Functional connectivity in autosomal dominant and late-onset Alzheimer disease

Jewell B. Thomas, Matthew R. Brier, Randall J. Bateman, Abraham Z. Snyder, Tammie L. Benzinger, Chengjie Xiong, Marcus Raichle, David M. Holtzman, Reisa A. Sperling, Richard Mayeux, Bernardino Ghetti, John M. Ringman, Stephen Salloway, Eric McDade, Martin N. Rossor, Sebastien Ourselin, Peter R. Schofield, Colin L. Masters, Ralph N. Martins, Michael W. WeinerPaul M. Thompson, Nick C. Fox, Robert A. Koeppe, Clifford R. Jack, Chester A. Mathis, Angela Oliver, Tyler M. Blazey, Krista Moulder, Virginia Buckles, Russ Hornbeck, Jasmeer Chhatwal, Aaron P. Schultz, Alison M. Goate, Anne M. Fagan, Nigel J. Cairns, Daniel S. Marcus, John C. Morris, Beau M. Ances

Research output: Contribution to journalArticlepeer-review

51 Scopus citations

Abstract

IMPORTANCE: Autosomal dominant Alzheimer disease (ADAD) is caused by rare genetic mutations in 3 specific genes in contrast to late-onset Alzheimer disease (LOAD), which has a more polygenetic risk profile. OBJECTIVE: To assess the similarities and differences in functional connectivity changes owing to ADAD and LOAD. DESIGN, SETTING, AND PARTICIPANTS: We analyzed functional connectivity in multiple brain resting state networks (RSNs) in a cross-sectional cohort of participants with ADAD (n = 79) and LOAD (n = 444), using resting-state functional connectivitymagnetic resonance imaging at multiple international academic sites. MAIN OUTCOMES AND MEASURES: For both types of AD, we quantified and compared functional connectivity changes in RSNs as a function of dementia severity measured by the Clinical Dementia Rating Scale. In ADAD, we qualitatively investigated functional connectivity changes with respect to estimated years from onset of symptoms within 5 RSNs. RESULTS: A decrease in functional connectivity with increasing Clinical Dementia Rating scores were similar for both LOAD and ADAD in multiple RSNs. Ordinal logistic regression models constructed in one type of Alzheimer disease accurately predicted clinical dementia rating scores in the other, further demonstrating the similarity of functional connectivity loss in each disease type. Among participants with ADAD, functional connectivity in multiple RSNs appeared qualitatively lower in asymptomatic mutation carriers near their anticipated age of symptom onset compared with asymptomatic mutation noncarriers. CONCLUSIONS AND RELEVANCE: Resting-state functional connectivity magnetic resonance imaging changes with progressing AD severity are similar between ADAD and LOAD. Resting-state functional connectivitymagnetic resonance imagingmay be a useful end point for LOAD and ADAD therapy trials. Moreover, the disease process of ADAD may be an effective model for the LOAD disease process.

Original languageEnglish
Pages (from-to)1111-1122
Number of pages12
JournalJAMA Neurology
Volume71
Issue number9
DOIs
StatePublished - Sep 1 2014

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