The apolipoprotein E gene affects the three-year trajectories of compensatory neural processes in the left-lateralized hippocampal network

Previous cross-sectional studies that investigated the effects of apolipoprotein E (ApoE) ε4 status on hippocampal networks have shown inconsistent results. Aging is a well-known risk factor for Alzheimer’s disease (AD) and could strongly interact with ApoE-related vulnerabilities to affect AD risk. However, no longitudinal data have been published regarding the interaction of the ApoE genotype and aging on hippocampal networks. Fifty-one patients with amnestic-type mild cognitive impairment (aMCI) and 64 matched cognitively normal elderly subjects underwent resting-state fMRI scans and neuropsychological tests at baseline and at a 35-month follow-up. Hippocampal resting-state functional connectivity (FC) data were analyzed utilizing a mixed analysis of covariance with ApoE genotype, time points and disease as fixed factors, controlling for age, sex and years of education. The notable finding was that the FC between the left hippocampus and right frontal regions for ε4 carriers longitudinally increased in the normal subjects, but decreased in aMCI patients, whereas the FC for non-carriers was maintained in normal subjects but increased in aMCI patients. Specifically, the longitudinal increases in hippocampal FC with the right inferior frontal gyrus were positively correlated with the changes in episodic memory test scores in non-carriers with aMCI. The interaction between the ApoE genotype, aging and disease suggested that aging should be considered a key regulator of the impact of the ApoE genotype on the phenotypic variants of AD. These findings also demonstrated that compensatory neural processes were accelerated in genetically high risk individuals, but could be subsequently exhausted with the onset of cognitive impairment.

[1]  A. Fagan,et al.  APOE predicts amyloid‐beta but not tau Alzheimer pathology in cognitively normal aging , 2010, Annals of neurology.

[2]  Mark Jenkinson,et al.  Resting Functional Connectivity Reveals Residual Functional Activity in Alzheimer’s Disease , 2013, Biological Psychiatry.

[3]  Richard S. J. Frackowiak,et al.  Age effects on the neural correlates of successful memory encoding. , 2003, Brain : a journal of neurology.

[4]  S. Black,et al.  Evidence from Functional Neuroimaging of a Compensatory Prefrontal Network in Alzheimer's Disease , 2003, The Journal of Neuroscience.

[5]  R. Sperling,et al.  Hippocampal activation in adults with mild cognitive impairment predicts subsequent cognitive decline , 2007, Journal of Neurology, Neurosurgery, and Psychiatry.

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

[7]  Simon B. Eickhoff,et al.  One-year test–retest reliability of intrinsic connectivity network fMRI in older adults , 2012, NeuroImage.

[8]  Jonas Persson,et al.  Large Scale Neurocognitive Networks Underlying Episodic Memory , 2000, Journal of Cognitive Neuroscience.

[9]  R. Petersen.  Mild cognitive impairment as a diagnostic entity , 2004, Journal of internal medicine.

[10]  Patricia A. Reuter-Lorenz,et al.  How Does it STAC Up? Revisiting the Scaffolding Theory of Aging and Cognition , 2014, Neuropsychology Review.

[11]  H. Eichenbaum,et al.  Interplay of Hippocampus and Prefrontal Cortex in Memory , 2013, Current Biology.

[12]  S Laroche,et al.  Plasticity at hippocampal to prefrontal cortex synapses: Dual roles in working memory and consolidation , 2000, Hippocampus.

[13]  S. Rombouts,et al.  Reduced resting-state brain activity in the "default network" in normal aging. , 2008, Cerebral cortex.

[14]  D. Amaral,et al.  Hippocampal‐neocortical interaction: A hierarchy of associativity , 2000, Hippocampus.

[15]  Hiroaki Kazui,et al.  Accelerated hippocampal atrophy in Alzheimer's disease with apolipoprotein E ε4 allele , 2002 .

[16]  Kuncheng Li,et al.  The Baseline and Longitudinal Changes of PCC Connectivity in Mild Cognitive Impairment: A Combined Structure and Resting-State fMRI Study , 2012, PloS one.

[17]  Bradley P. Sutton,et al.  The impact of increased relational encoding demands on frontal and hippocampal function in older adults , 2010, Cortex.

[18]  M. Pericak-Vance,et al.  Apolipoprotein E: high-avidity binding to beta-amyloid and increased frequency of type 4 allele in late-onset familial Alzheimer disease. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[19]  G. Alexander,et al.  Fibrillar amyloid-β burden in cognitively normal people at 3 levels of genetic risk for Alzheimer's disease , 2009, Proceedings of the National Academy of Sciences.

[20]  Gang Chen,et al.  Aberrant functional connectivity in Papez circuit correlates with memory performance in cognitively intact middle-aged APOE4 carriers , 2014, Cortex.

[21]  Denise C. Park,et al.  The adaptive brain: aging and neurocognitive scaffolding. , 2009, Annual review of psychology.

[22]  Loraine K. Obler,et al.  Bilateral brain regions associated with naming in older adults , 2010, Brain and Language.

[23]  C R Jack,et al.  Spotlight on the January 24 Issue , 2012, Neurology.

[24]  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.

[25]  H. Soininen,et al.  Hippocampus and entorhinal cortex in mild cognitive impairment and early AD , 2004, Neurobiology of Aging.

[26]  Zhijun Zhang,et al.  Aberrant Hippocampal Subregion Networks Associated with the Classifications of aMCI Subjects: A Longitudinal Resting-State Study , 2011, PloS one.

[27]  M. Rugg,et al.  The relationship between aging, performance, and the neural correlates of successful memory encoding. , 2009, Cerebral cortex.

[28]  Alan C. Evans,et al.  Apolipoprotein E ε4 Modulates Cognitive Profiles, Hippocampal Volume, and Resting-State Functional Connectivity in Alzheimer's Disease. , 2015, Journal of Alzheimer's disease : JAD.

[29]  Yufeng Zang,et al.  Abnormal Functional Connectivity of Hippocampus During Episodic Memory Retrieval Processing Network in Amnestic Mild Cognitive Impairment , 2009, Biological Psychiatry.

[30]  G. Alexander,et al.  Posterior cingulate glucose metabolism, hippocampal glucose metabolism, and hippocampal volume in cognitively normal, late-middle-aged persons at 3 levels of genetic risk for Alzheimer disease. , 2013, JAMA neurology.

[31]  Ching-Po Lin,et al.  Age‐Related Changes in Resting‐State Networks of A Large Sample Size of Healthy Elderly , 2015, CNS neuroscience & therapeutics.

[32]  W. Perlstein,et al.  Age-related changes in word retrieval: Role of bilateral frontal and subcortical networks , 2008, Neurobiology of Aging.

[33]  D. Prvulovic,et al.  Age-Related Effects of the Apolipoprotein E Gene on Brain Function. , 2016, Journal of Alzheimer's disease : JAD.

[34]  David M Holtzman,et al.  Human Apoe Isoforms Differentially Regulate Brain Amyloid-β Peptide Clearance Nih Public Access , 2022 .

[35]  A. Saykin,et al.  Neuroanatomic substrates of semantic memory impairment in Alzheimer's disease: Patterns of functional MRI activation , 1999, Journal of the International Neuropsychological Society.

[36]  Changwei W. Wu,et al.  APOE-ε4 Allele Altered the Rest-Stimulus Interactions in Healthy Middle-Aged Adults , 2015, PloS one.

[37]  Amy L. Shelton,et al.  Reduction of Hippocampal Hyperactivity Improves Cognition in Amnestic Mild Cognitive Impairment , 2012, Neuron.

[38]  Tianzi Jiang,et al.  Changes in hippocampal connectivity in the early stages of Alzheimer's disease: Evidence from resting state fMRI , 2006, NeuroImage.

[39]  Vince D. Calhoun,et al.  Save the Global: Global Signal Connectivity as a Tool for Studying Clinical Populations with Functional Magnetic Resonance Imaging , 2014, Brain Connect..

[40]  L. Nyberg,et al.  Functional brain imaging of episodic memory decline in ageing , 2017, Journal of internal medicine.

[41]  Kiralee M. Hayashi,et al.  Conversion of mild cognitive impairment to Alzheimer disease predicted by hippocampal atrophy maps. , 2006, Archives of neurology.

[42]  C. Rowe,et al.  Amyloid imaging results from the Australian Imaging, Biomarkers and Lifestyle (AIBL) study of aging , 2010, Neurobiology of Aging.

[43]  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.

[44]  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.

[45]  Stephen M. Rao,et al.  Genetic risk for Alzheimer's disease alters the five-year trajectory of semantic memory activation in cognitively intact elders , 2015, NeuroImage.

[46]  Paul M. Thompson,et al.  APOE4 is associated with greater atrophy of the hippocampal formation in Alzheimer's disease , 2011, NeuroImage.

[47]  R. Sperling,et al.  Longitudinal fMRI in elderly reveals loss of hippocampal activation with clinical decline , 2010, Neurology.

[48]  C. Jack,et al.  Mild cognitive impairment – beyond controversies, towards a consensus: report of the International Working Group on Mild Cognitive Impairment , 2004, Journal of internal medicine.

[49]  Chin‐Chang Huang,et al.  Association of Apolipoproteins E4 and C1 With Onset Age and Memory: A Study of Sporadic Alzheimer Disease in Taiwan , 2010, Journal of geriatric psychiatry and neurology.

[50]  Paul M. Thompson,et al.  Age, APOE and sex: Triad of risk of Alzheimer’s disease , 2016, The Journal of Steroid Biochemistry and Molecular Biology.

[51]  Kwangsun Yoo,et al.  Progressive Changes in Hippocampal Resting-state Connectivity Across Cognitive Impairment: A Cross-sectional Study From Normal to Alzheimer Disease , 2014, Alzheimer disease and associated disorders.