The Association between Polygenic Hazard and Markers of Alzheimer’s Disease Following Stratification for APOE Genotype

Author(s): Matteo De Marco, Riccardo Manca, Janine Kirby, Guillaume M. Hautbergue, Daniel J. Blackburn, Stephen B. Wharton, Annalena Venneri*, Alzheimer’s Disease Neuroimaging Initiative

Journal Name: Current Alzheimer Research

Volume 17 , Issue 7 , 2020


  Journal Home
Translate in Chinese
Become EABM
Become Reviewer
Call for Editor

Abstract:

Background: Research indicates that polygenic indices of risk of Alzheimer’s disease are linked to clinical profiles.

Objective: Given the “genetic centrality” of the APOE gene, we tested whether this held true for both APOE-ε4 carriers and non-carriers.

Methods: A polygenic hazard score (PHS) was extracted from 784 non-demented participants recruited in the Alzheimer’s Disease Neuroimaging Initiative and stratified by APOE ε4 status. Datasets were split into sub-cohorts defined by clinical (unimpaired/MCI) and amyloid status (Aβ+/Aβ-). Linear models were devised in each sub-cohort and for each APOE-ε4 status to test the association between PHS and memory, executive functioning and grey-matter volumetric maps.

Results: PHS predicted memory and executive functioning in ε4ε3 MCI patients, memory in ε3ε3 MCI patients, and memory in ε4ε3 Aβ+ participants. PHS also predicted volume in sensorimotor regions in ε3ε3 Aβ+ participants.

Conclusion: The link between polygenic hazard and neurocognitive variables varies depending on APOE-ε4 allele status. This suggests that clinical phenotypes might be influenced by complex genetic interactions.

Keywords: Mild cognitive impairment, apolipoprotein, memory, executive function, polygenic traits, amyloid.

[1]
Lahiri DK. Lessons from Alzheimer’s disease (AD) clinical trials: Instead of “A-Drug”, AD-D prevention to Avert AD. Curr Alzheimer Res 2019; 16(4): 279-80.
[http://dx.doi.org/10.2174/156720501604190424114752] [PMID: 31104627]
[2]
Lam B, Masellis M, Freedman M, Stuss DT, Black SE. Clinical, imaging, and pathological heterogeneity of the Alzheimer’s disease syndrome. Alzheimers Res Ther 2013; 5(1): 1.
[http://dx.doi.org/10.1186/alzrt155] [PMID: 23302773]
[3]
Hartmann S, Ledur Kist TB. A review of biomarkers of Alzheimer’s disease in noninvasive samples. Biomarkers Med 2018; 12(6): 677-90.
[http://dx.doi.org/10.2217/bmm-2017-0388] [PMID: 29896987]
[4]
Lambert JC, Ibrahim-Verbaas CA, Harold D, et al. European Alzheimer’s disease initiative (eadi); genetic and environmental risk in Alzheimer’s disease; Alzheimer’s disease genetic consortium; cohorts for heart and aging research in genomic epidemiology. Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer’s disease. Nat Genet 2013; 45(12): 1452-8.
[http://dx.doi.org/10.1038/ng.2802] [PMID: 24162737]
[5]
Medway C, Morgan K. Review: The genetics of Alzheimer’s disease; putting flesh on the bones. Neuropathol Appl Neurobiol 2014; 40(2): 97-105.
[http://dx.doi.org/10.1111/nan.12101] [PMID: 24443964]
[6]
Cuyvers E, Sleegers K. Genetic variations underlying Alzheimer’s disease: Evidence from genome-wide association studies and beyond. Lancet Neurol 2016; 15(8): 857-68.
[http://dx.doi.org/10.1016/S1474-4422(16)00127-7] [PMID: 27302364]
[7]
Zhang P, Qin W, Wang D, et al. Impacts of PICALM and CLU variants associated with Alzheimer’s disease on the functional connectivity of the hippocampus in healthy young adults. Brain Struct Funct 2015; 220(3): 1463-75.
[http://dx.doi.org/10.1007/s00429-014-0738-4] [PMID: 24578178]
[8]
Zhang X, Yu JT, Li J, et al. Bridging Integrator 1 (BIN1) genotype effects on working memory, hippocampal volume, and functional connectivity in young healthy individuals. Neuropsychopharmacology 2015; 40(7): 1794-803.
[http://dx.doi.org/10.1038/npp.2015.30] [PMID: 25630570]
[9]
Zhu XC, Wang HF, Jiang T, et al. Alzheimer’s Disease Neuroimaging Initiative. Effect of CR1 genetic variants on cerebrospinal fluid and neuroimaging biomarkers in healthy, mild cognitive impairment and Alzheimer’s disease cohorts. Mol Neurobiol 2017; 54(1): 551-62.
[http://dx.doi.org/10.1007/s12035-015-9638-8] [PMID: 26742530]
[10]
Chasioti D, Yan J, Nho K, Saykin AJ. Progress in polygenic composite scores in Alzheimer’s and other complex diseases. Trends Genet 2019; 35(5): 371-82.
[http://dx.doi.org/10.1016/j.tig.2019.02.005] [PMID: 30922659]
[11]
Leonenko G, Sims R, Shoai M, et al. GERAD consortium. Polygenic risk and hazard scores for Alzheimer’s disease prediction. Ann Clin Transl Neurol 2019; 6(3): 456-65.
[http://dx.doi.org/10.1002/acn3.716] [PMID: 30911569]
[12]
Axelrud LK, Santoro ML, Pine DS, et al. Polygenic risk score for Alzheimer’s disease: Implications for memory performance and hippocampal volumes in early life. Am J Psychiatry 2018; 175(6): 555-63.
[http://dx.doi.org/10.1176/appi.ajp.2017.17050529] [PMID: 29495896]
[13]
Li J, Zhang X, Li A, et al. Polygenic risk for Alzheimer’s disease influences precuneal volume in two independent general populations. Neurobiol Aging 2018; 64: 116-22.
[http://dx.doi.org/10.1016/j.neurobiolaging.2017.12.022] [PMID: 29358118]
[14]
Tan CH, Bonham LW, Fan CC, et al. Alzheimer’s Disease Neuroimaging Initiative. Polygenic hazard score, amyloid deposition and Alzheimer’s neurodegeneration. Brain 2019; 142(2): 460-70.
[http://dx.doi.org/10.1093/brain/awy327] [PMID: 30689776]
[15]
Verhaaren BF, Vernooij MW, Koudstaal PJ, et al. Alzheimer’s disease genes and cognition in the nondemented general population. Biol Psychiatry 2013; 73(5): 429-34.
[http://dx.doi.org/10.1016/j.biopsych.2012.04.009] [PMID: 22592056]
[16]
Adams HH, de Bruijn RF, Hofman A, et al. Genetic risk of neurodegenerative diseases is associated with mild cognitive impairment and conversion to dementia. Alzheimers Dement 2015; 11(11): 1277-85.
[http://dx.doi.org/10.1016/j.jalz.2014.12.008] [PMID: 25916564]
[17]
Andrews SJ, Das D, Cherbuin N, Anstey KJ, Easteal S. Association of genetic risk factors with cognitive decline:The PATH through life project. Neurobiol Aging 2016; 41: 150-8.
[http://dx.doi.org/10.1016/j.neurobiolaging.2016.02.016] [PMID: 27103528]
[18]
Desikan RS, Fan CC, Wang Y, et al. Genetic assessment of age-associated Alzheimer disease risk: Development and validation of a polygenic hazard score. PLoS Med 2017; 14(3)e1002258
[http://dx.doi.org/10.1371/journal.pmed.1002258] [PMID: 28323831]
[19]
Kauppi K, Fan CC, McEvoy LK, et al. Alzheimer’s Disease Neuroimaging Initiative. Combining polygenic hazard score with volumetric MRI and cognitive measures improves prediction of progression from mild cognitive impairment to Alzheimer’s disease. Front Neurosci 2018; 12: 260.
[http://dx.doi.org/10.3389/fnins.2018.00260] [PMID: 29760643]
[20]
Tan CH, Fan CC, Mormino EC, et al. Alzheimer’s Disease Neuroimaging Initiative. Polygenic hazard score: An enrichment marker for Alzheimer’s associated amyloid and tau deposition. Acta Neuropathol 2018; 135(1): 85-93.
[http://dx.doi.org/10.1007/s00401-017-1789-4] [PMID: 29177679]
[21]
Mattsson N, Groot C, Jansen WJ, et al. Prevalence of the apolipoprotein E ε4 allele in amyloid β positive subjects across the spectrum of Alzheimer’s disease. Alzheimers Dement 2018; 14(7): 913-24.
[http://dx.doi.org/10.1016/j.jalz.2018.02.009] [PMID: 29601787]
[22]
Jack CR Jr, Bernstein MA, Fox NC, et al. The Alzheimer’s disease neuroimaging initiative (ADNI): MRI methods. J Magn Reson Imaging 2008; 27(4): 685-91.
[http://dx.doi.org/10.1002/jmri.21049] [PMID: 18302232]
[23]
Ashburner J, Friston KJ. Voxel-based morphometry-the methods. Neuroimage 2000; 11(6 Pt 1): 805-21.
[http://dx.doi.org/10.1006/nimg.2000.0582] [PMID: 10860804]
[24]
Malone IB, Leung KK, Clegg S, et al. Accurate automatic estimation of total intracranial volume: A nuisance variable with less nuisance. Neuroimage 2015; 104: 366-72.
[http://dx.doi.org/10.1016/j.neuroimage.2014.09.034] [PMID: 25255942]
[25]
Jack CR Jr, Bennett DA, Blennow K, et al. Contributors. NIA-AA Research Framework: Toward a biological definition of Alzheimer’s disease. Alzheimers Dement 2018; 14(4): 535-62.
[http://dx.doi.org/10.1016/j.jalz.2018.02.018] [PMID: 29653606]
[26]
Hansson O, Seibyl J, Stomrud E, et al. Swedish BioFINDER study group; Alzheimer’s Disease Neuroimaging Initiative. CSF biomarkers of Alzheimer’s disease concord with amyloid-β PET and predict clinical progression: A study of fully automated immunoassays in BioFINDER and ADNI cohorts. Alzheimers Dement 2018; 14(11): 1470-81.
[http://dx.doi.org/10.1016/j.jalz.2018.01.010] [PMID: 29499171]
[27]
Crane PK, Carle A, Gibbons LE, et al. Alzheimer’s Disease Neuroimaging Initiative. Development and assessment of a composite score for memory in the Alzheimer’s Disease Neuroimaging Initiative (ADNI). Brain Imaging Behav 2012; 6(4): 502-16.
[http://dx.doi.org/10.1007/s11682-012-9186-z] [PMID: 22782295]
[28]
Gibbons LE, Carle AC, Mackin RS, et al. Alzheimer’s Disease Neuroimaging Initiative. A composite score for executive functioning, validated in Alzheimer’s Disease Neuroimaging Initiative (ADNI) participants with baseline mild cognitive impairment. Brain Imaging Behav 2012; 6(4): 517-27.
[http://dx.doi.org/10.1007/s11682-012-9176-1] [PMID: 22644789]
[29]
Lancaster JL, Woldorff MG, Parsons LM, et al. Automated Talairach atlas labels for functional brain mapping. Hum Brain Mapp 2000; 10(3): 120-31.
[PMID: 10912591]
[30]
Fan L, Li H, Zhuo J, et al. The Human Brainnetome Atlas: A new brain atlas based on connectional architecture. Cereb Cortex 2016; 26(8): 3508-26.
[http://dx.doi.org/10.1093/cercor/bhw157] [PMID: 27230218]
[31]
Melzer D, Dik MG, van Kamp GJ, Jonker C, Deeg DJ. The apolipoprotein E e4 polymorphism is strongly associated with poor mobility performance test results but not self-reported limitation in older people. J Gerontol A Biol Sci Med Sci 2005; 60(10): 1319-23.
[http://dx.doi.org/10.1093/gerona/60.10.1319] [PMID: 16282567]
[32]
Buchman AS, Boyle PA, Wilson RS, Beck TL, Kelly JF, Bennett DA. Apolipoprotein E e4 allele is associated with more rapid motor decline in older persons. Alzheimer Dis Assoc Disord 2009; 23(1): 63-9.
[http://dx.doi.org/10.1097/WAD.0b013e31818877b5] [PMID: 19266700]
[33]
Nadkarni NK, Perera S, Snitz BE, et al. Association of brain amyloid-β with slow gait in elderly individuals without dementia: Influence of cognition and apolipoprotein E ε4 genotype. JAMA Neurol 2017; 74(1): 82-90.
[http://dx.doi.org/10.1001/jamaneurol.2016.3474] [PMID: 27842173]
[34]
Shu H, Shi Y, Chen G, et al. Distinct neural correlates of episodic memory among apolipoprotein E alleles in cognitively normal elderly. Brain Imaging Behav 2019; 13(1): 255-69.
[http://dx.doi.org/10.1007/s11682-017-9818-4] [PMID: 29396739]
[35]
Ge T, Sabuncu MR, Smoller JW, Sperling RA, Mormino EC. Alzheimer’s disease Neuroimaging Initiative. Dissociable influences of APOE ε4 and polygenic risk of AD dementia on amyloid and cognition. Neurology 2018; 90(18): e1605-12.
[http://dx.doi.org/10.1212/WNL.0000000000005415] [PMID: 29592889]
[36]
Karch CM, Cruchaga C, Goate AM. Alzheimer’s disease genetics: From the bench to the clinic. Neuron 2014; 83: 11-26.
[37]
Escott-Price V, Myers AJ, Huentelman M, Hardy J. Polygenic risk score analysis of pathologically confirmed Alzheimer disease. Ann Neurol 2017; 82(2): 311-4.
[http://dx.doi.org/10.1002/ana.24999] [PMID: 28727176]
[38]
Escott-Price V, Myers A, Huentelman M, Shoai M, Hardy J. Polygenic risk score analysis of Alzheimer’s disease in cases without APOE4 or APOE2 alleles. J Prev Alzheimers Dis 2019; 6(1): 16-9.
[PMID: 30569081]
[39]
Andrews SJ, Fulton-Howard B, Goate A. Interpretation of risk loci from genome-wide association studies of Alzheimer’s disease. Lancet Neurol 2020; 19(4): 326-35.
[http://dx.doi.org/10.1016/S1474-4422(19)30435-1] [PMID: 31986256]
[40]
Altmann A, Scelsi MA, Shoai M, de Silva E, Aksman LM, Cash DM, et al. A comprehensive analysis of methods for assessing polygenic burden on Alzheimer's disease pathology and risk beyond APOE Brain Commun 2020; 2(1) fcz047
[http://dx.doi.org/ 10.1093/braincomms/fcz047]
[41]
Maloney B, Ge YW, Petersen RC, et al. Functional characterization of three single-nucleotide polymorphisms present in the human APOE promoter sequence: Differential effects in neuronal cells and on DNA-protein interactions. Am J Med Genet B Neuropsychiatr Genet 2010; 153B(1): 185-201.
[PMID: 19504470]


Rights & PermissionsPrintExport Cite as

Article Details

VOLUME: 17
ISSUE: 7
Year: 2020
Page: [667 - 679]
Pages: 13
DOI: 10.2174/1567205017666201006161800
Price: $65

Article Metrics

PDF: 19
HTML: 15