Functional Connectivity in Autosomal Dominant and Late-Onset Alzheimer Disease
Open accessAbstract
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 connectivity magnetic 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 connectivity magnetic resonance imaging may 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.
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Studies indicate that familial and sporadic Alzheimer's disease have very similar pathogenesis, pathophysiology, and progression.
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- Authors
- Thomas, J. B., Brier, M. R., Bateman, R. J., Snyder, A. Z., Benzinger, T. L., Xiong, C., Raichle, M., Holtzman, D. M., Sperling, R. A., Mayeux, R., Ghetti, B., Ringman, J. M., Salloway, S., McDade, E., Rossor, M. N., Ourselin, S., Schofield, P. R., Masters, C. L., Martins, R. N., Weiner, M. W., Thompson, P. M., Fox, N. C., Koeppe, R. A., Jack, C. R., Mathis, C. A., Oliver, A., Blazey, T. M., Moulder, K., Buckles, V., Hornbeck, R., Chhatwal, J., Schultz, A. P., Goate, A. M., Fagan, A. M., Cairns, N. J., Marcus, D. S., Morris, J. C., & Ances, B. M.
- Affiliations
- Washington University in St. Louis (US)
- Brigham and Women's Hospital (US)
- Columbia University Irving Medical Center (US)
- Indiana University Bloomington (US)
- University of California, Los Angeles (US)
- Brown University (US)
- University of Pittsburgh (US)
- UCL Queen Square Institute of Neurology (GB)
- Dementia Research Centre, Institute of Neurology, University College London, London, England
- UNSW Sydney (AU)
- Mental Health Research Institute (AU)
- Edith Cowan University (AU)
- University of California, San Francisco (US)
- University of Michigan (US)
- Mayo Clinic (US)
- Harvard University (US)
- Corresponding author
- Ances, Beau M.
- ORCID
- Brier, Matthew R.
- Bateman, Randall J.
- Snyder, Abraham Z.
- Benzinger, Tammie L.
- Xiong, Chengjie
- Raichle, Marcus
- Holtzman, David M.
- Sperling, Reisa A.
- Mayeux, Richard
- Ghetti, Bernardino
- Ringman, John M.
- Salloway, Stephen
- McDade, Eric
- Rossor, Martin N.
- Schofield, Peter R.
- Masters, Colin L.
- Martins, Ralph N.
- Weiner, Michael W.
- Thompson, Paul M.
- Fox, Nick C.
- Koeppe, Robert A.
- Jack, Clifford R.
- Mathis, Chester A.
- Oliver, Angela
- Blazey, Tyler M.
- Hornbeck, Russ
- Chhatwal, Jasmeer
- Schultz, Aaron P.
- Goate, Alison M.
- Fagan, Anne M.
- Cairns, Nigel J.
- Marcus, Daniel S.
- Morris, John C.
- Ances, Beau M.
- Venue
- JAMA Neurology
- Publisher
- American Medical Association (AMA)
- Published
- 2014-09-01
- Volume
- 71
- Issue
- 9
- Pages
- 1111
- ISSN
- 2168-6149 (ISSN-L)
- PMC
- PMC4240274
- OpenAlex
- W2047301935
- Cited by
- 129
- References
- 47
- Citations by year
- 2026: 7 · 2025: 5 · 2024: 9 · 2023: 7 · 2022: 8 · 2021: 13 · 2020: 7 · 2019: 30 · 2018: 6 · 2017: 8 · 2016: 15 · 2015: 10 · 2014: 4
- FWCI
- 6.88
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- JAMA Neurology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- UNSWorks (University of New South Wales, Sydney, Australia) (submittedVersion, cc-by-nc-nd)
- eScholarship (California Digital Library) (submittedVersion)
- Australasian Journal of Paramedicine (submittedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Minerva Access (University of Melbourne) (submittedVersion)
- Research Portal (King's College London) (submittedVersion)
- Funders
- Washington University in St. Louis
- National Institute for Health and Care Research (NF-SI-0512-10033, NF-SI-0513-10134, NF-SI-0508-10123)
- University College London (EP/K005278)
- University College London Hospitals NHS Foundation Trust
- National Institutes of Health (5u01ag024904-10)
- Medical Research Council (MR/J01107X/, FP7-ICT-2011-9-601055, MR/J01107X/1)
- Engineering and Physical Sciences Research Council (EP/J020990/1, EP/H046410/1)
- National Institute on Aging (U01-AG-024904, R01 AG37551, R01AG043392, U01AG06786, U01AG006786, 19-AG032438, R01AG040060, R01AG011378, P 50 AG05681, UF1AG032438, P50AG005681, P01 AG0 3991, P01AG003991, P50AG005134, U19AG032438, R01AG037551, U01AG032438, R01AG041851, P01AG026276, P30AG062421)
- National Heart, Lung, and Blood Institute (U01HL096917)
- National Institute of Mental Health (K23MH081786, R21MH099979)
- National Institute of Nursing Research (R01NR012657, R01NR012907, R01NR014449)
- National Institute of Neurological Disorders and Stroke (P30NS048056)
- National Institute of Biomedical Imaging and Bioengineering (U54EB020403)
- FP7 Information and Communication Technologies (FP7‐ICT‐2011‐9‐601055)
- Topics
- Life Sciences › Neuroscience › Cognitive Neuroscience › Functional Brain Connectivity Studies
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Keywords
- autosomal dominant Alzheimer's disease, late-onset Alzheimer's disease, resting-state functional connectivity, resting-state networks, dementia severity, Clinical Dementia Rating, asymptomatic mutation carriers, age of symptom onset, disease progression
- MeSH terms
- Adult, Aged, Aged, 80 and over, Alzheimer Disease, Cross-Sectional Studies, Female, Humans, Magnetic Resonance Imaging, Male, Middle Aged, Nerve Net, Severity of Illness Index, Cohort Studies, Age of Onset, Connectome
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