Segregation of functional networks is associated with cognitive resilience in Alzheimer's disease

Cognitive resilience is an important modulating factor of cognitive decline in Alzheimer's disease, but the functional brain mechanisms that support cognitive resilience remain elusive. Given previous findings in normal ageing, we tested the hypothesis that higher segregation of the brain's connectome into distinct functional networks represents a functional mechanism underlying cognitive resilience in Alzheimer's 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's disease and 71 non-carrier controls; and (ii) 156 amyloid-PET-positive subjects across the spectrum of sporadic Alzheimer's disease and 184 amyloid-negative controls. In the autosomal dominant Alzheimer's disease sample, disease severity was assessed by estimated years from symptom onset. In the sporadic Alzheimer's 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's 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 = 0.007). Similarly, for patients with sporadic Alzheimer's disease, higher functional MRI-assessed system segregation was associated with less decrement in global cognition (P = 0.001) and episodic memory (P = 0.004) 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's disease.Fil: Ewers, Michael. Ludwig Maximilians Universitat; Alemania. German Center for Neurodegenerative Diseases; AlemaniaFil: Luan, Ying. Ludwig Maximilians Universitat; AlemaniaFil: Frontzkowski, Lukas. Ludwig Maximilians Universitat; AlemaniaFil: Neitzel, Julia. Ludwig Maximilians Universitat; AlemaniaFil: Rubinski, Anna. Ludwig Maximilians Universitat; AlemaniaFil: Dichgans, Martin. Ludwig Maximilians Universitat; Alemania. German Center for Neurodegenerative Diseases; AlemaniaFil: Hassenstab, Jason. Washington University in St. Louis; Estados UnidosFil: Gordon, Brian A. Washington University in St. Louis; Estados UnidosFil: Chhatwal, Jasmeer P. Harvard Medical School; Estados UnidosFil: Levin, Johannes. Ludwig Maximilians Universitat; Alemania. German Center for Neurodegenerative Diseases; AlemaniaFil: Schofield, Peter. University of New South Wales; Australia. Neuroscience Research Australia; AustraliaFil: Benzinger, Tammie L. S. Washington University in St. Louis; Estados UnidosFil: Morris, John C. Washington University in St. Louis; Estados UnidosFil: Goate, Alison. Icahn School Of Medicine At Mount Sinai (icahn School Of Medicine);Fil: Karch, Celeste M. Washington University in St. Louis; Estados UnidosFil: Fagan, Anne M. Washington University in St. Louis; Estados UnidosFil: McDade, Eric. Washington University in St. Louis; Estados UnidosFil: Allegri, Ricardo Francisco. Fundación para la Lucha contra las Enfermedades Neurológicas de la Infancia. Instituto de Neurociencias - Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Neurociencias; ArgentinaFil: Berman, Sarah. University of Pittsburgh; Estados UnidosFil: Chui, Helena. University of Southern California; Estados UnidosFil: Cruchaga, Carlos. Washington University in St. Louis; Estados UnidosFil: Farlow, Marty. Indiana University; Estados UnidosFil: Graff Radford, Neill. Mayo Clinic Cancer Center; Estados UnidosFil: Jucker, Mathias. German Center for Neurodegenerative Diseases; Alemania. Eberhard Karls Universität Tübingen; Alemania. Hertie Institute for Clinical Brain Research; AlemaniaFil: Lee, Jae Hong. University of Ulsan; Corea del SurFil: Martins, Ralph N. Edith Cowan University; Australia. Macquarie University; Australia. Australian Alzheimer’s Research Foundation; AustraliaFil: Mori, Hiroshi. Osaka City University Medical School; JapónFil: Perrin, Richard. Washington University in St. Louis; Estados UnidosFil: Xiong, Chengjie. Washington University in St. Louis; Estados UnidosFil: Rossor, Martin. University College London; Estados Unido