Functional segregation loss over time is moderated by APOE genotype in healthy elderly

We investigated the influence of the apolipoprotein E‐ɛ4 allele (APOE‐ɛ4) on longitudinal age‐related changes in brain functional connectivity (FC) and cognition, in view of mixed cross‐sectional findings. One hundred and twenty‐two healthy older adults (aged 58–79; 25 APOE‐ɛ4 carriers) underwent task‐free fMRI scans at baseline. Seventy‐eight (16 carriers) had at least one follow‐up (every 2 years). Changes in intra‐ and internetwork FCs among the default mode (DMN), executive control (ECN), and salience (SN) networks, as well as cognition, were quantified using linear mixed models. Cross‐sectionally, APOE‐ɛ4 carriers had lower functional connectivity between the ECN and SN than noncarriers. Carriers also showed a stronger age‐dependent decrease in visuospatial memory performance. Longitudinally, carriers had steeper increase in inter‐ECN‐DMN FC, indicating loss of functional segregation. The longitudinal change in processing speed performance was not moderated by APOE‐ɛ4 genotype, but the brain–cognition association was. In younger elderly, faster loss of segregation was correlated with greater decline in processing speed regardless of genotype. In older elderly, such relation remained for noncarriers but reversed for carriers. APOE‐ɛ4 may alter aging by accelerating the change in segregation between high‐level cognitive systems. Its modulation on the longitudinal brain–cognition relationship was age‐dependent.

[1]  Jessica S. Damoiseaux,et al.  Effects of aging on functional and structural brain connectivity , 2017, NeuroImage.

[2]  Thomas Espeseth,et al.  Neuroscience and Biobehavioral Reviews Apoe-related Biomarker Profiles in Non-pathological Aging and Early Phases of Alzheimer's Disease , 2022 .

[3]  Jerry L Prince,et al.  Changes in Aβ biomarkers and associations with APOE genotype in 2 longitudinal cohorts , 2015, Neurobiology of Aging.

[4]  Jonas Persson,et al.  Reduced functional brain activity response in cognitively intact apolipoprotein E ε4 carriers , 2006 .

[5]  Prashanthi Vemuri,et al.  Effect of APOE ε4 status on intrinsic network connectivity in cognitively normal elderly subjects. , 2011, Archives of neurology.

[6]  Keith A. Johnson,et al.  Phases of Hyperconnectivity and Hypoconnectivity in the Default Mode and Salience Networks Track with Amyloid and Tau in Clinically Normal Individuals , 2017, The Journal of Neuroscience.

[7]  Ian J. Deary,et al.  Cognitive change and the APOE epsilon 4 allele. , 2002 .

[8]  Michael W. L. Chee,et al.  Cognitive function and brain structure correlations in healthy elderly East Asians , 2009, NeuroImage.

[9]  S. Folstein,et al.  "Mini-mental state". A practical method for grading the cognitive state of patients for the clinician. , 1975, Journal of psychiatric research.

[10]  N. Maurits,et al.  A Brain-Wide Study of Age-Related Changes in Functional Connectivity. , 2015, Cerebral cortex.

[11]  Marisa O. Hollinshead,et al.  The organization of the human cerebral cortex estimated by intrinsic functional connectivity. , 2011, Journal of neurophysiology.

[12]  G. Rees,et al.  Operationalizing compensation over time in neurodegenerative disease , 2017, Brain : a journal of neurology.

[13]  Daniel L. Schacter,et al.  Ageing and the resting state: is cognition obsolete? , 2017, Language, cognition and neuroscience.

[14]  Junjie Wu,et al.  Interactions of the Salience Network and Its Subsystems with the Default-Mode and the Central-Executive Networks in Normal Aging and Mild Cognitive Impairment , 2017, Brain Connect..

[15]  Masaki Ishihara,et al.  Decreased Functional Connectivity by Aging Is Associated with Cognitive Decline , 2012, Journal of Cognitive Neuroscience.

[16]  Wenjun Li,et al.  A method to determine the necessity for global signal regression in resting‐state fMRI studies , 2012, Magnetic resonance in medicine.

[17]  W. Abraham,et al.  Lack of effect of the apolipoprotein E ε4 genotype on cognition during healthy aging , 2014, Journal of clinical and experimental neuropsychology.

[18]  C. Peng,et al.  The APOE ɛ4 allele affects complexity and functional connectivity of resting brain activity in healthy adults , 2014, Human brain mapping.

[19]  Keith A. Johnson,et al.  Functional network integrity presages cognitive decline in preclinical Alzheimer disease , 2017, Neurology.

[20]  P. Rosa-Neto,et al.  Is ApoE ɛ 4 a good biomarker for amyloid pathology in late onset Alzheimer’s disease? , 2016, Translational Neurodegeneration.

[21]  Karl J. Friston,et al.  Structural and Functional Brain Networks: From Connections to Cognition , 2013, Science.

[22]  A. McIntosh,et al.  Aging Effects on Whole-Brain Functional Connectivity in Adults Free of Cognitive and Psychiatric Disorders. , 2016, Cerebral cortex.

[23]  Zhijun Zhang,et al.  Imbalanced hippocampal functional networks associated with remitted geriatric depression and apolipoprotein E ε4 allele in nondemented elderly: a preliminary study. , 2014, Journal of affective disorders.

[24]  Li Yao,et al.  A Triple Network Connectivity Study of Large-Scale Brain Systems in Cognitively Normal APOE4 Carriers , 2016, Front. Aging Neurosci..

[25]  S. Thibodeau,et al.  Preclinical evidence of Alzheimer's disease in persons homozygous for the epsilon 4 allele for apolipoprotein E. , 1996, The New England journal of medicine.

[26]  Zan Wang,et al.  Opposite Neural Trajectories of Apolipoprotein E ϵ4 and ϵ2 Alleles with Aging Associated with Different Risks of Alzheimer's Disease. , 2016, Cerebral cortex.

[27]  K. Yaffe,et al.  Dementia in the oldest old: a multi-factorial and growing public health issue , 2013, Alzheimer's Research & Therapy.

[28]  H. Kraemer,et al.  How can we learn about developmental processes from cross-sectional studies, or can we? , 2000, The American journal of psychiatry.

[29]  G. Glover,et al.  Dissociable Intrinsic Connectivity Networks for Salience Processing and Executive Control , 2007, The Journal of Neuroscience.

[30]  Daniel Rueckert,et al.  Human brain mapping: A systematic comparison of parcellation methods for the human cerebral cortex , 2017, NeuroImage.

[31]  Paul S Tofts,et al.  Structural and resting‐state MRI detects regional brain differences in young and mid‐age healthy APOE‐e4 carriers compared with non‐APOE‐e4 carriers , 2016, NMR in biomedicine.

[32]  Lin Ma,et al.  Alterations of functional connectivities from early to middle adulthood: Clues from multivariate pattern analysis of resting-state fMRI data , 2016, NeuroImage.

[33]  Lars T Westlye,et al.  Accelerated age-related cortical thinning in healthy carriers of apolipoprotein E epsilon 4. , 2008, Neurobiology of aging.

[34]  C. Malherbe,et al.  Cognitive Decline and Reorganization of Functional Connectivity in Healthy Aging: The Pivotal Role of the Salience Network in the Prediction of Age and Cognitive Performances , 2016, Front. Aging Neurosci..

[35]  Danielle S Bassett,et al.  Motion artifact in studies of functional connectivity: Characteristics and mitigation strategies , 2019, Human brain mapping.

[36]  Vijay K. Venkatraman,et al.  Brain network changes and memory decline in aging , 2016, Brain Imaging and Behavior.

[37]  N. Filippini,et al.  Distinct patterns of brain activity in young carriers of the APOE e4 allele , 2009, NeuroImage.

[38]  D. Schacter,et al.  The Brain's Default Network , 2008, Annals of the New York Academy of Sciences.

[39]  B. Biswal,et al.  Functional connectivity in the motor cortex of resting human brain using echo‐planar mri , 1995, Magnetic resonance in medicine.

[40]  Michael W. L. Chee,et al.  Reduced functional segregation between the default mode network and the executive control network in healthy older adults: A longitudinal study , 2016, NeuroImage.

[41]  Tianzi Jiang,et al.  Age-related decrease in functional connectivity of the right fronto-insular cortex with the central executive and default-mode networks in adults from young to middle age , 2013, Neuroscience Letters.

[42]  R. Nathan Spreng,et al.  Prefrontal Engagement and Reduced Default Network Suppression Co-occur and Are Dynamically Coupled in Older Adults: The Default–Executive Coupling Hypothesis of Aging , 2015, Journal of Cognitive Neuroscience.

[43]  Lars T Westlye,et al.  Increased Hippocampal Default Mode Synchronization during Rest in Middle-Aged and Elderly APOE ε4 Carriers: Relationships with Memory Performance , 2011, The Journal of Neuroscience.

[44]  Y. Um,et al.  Impact of Amyloid Burden on Regional Functional Synchronization in the Cognitively Normal Older Adults , 2017, Scientific Reports.

[45]  L. Nyberg,et al.  Altered deactivation in individuals with genetic risk for Alzheimer's disease , 2008, Neuropsychologia.

[46]  P. Murali Doraiswamy,et al.  Mapping the effect of the apolipoprotein E genotype on 4-year atrophy rates in an Alzheimer disease-related brain network. , 2014, Radiology.

[47]  G. Chételat,et al.  Imaging Brain Effects of APOE4 in Cognitively Normal Individuals Across the Lifespan , 2014, Neuropsychology Review.

[48]  Y. Stern,et al.  Unilateral disruptions in the default network with aging in native space , 2013, Brain and behavior.

[49]  Emily L. Dennis,et al.  Functional Brain Connectivity Using fMRI in Aging and Alzheimer’s Disease , 2014, Neuropsychology Review.

[50]  J. Rusted,et al.  Cognitive and neural signatures of the APOE E4 allele in mid-aged adults , 2014, Neurobiology of Aging.

[51]  Mayo Clinic,et al.  PRECLINICAL EVIDENCE OF ALZHEIMER’S DISEASE IN PERSONS HOMOZYGOUS FOR THE , 2000 .

[52]  Lars Bäckman,et al.  Apolipoprotein E and cognitive performance: a meta-analysis. , 2004, Psychology and aging.

[53]  Susan M. Resnick,et al.  Frontal function and executive processing in older adults: Process and region specific age-related longitudinal functional changes , 2013, NeuroImage.

[54]  Theresa M. Harrison,et al.  Neuroimaging genetic risk for Alzheimer's disease in preclinical individuals: From candidate genes to polygenic approaches. , 2016, Biological psychiatry. Cognitive neuroscience and neuroimaging.

[55]  D. T. Vernier,et al.  Restriction isotyping of human apolipoprotein E by gene amplification and cleavage with HhaI. , 1990, Journal of lipid research.

[56]  Efstathios D. Gennatas,et al.  Predicting Regional Neurodegeneration from the Healthy Brain Functional Connectome , 2012, Neuron.

[57]  Denise C. Park,et al.  Decreased segregation of brain systems across the healthy adult lifespan , 2014, Proceedings of the National Academy of Sciences.

[58]  Thomas T. Liu,et al.  Global signal regression acts as a temporal downweighting process in resting-state fMRI , 2017, NeuroImage.

[59]  J. Haines,et al.  Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families. , 1993, Science.

[60]  Jian-Min Yuan,et al.  Sleep Duration and Risk of Stroke Mortality Among Chinese Adults: Singapore Chinese Health Study , 2014, Stroke.

[61]  Huaxi Xu,et al.  Apolipoprotein E and Alzheimer disease: risk, mechanisms and therapy , 2013, Nature Reviews Neurology.

[62]  Timothy O. Laumann,et al.  Sources and implications of whole-brain fMRI signals in humans , 2017, NeuroImage.

[63]  Hui Zheng,et al.  Differential age-dependent associations of gray matter volume and white matter integrity with processing speed in healthy older adults , 2015, NeuroImage.

[64]  Caroline Hayward,et al.  Ageing: Cognitive change and the APOE ɛ4 allele , 2002, Nature.

[65]  Christian Windischberger,et al.  Toward discovery science of human brain function , 2010, Proceedings of the National Academy of Sciences.

[66]  Stephen M. Smith,et al.  Distinct resting-state functional connections associated with episodic and visuospatial memory in older adults , 2017, NeuroImage.

[67]  Anders M. Fjell,et al.  Accelerated age-related cortical thinning in healthy carriers of apolipoprotein E ɛ4 , 2008, Neurobiology of Aging.

[68]  Jim Mintz,et al.  Apolipoprotein E Affects Both Myelin Breakdown and Cognition: Implications for Age-Related Trajectories of Decline Into Dementia , 2007, Biological Psychiatry.

[69]  Chunming Xie,et al.  The apolipoprotein E gene affects the three-year trajectories of compensatory neural processes in the left-lateralized hippocampal network , 2017, Brain Imaging and Behavior.

[70]  Jonathan D. Power,et al.  Recent progress and outstanding issues in motion correction in resting state fMRI , 2015, NeuroImage.

[71]  Alina Jurcoane,et al.  Differential effects of the ApoE4 genotype on brain structure and function , 2014, NeuroImage.

[72]  L. Uddin Salience processing and insular cortical function and dysfunction , 2014, Nature Reviews Neuroscience.

[73]  Jonas Persson,et al.  Reduced functional brain activity response in cognitively intact apolipoprotein E epsilon4 carriers. , 2006, Brain : a journal of neurology.

[74]  Sachin Dixit,et al.  APOE4 Allele Disrupts Resting State fMRI Connectivity in the Absence of Amyloid Plaques or Decreased CSF Aβ42 , 2010, The Journal of Neuroscience.

[75]  Olaf Sporns,et al.  Network attributes for segregation and integration in the human brain , 2013, Current Opinion in Neurobiology.

[76]  Clare E. Mackay,et al.  The effects of APOE on brain activity do not simply reflect the risk of Alzheimer's disease , 2012, Neurobiology of Aging.