Abstract
Apolipoprotein E (ApoE) ε4 allele and cerebral blood flow (CBF) changes are related to the increased risk of cognitive impairment independently. However, whether there are interactions between ApoE ε4 and CBF on memory performance in older adults with normal cognition remains unknown. This study determined whether the association between CBF and memory performance could be moderated by ApoE ε4 within a sample of cognitively normal older adults from the ADNI. 62 participants, including 23 with ApoE ε4 (ApoE ε4+) and 39 without ApoE ε4 (ApoE ε4−), underwent resting CBF measurement and memory testing. CBF was measured by arterial spin labeling MRI and memory performance was evaluated by the Rey Auditory Verbal Learning Test. By using linear regression models, CBF was negatively associated with memory function in ApoE ε4+ group, whereas positively in ApoE ε4− group by contrast. This study suggests that different CBF-memory relationships can be detected in cognitively normal ApoE ε4 carriers compared to ApoE ε4 non-carriers. Associations between hyperperfusion and worse memory performance in ApoE ε4 carriers may reflect vascular and/or cellular dysfunction.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Armulik A et al (2010) Pericytes regulate the blood–brain barrier. Nature 468:557–561. https://doi.org/10.1038/nature09522
Bangen KJ, Restom K, Liu TT, Wierenga CE, Jak AJ, Salmon DP, Bondi MW (2012) Assessment of Alzheimer’s disease risk with functional magnetic resonance imaging: an arterial spin labeling study. J Alzheimer’s Dis: JAD 31(Suppl 3):S59–74. https://doi.org/10.3233/JAD-2012-120292
Beason-Held LL, Goh JO, An Y, Kraut MA, O’Brien RJ, Ferrucci L, Resnick SM (2013) Changes in brain function occur years before the onset of cognitive impairment. J Neurosci 33:18008–18014
Bell RD, Sagare AP, Friedman AE, Bedi GS, Holtzman DM, Deane R, Zlokovic BV (2007) Transport pathways for clearance of human Alzheimer’s amyloid beta-peptide and apolipoproteins E and J in the mouse central nervous system. J Cereb Blood Flow Metab 27:909–918. https://doi.org/10.1038/sj.jcbfm.9600419
Bell RD, Winkler EA, Sagare AP, Singh I, LaRue B, Deane R, Zlokovic BV (2010) Pericytes control key neurovascular functions and neuronal phenotype in the adult brain and during brain aging. Neuron 68:409–427. https://doi.org/10.1016/j.neuron.2010.09.043
Bell RD et al (2012) Apolipoprotein E controls cerebrovascular integrity via cyclophilin A. Nature 485:512–516. https://doi.org/10.1038/nature11087
Bertsch K, Hagemann D, Hermes M, Walter C, Khan R, Naumann E (2009) Resting cerebral blood flow, attention, and aging. Brain Res 1267:77–88. https://doi.org/10.1016/j.brainres.2009.02.053
Bondi MW et al (2014) Neuropsychological criteria for mild cognitive impairment improves diagnostic precision, biomarker associations, and progression rates. J Alzheimer’s Dis: JAD 42:275–289. https://doi.org/10.3233/jad-140276
Castellano JM et al (2011) Human apoE isoforms differentially regulate brain amyloid-beta peptide clearance. Sci Transl Med 3:89ra57. https://doi.org/10.1126/scitranslmed.3002156
Chao LL, Buckley ST, Kornak J, Schuff N, Madison C, Yaffe K, Miller BL, Kramer JH, Weiner MW (2010) ASL perfusion MRI predicts cognitive decline and conversion from MCI to dementia. Alzheimer Dis Assoc Disord 24:19–27
Corder EH et al (1993) Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer’s disease in late onset families. Science 261:921–923
Dai W, Lopez OL, Carmichael OT, Becker JT, Kuller LH, Gach HM (2009) Mild cognitive impairment and alzheimer disease: patterns of altered cerebral blood flow at MR imaging. Radiology 250:856–866
Daneman R, Zhou L, Kebede AA, Barres BA (2010) Pericytes are required for blood–brain barrier integrity during embryogenesis. Nature 468:562–566. https://doi.org/10.1038/nature09513
Edmonds EC et al (2015) Susceptibility of the conventional criteria for mild cognitive impairment to false-positive diagnostic errors. Alzheimer’s Dement 11:415–424. https://doi.org/10.1016/j.jalz.2014.03.005
Fleisher AS et al (2009) Cerebral perfusion and oxygenation differences in Alzheimer’s disease risk. Neurobiol Aging 30:1737–1748
Halliday MR, Rege SV, Ma Q, Zhao Z, Miller CA, Winkler EA, Zlokovic BV (2016) Accelerated pericyte degeneration and blood–brain barrier breakdown in apolipoprotein E4 carriers with Alzheimer’s disease. J Cereb Blood Flow Metab 36:216–227. https://doi.org/10.1038/jcbfm.2015.44
Heo S, Prakash RS, Voss MW, Erickson KI, Ouyang C, Sutton BP, Kramer AF (2010) Resting hippocampal blood flow, spatial memory and aging. Brain Res 1315:119–127. https://doi.org/10.1016/j.brainres.2009.12.020
Iadecola C (2004) Neurovascular regulation in the normal brain and in Alzheimer’s disease. Nat Rev Neurosci 5:347–360. https://doi.org/10.1038/nrn1387
Iadecola C (2013) The pathobiology of vascular dementia. Neuron 80:844–866. https://doi.org/10.1016/j.neuron.2013.10.008
Jak AJ, Bondi MW, Delano-Wood L, Wierenga C, Corey-Bloom J, Salmon DP, Delis DC (2009) Quantification of five neuropsychological approaches to defining mild cognitive impairment. Am J Geriatr Psychiatry 17:368–375. https://doi.org/10.1097/JGP.0b013e31819431d5
Kelleher RJ, Soiza RL (2013) Evidence of endothelial dysfunction in the development of Alzheimer’s disease: is Alzheimer’s a vascular disorder? Am J Cardiovasc Dis 3:197–226
Kim J, Basak JM, Holtzman DM (2009) The role of apolipoprotein E in Alzheimer’s disease. Neuron 63:287–303. https://doi.org/10.1016/j.neuron.2009.06.026
Kim SM, Kim MJ, Rhee HY, Ryu CW, Kim EJ, Petersen ET, Jahng GH (2013) Regional cerebral perfusion in patients with Alzheimer’s disease and mild cognitive impairment: effect of APOE epsilon4 allele. Neuroradiology 55:25–34
Knopman DS, Roberts R (2010) Vascular risk factors: imaging and neuropathologic correlates. J Alzheimer’s Dis: JAD 20:699–709. https://doi.org/10.3233/JAD-2010-091555
Luh WM, Wong EC, Bandettini PA, Hyde JS (1999) QUIPSS II with thin-slice TI1 periodic saturation: a method for improving accuracy of quantitative perfusion imaging using pulsed arterial spin labeling. Magn Reson Med 41:1246–1254
Mahley RW, Weisgraber KH, Huang Y (2009) Apolipoprotein E: structure determines function, from atherosclerosis to Alzheimer’s disease to AIDS. J Lipid Res 50(Suppl):S183–188. https://doi.org/10.1194/jlr.r800069-jlr200
Montagne A et al (2015a) Blood–brain barrier breakdown in the aging human hippocampus. Neuron 85:296–302. https://doi.org/10.1016/j.neuron.2014.12.032
Montagne A, Pa J, Zlokovic BV (2015b) Vascular plasticity and cognition during normal aging and dementia. JAMA Neurol 72:495–496. https://doi.org/10.1001/jamaneurol.2014.4636
Rabbitt P, Scott M, Thacker N, Lowe C, Jackson A, Horan M, Pendleton N (2006) Losses in gross brain volume and cerebral blood flow account for age-related differences in speed but not in fluid intelligence. Neuropsychology 20:549–557
Reiman EM et al (2004) Functional brain abnormalities in young adults at genetic risk for late-onset Alzheimer’s dementia. Proc Natl Acad Sci USA 101:284–289. https://doi.org/10.1073/pnas.2635903100
Roses AD (1996) Apolipoprotein E alleles as risk factors in Alzheimer’s disease. Annu Rev Med 47:387–400. https://doi.org/10.1146/annurev.med.47.1.387
Saunders AM et al (1993) Association of apolipoprotein E allele epsilon 4 with late-onset familial and sporadic Alzheimer’s disease. Neurology 43:1467–1472
Sheline YI, Morris JC, Snyder AZ, Price JL, Yan Z, D’Angelo G, Liu C, Dixit S, Benzinger T, Fagan A, Goate A et al (2010) APOE4 allele disrupts resting state fMRI connectivity in the absence of amyloid plaques or decreased CSF Aβ42. J Neurosci 30:17035–17040
Steffener J, Brickman AM, Habeck CG, Salthouse TA, Stern Y (2013) Cerebral blood flow and gray matter volume covariance patterns of cognition in aging. Hum Brain Mapp 34:3267–3279. https://doi.org/10.1002/hbm.22142
Thambisetty M, Beason-Held L, An Y, Kraut MA, Resnick SM (2010) APOE epsilon4 genotype and longitudinal changes in cerebral blood flow in normal aging. Arch Neurol 67:93–98. https://doi.org/10.1001/archneurol.2009.913
Verghese PB, Castellano JM, Holtzman DM (2011) Apolipoprotein E in Alzheimer’s disease and other neurological disorders. Lancet Neurol 10:241–252
Wierenga CE et al (2013) Interaction of age and APOE genotype on cerebral blood flow at rest. J Alzheimer’s Dis: JAD 34:921–935. https://doi.org/10.3233/JAD-121897
Wierenga CE, Hays CC, Zlatar ZZ (2014) Cerebral blood flow measured by arterial spin labeling MRI as a preclinical marker of Alzheimer’s disease. J Alzheimer’s Dis: JAD 42(Suppl 4):S411–419. https://doi.org/10.3233/JAD-141467
Wong EC, Buxton RB, Frank LR (1997) Implementation of quantitative perfusion imaging techniques for functional brain mapping using pulsed arterial spin labeling. NMR Biomed 10:237–249
Zlatar ZZ, Wierenga CE, Bangen KJ, Liu TT, Jak AJ (2014) Increased hippocampal blood flow in sedentary older adults at genetic risk for Alzheimer’s disease. J Alzheimer’s Dis: JAD 41:809–817
Zlokovic BV (1995) Cerebrovascular permeability to peptides: manipulations of transport systems at the blood–brain barrier. Pharm Res 12:1395–1406
Zlokovic BV (2008) The blood–brain barrier in health and chronic neurodegenerative disorders. Neuron 57:178–201. https://doi.org/10.1016/j.neuron.2008.01.003
Zlokovic BV (2011) Neurovascular pathways to neurodegeneration in Alzheimer’s disease and other disorders. Nat Rev Neurosci 12:723–738. https://doi.org/10.1038/nrn3114
Zlokovic BV (2013) Cerebrovascular effects of apolipoprotein E: implications for Alzheimer disease. JAMA Neurol 70:440–444
Zlokovic BV, Begley DJ, Chain-Eliash DG (1985) Blood–brain barrier permeability to leucine-enkephalin, d-alanine2-d-leucine5-enkephalin and their N-terminal amino acid (tyrosine). Brain Res 336:125–132
Zlokovic BV, Lipovac MN, Begley DJ, Davson H, Rakic L (1987) Transport of leucine-enkephalin across the blood–brain barrier in the perfused guinea pig brain. J Neurochem 49:310–315
Acknowledgements
Data collection and sharing for this project was funded by the Alzheimer’s Disease Neuroimaging Initiative (ADNI) (National Institutes of Health Grant U01 AG024904) and DOD ADNI (Department of Defense award number W81XWH-12-2-0012). ADNI is funded by the National Institute on Aging, the National Institute of Biomedical Imaging and Bioengineering, and through generous contributions from the following: Alzheimer’s Association, Alzheimer’s Drug Discovery Foundation, Araclon Biotech, BioClinica, Inc., Biogen Idec Inc., BristolMyers Squibb Company, Eisai Inc., Elan Pharmaceuticals, Inc., Eli Lilly and Company, EuroImmun, F. HoffmannLa Roche Ltd and its affiliated company Genentech, Inc., Fujirebio; GE Healthcare, IXICO Ltd., Janssen Alzheimer Immunotherapy Research & Development, LLC., Johnson & Johnson Pharmaceutical Research & Development LLC., Medpace, Inc., Merck & Co., Inc., Meso Scale Diagnostics, LLC., NeuroRx Research, Neurotrack Technologies, Novartis Pharmaceuticals Corporation, Pfizer Inc., Piramal Imaging, Servier, Synarc Inc., and Takeda Pharmaceutical Company. The Canadian Institutes of Health Research is providing funds to support ADNI clinical sites in Canada. Private sector contributions are facilitated by the Foundation for the National Institutes of Health (www.fnih.org). The grantee organization is the Northern Alzheimer’s Disease Cooperative Study at the University of California, San Diego. ADNI data are disseminated by the Laboratory for Neuro Imaging at the University of Southern California.
Funding
This study was funded by the Ministry of Science and Technology of the People’s Republic of China (2016YFC1306402), the Science Technology Department of Zhejiang Province (2017C03011), and the Medical Science and Technology Project co-founded by Zhejiang Province and the Ministry of Health of China (WKJ-ZJ-1612).
Author information
Authors and Affiliations
Consortia
Contributions
JYW designed the experiment, analyzed the data and drafted this manuscript. GPP, PL, XFT are responsible for revising this manuscript. BYL is responsible for designing this experiment, revising and finalizing this manuscript.
Corresponding author
Ethics declarations
Conflict of interest
The authors declare that they have no conflict of interest.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
Wang, J., Peng, G., Liu, P. et al. Regulating effect of CBF on memory in cognitively normal older adults with different ApoE genotype: the Alzheimer’s Disease Neuroimaging Initiative (ADNI). Cogn Neurodyn 13, 513–518 (2019). https://doi.org/10.1007/s11571-019-09536-x
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11571-019-09536-x