blood monocytes and serum calcium, and higher blood glucose levels. Conclusions: Our results, 'learned' from clinical data, indicate the existence of at least three subgroups of Alzheimer's patients, each demonstrating a different trajectory of disease progression. This hypothesis-generating approach has detected distinct AD subgroups that may prove to be discrete endophenotypes linked to specific aetiologies. These findings could enable stratification within a clinical trial or study context, which may help identify new targets for intervention and guide better care.
NoteOpen access journal.
VersionFinal published version
SponsorsNational Institute on Aging [R34 AG049652, P01 AG026572]; Medical Research Council; Engineering and Physical Sciences Research Council grant [MR/N00583X/1]; National Institute of Health [R01 AG037561]