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Given previous findings in normal ageing, we tested the hypothesis that higher segregation of the brain\u2019s connectome into distinct functional networks represents a functional mechanism underlying cognitive resilience in Alzheimer\u2019s disease. Using resting-state functional MRI, we assessed both resting-state functional MRI global system segregation, i.e. the balance of between-network to within-network connectivity, and the alternate index of modularity Q as predictors of cognitive resilience. We performed all analyses in two independent samples for validation: (i) 108 individuals with autosomal dominantly inherited Alzheimer\u2019s disease and 71 non-carrier controls; and (ii) 156 amyloid-PET-positive subjects across the spectrum of sporadic Alzheimer\u2019s disease and 184 amyloid-negative controls. In the autosomal dominant Alzheimer\u2019s disease sample, disease severity was assessed by estimated years from symptom onset. In the sporadic Alzheimer\u2019s sample, disease stage was assessed by temporal lobe tau-PET (i.e. composite across Braak stage I and III regions). In both samples, we tested whether the effect of disease severity on cognition was attenuated at higher levels of functional network segregation. For autosomal dominant Alzheimer\u2019s disease, we found higher functional MRI-assessed system segregation to be associated with an attenuated effect of estimated years from symptom onset on global cognition (P\u2009=\u20090.007). Similarly, for patients with sporadic Alzheimer\u2019s disease, higher functional MRI-assessed system segregation was associated with less decrement in global cognition (P\u2009=\u20090.001) and episodic memory (P\u2009=\u20090.004) per unit increase of temporal lobe tau-PET. Confirmatory analyses using the alternate index of modularity Q revealed consistent results. In conclusion, higher segregation of functional connections into distinct large-scale networks supports cognitive resilience in Alzheimer\u2019s disease.<\/jats:p>","DOI":"10.1093\/brain\/awab112","type":"journal-article","created":{"date-parts":[[2021,3,12]],"date-time":"2021-03-12T07:14:38Z","timestamp":1615533278000},"page":"2176-2185","source":"Crossref","is-referenced-by-count":143,"title":["Segregation of functional networks is associated with cognitive resilience in Alzheimer\u2019s disease"],"prefix":"10.1093","volume":"144","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5231-1714","authenticated-orcid":false,"given":"Michael","family":"Ewers","sequence":"first","affiliation":[{"name":"Institute for Stroke and Dementia Research, University Hospital, Ludwig-Maximilian-University LMU, Munich, Germany"},{"name":"German Center for Neurodegenerative Diseases (DZNE), Munich, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying","family":"Luan","sequence":"additional","affiliation":[{"name":"Institute for Stroke and Dementia Research, University Hospital, Ludwig-Maximilian-University LMU, Munich, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lukas","family":"Frontzkowski","sequence":"additional","affiliation":[{"name":"Institute for Stroke and Dementia Research, University Hospital, Ludwig-Maximilian-University LMU, Munich, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julia","family":"Neitzel","sequence":"additional","affiliation":[{"name":"Institute for Stroke and Dementia Research, University Hospital, Ludwig-Maximilian-University LMU, Munich, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Rubinski","sequence":"additional","affiliation":[{"name":"Institute for Stroke and Dementia Research, University Hospital, Ludwig-Maximilian-University LMU, Munich, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin","family":"Dichgans","sequence":"additional","affiliation":[{"name":"Institute for Stroke and Dementia Research, University Hospital, Ludwig-Maximilian-University LMU, Munich, Germany"},{"name":"German Center for Neurodegenerative Diseases (DZNE), Munich, Germany"},{"name":"Munich Cluster for Systems Neurology, SyNergy, Ludwig-Maximilian-University LMU, Munich, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jason","family":"Hassenstab","sequence":"additional","affiliation":[{"name":"Knight Alzheimer\u2019s Disease Research Center, Washington University in St. Louis, St. Louis, MO, USA"},{"name":"Department of Neurology, Washington University in St. Louis, St. Louis, MO, USA"},{"name":"Department of Psychological and Brain Sciences, Washington University, St. Louis, MO, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2109-2955","authenticated-orcid":false,"given":"Brian A","family":"Gordon","sequence":"additional","affiliation":[{"name":"Knight Alzheimer\u2019s Disease Research Center, Washington University in St. Louis, St. Louis, MO, USA"},{"name":"Department of Neurology, Washington University in St. Louis, St. Louis, MO, USA"},{"name":"Department of Psychological and Brain Sciences, Washington University, St. Louis, MO, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jasmeer P","family":"Chhatwal","sequence":"additional","affiliation":[{"name":"Massachusetts General Hospital, Department of Neurology, Harvard Medical School, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johannes","family":"Levin","sequence":"additional","affiliation":[{"name":"German Center for Neurodegenerative Diseases (DZNE), Munich, Germany"},{"name":"Department of Neurology, Ludwig-Maximilians-Universit\u00e4t M\u00fcnchen, Munich, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"Schofield","sequence":"additional","affiliation":[{"name":"Neuroscience Research Australia, Sydney, NSW, Australia"},{"name":"School of Medical Sciences, University of New South Wales, Sydney, NSW, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tammie L S","family":"Benzinger","sequence":"additional","affiliation":[{"name":"Knight Alzheimer\u2019s Disease Research Center, Washington University in St. Louis, St. Louis, MO, USA"},{"name":"Department of Radiology, Washington University in St Louis, St Louis, MO, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John C","family":"Morris","sequence":"additional","affiliation":[{"name":"Knight Alzheimer\u2019s Disease Research Center, Washington University in St. Louis, St. Louis, MO, USA"},{"name":"Department of Neurology, Washington University in St. Louis, St. Louis, MO, USA"},{"name":"Department of Psychiatry, Washington University in St. Louis, St. Louis, MO, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alison","family":"Goate","sequence":"additional","affiliation":[{"name":"Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA"},{"name":"Ronald M. Loeb Center for Alzheimer\u2019s Disease, Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Celeste M","family":"Karch","sequence":"additional","affiliation":[{"name":"Knight Alzheimer\u2019s Disease Research Center, Washington University in St. Louis, St. Louis, MO, USA"},{"name":"Department of Psychiatry, Washington University in St. Louis, St. Louis, MO, USA"},{"name":"Hope Center for Neurological Disorders, Washington University in St. Louis, St. Louis, MO, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anne M","family":"Fagan","sequence":"additional","affiliation":[{"name":"Knight Alzheimer\u2019s Disease Research Center, Washington University in St. Louis, St. Louis, MO, USA"},{"name":"Department of Neurology, Washington University in St. Louis, St. Louis, MO, USA"},{"name":"Hope Center for Neurological Disorders, Washington University in St. Louis, St. 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