Association of Apolipoprotein E ɛ4, Educational Level, and Sex With Tau Deposition and Tau-Mediated Metabolic Dysfunction in Older Adults | Dementia and Cognitive Impairment | JAMA Network Open | JAMA Network
[Skip to Navigation]
Access to paid content on this site is currently suspended due to excessive activity being detected from your IP address 35.153.100.128. Please contact the publisher to request reinstatement.
1.
Jack  CR  Jr, Knopman  DS, Jagust  WJ,  et al.  Tracking pathophysiological processes in Alzheimer’s disease: an updated hypothetical model of dynamic biomarkers.  Lancet Neurol. 2013;12(2):207-216. doi:10.1016/S1474-4422(12)70291-0PubMedGoogle ScholarCrossref
2.
Jack  CR  Jr, Bennett  DA, Blennow  K,  et al.  A/T/N: an unbiased descriptive classification scheme for Alzheimer disease biomarkers.  Neurology. 2016;87(5):539-547. doi:10.1212/WNL.0000000000002923PubMedGoogle ScholarCrossref
3.
Jack  CR  Jr, Wiste  HJ, Weigand  SD,  et al.  Age-specific and sex-specific prevalence of cerebral β-amyloidosis, tauopathy, and neurodegeneration in cognitively unimpaired individuals aged 50-95 years: a cross-sectional study.  Lancet Neurol. 2017;16(6):435-444. doi:10.1016/S1474-4422(17)30077-7PubMedGoogle ScholarCrossref
4.
Jack  CR  Jr, Bennett  DA, Blennow  K,  et al.  NIA-AA research framework: toward a biological definition of Alzheimer’s disease.  Alzheimers Dement. 2018;14(4):535-562. doi:10.1016/j.jalz.2018.02.018PubMedGoogle ScholarCrossref
5.
Ramanan  VK, Risacher  SL, Nho  K,  et al; Alzheimer’s Disease Neuroimaging Initiative.  GWAS of longitudinal amyloid accumulation on 18F-florbetapir PET in Alzheimer’s disease implicates microglial activation gene IL1RAP Brain. 2015;138(Pt 10):3076-3088. doi:10.1093/brain/awv231PubMedGoogle ScholarCrossref
6.
Ramanan  VK, Risacher  SL, Nho  K,  et al; Alzheimer’s Disease Neuroimaging Initiative.  APOE and BCHE as modulators of cerebral amyloid deposition: a florbetapir PET genome-wide association study.  Mol Psychiatry. 2014;19(3):351-357. doi:10.1038/mp.2013.19PubMedGoogle ScholarCrossref
7.
Vemuri  P, Lesnick  TG, Przybelski  SA,  et al.  Effect of intellectual enrichment on AD biomarker trajectories: longitudinal imaging study.  Neurology. 2016;86(12):1128-1135. doi:10.1212/WNL.0000000000002490PubMedGoogle ScholarCrossref
8.
Protas  HD, Chen  K, Langbaum  JB,  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.  JAMA Neurol. 2013;70(3):320-325. doi:10.1001/2013.jamaneurol.286PubMedGoogle ScholarCrossref
9.
Reiman  EM, Chen  K, Liu  X,  et al.  Fibrillar amyloid-beta burden in cognitively normal people at 3 levels of genetic risk for Alzheimer’s disease.  Proc Natl Acad Sci U S A. 2009;106(16):6820-6825. doi:10.1073/pnas.0900345106PubMedGoogle ScholarCrossref
10.
Vemuri  P, Wiste  HJ, Weigand  SD,  et al; Alzheimer’s Disease Neuroimaging Initiative.  Effect of apolipoprotein E on biomarkers of amyloid load and neuronal pathology in Alzheimer disease.  Ann Neurol. 2010;67(3):308-316.PubMedGoogle Scholar
11.
Strittmatter  WJ, Saunders  AM, Goedert  M,  et al.  Isoform-specific interactions of apolipoprotein E with microtubule-associated protein tau: implications for Alzheimer disease.  Proc Natl Acad Sci U S A. 1994;91(23):11183-11186. doi:10.1073/pnas.91.23.11183PubMedGoogle ScholarCrossref
12.
Wadhwani  AR, Affaneh  A, Van Gulden  S, Kessler  JA.  Neuronal apolipoprotein E4 increases cell death and phosphorylated tau release in Alzheimer disease.  Ann Neurol. 2019;85(5):726-739. doi:10.1002/ana.25455PubMedGoogle ScholarCrossref
13.
Shi  Y, Yamada  K, Liddelow  SA,  et al; Alzheimer’s Disease Neuroimaging Initiative.  ApoE4 markedly exacerbates tau-mediated neurodegeneration in a mouse model of tauopathy.  Nature. 2017;549(7673):523-527. doi:10.1038/nature24016PubMedGoogle ScholarCrossref
14.
Arenaza-Urquijo  EM, Gonneaud  J, Fouquet  M,  et al.  Interaction between years of education and APOE ε4 status on frontal and temporal metabolism.  Neurology. 2015;85(16):1392-1399. doi:10.1212/WNL.0000000000002034PubMedGoogle ScholarCrossref
15.
Snowdon  DA.  Aging and Alzheimer’s disease: lessons from the Nun Study.  Gerontologist. 1997;37(2):150-156. doi:10.1093/geront/37.2.150PubMedGoogle ScholarCrossref
16.
Rolstad  S, Nordlund  A, Eckerström  C,  et al.  High education may offer protection against tauopathy in patients with mild cognitive impairment.  J Alzheimers Dis. 2010;21(1):221-228. doi:10.3233/JAD-2010-091012PubMedGoogle ScholarCrossref
17.
Almeida  RP, Schultz  SA, Austin  BP,  et al.  Effect of cognitive reserve on age-related changes in cerebrospinal fluid biomarkers of Alzheimer disease.  JAMA Neurol. 2015;72(6):699-706. doi:10.1001/jamaneurol.2015.0098PubMedGoogle ScholarCrossref
18.
Ewers  M, Insel  PS, Stern  Y, Weiner  MW; Alzheimer’s Disease Neuroimaging Initiative.  Cognitive reserve associated with FDG-PET in preclinical Alzheimer disease.  Neurology. 2013;80(13):1194-1201. doi:10.1212/WNL.0b013e31828970c2PubMedGoogle ScholarCrossref
19.
Arenaza-Urquijo  EM, Vemuri  P.  Resistance vs resilience to Alzheimer disease: clarifying terminology for preclinical studies.  Neurology. 2018;90(15):695-703. doi:10.1212/WNL.0000000000005303PubMedGoogle ScholarCrossref
20.
Fisher  DW, Bennett  DA, Dong  H.  Sexual dimorphism in predisposition to Alzheimer’s disease.  Neurobiol Aging. 2018;70:308-324. doi:10.1016/j.neurobiolaging.2018.04.004PubMedGoogle ScholarCrossref
21.
Neu  SC, Pa  J, Kukull  W,  et al.  Apolipoprotein E genotype and sex risk factors for Alzheimer disease: a meta-analysis.  JAMA Neurol. 2017;74(10):1178-1189. doi:10.1001/jamaneurol.2017.2188PubMedGoogle ScholarCrossref
22.
Mielke  MM, Vemuri  P, Rocca  WA.  Clinical epidemiology of Alzheimer’s disease: assessing sex and gender differences.  Clin Epidemiol. 2014;6:37-48. doi:10.2147/CLEP.S37929PubMedGoogle ScholarCrossref
23.
Nebel  RA, Aggarwal  NT, Barnes  LL,  et al.  Understanding the impact of sex and gender in Alzheimer’s disease: a call to action.  Alzheimers Dement. 2018;14(9):1171-1183. doi:10.1016/j.jalz.2018.04.008PubMedGoogle ScholarCrossref
24.
Hohman  TJ, Dumitrescu  L, Barnes  LL,  et al; Alzheimer’s Disease Genetics Consortium and the Alzheimer’s Disease Neuroimaging Initiative.  Sex-specific association of apolipoprotein E with cerebrospinal fluid levels of tau.  JAMA Neurol. 2018;75(8):989-998. doi:10.1001/jamaneurol.2018.0821PubMedGoogle ScholarCrossref
25.
Buckley  RF, Mormino  EC, Chhatwal  J,  et al; Alzheimer’s Disease Neuroimaging Initiative.  Associations between baseline amyloid, sex, and APOE on subsequent tau accumulation in cerebrospinal fluid.  Neurobiol Aging. 2019;78:178-185. doi:10.1016/j.neurobiolaging.2019.02.019PubMedGoogle ScholarCrossref
26.
Altmann  A, Tian  L, Henderson  VW, Greicius  MD; Alzheimer’s Disease Neuroimaging Initiative Investigators.  Sex modifies the APOE-related risk of developing Alzheimer disease.  Ann Neurol. 2014;75(4):563-573. doi:10.1002/ana.24135PubMedGoogle ScholarCrossref
27.
Buckley  RF, Mormino  EC, Rabin  JS,  et al.  Sex differences in the association of global amyloid and regional tau deposition measured by positron emission tomography in clinically normal older adults.  JAMA Neurol. 2019;76(5):542-551. doi:10.1001/jamaneurol.2018.4693PubMedGoogle ScholarCrossref
28.
Roberts  RO, Geda  YE, Knopman  DS,  et al.  The Mayo Clinic Study of Aging: design and sampling, participation, baseline measures and sample characteristics.  Neuroepidemiology. 2008;30(1):58-69. doi:10.1159/000115751PubMedGoogle ScholarCrossref
29.
Petersen  RC, Roberts  RO, Knopman  DS,  et al.  Prevalence of mild cognitive impairment is higher in men: the Mayo Clinic Study of Aging.  Neurology. 2010;75(10):889-897. doi:10.1212/WNL.0b013e3181f11d85PubMedGoogle ScholarCrossref
30.
Rocca  WA, Yawn  BP, St Sauver  JL, Grossardt  BR, Melton  LJ  III.  History of the Rochester Epidemiology Project: half a century of medical records linkage in a US population.  Mayo Clin Proc. 2012;87(12):1202-1213. doi:10.1016/j.mayocp.2012.08.012PubMedGoogle ScholarCrossref
31.
St Sauver  JL, Grossardt  BR, Yawn  BP,  et al.  Data resource profile: the Rochester Epidemiology Project (REP) medical records-linkage system.  Int J Epidemiol. 2012;41(6):1614-1624. doi:10.1093/ije/dys195PubMedGoogle ScholarCrossref
32.
Hixson  JE, Vernier  DT.  Restriction isotyping of human apolipoprotein E by gene amplification and cleavage with HhaI.  J Lipid Res. 1990;31(3):545-548.PubMedGoogle Scholar
33.
Vemuri  P, Lesnick  TG, Przybelski  SA,  et al.  Age, vascular health, and Alzheimer disease biomarkers in an elderly sample.  Ann Neurol. 2017;82(5):706-718. doi:10.1002/ana.25071PubMedGoogle ScholarCrossref
34.
Jack  CR  Jr, Wiste  HJ, Weigand  SD,  et al.  Defining imaging biomarker cut points for brain aging and Alzheimer’s disease.  Alzheimers Dement. 2017;13(3):205-216. doi:10.1016/j.jalz.2016.08.005PubMedGoogle ScholarCrossref
35.
Klunk  WE, Engler  H, Nordberg  A,  et al.  Imaging brain amyloid in Alzheimer’s disease with Pittsburgh compound-B.  Ann Neurol. 2004;55(3):306-319. doi:10.1002/ana.20009PubMedGoogle ScholarCrossref
36.
Lowe  VJ, Bruinsma  TJ, Wiste  HJ,  et al.  Cross-sectional associations of tau-PET signal with cognition in cognitively unimpaired adults.  Neurology. 2019;93(1):e29-e39. doi:10.1212/WNL.0000000000007728PubMedGoogle ScholarCrossref
37.
Vemuri  P, Lowe  VJ, Knopman  DS,  et al.  Tau-PET uptake: regional variation in average SUVR and impact of amyloid deposition.  Alzheimers Dement (Amst). 2016;6:21-30. doi:10.1016/j.dadm.2016.12.010PubMedGoogle Scholar
38.
Johnson  KA, Schultz  A, Betensky  RA,  et al.  Tau positron emission tomographic imaging in aging and early Alzheimer disease.  Ann Neurol. 2016;79(1):110-119. doi:10.1002/ana.24546PubMedGoogle ScholarCrossref
39.
Geroldi  C, Pihlajamäki  M, Laakso  MP,  et al.  APOE-epsilon4 is associated with less frontal and more medial temporal lobe atrophy in AD.  Neurology. 1999;53(8):1825-1832. doi:10.1212/WNL.53.8.1825PubMedGoogle ScholarCrossref
40.
Zhao  N, Liu  CC, Van Ingelgom  AJ,  et al.  APOE ε2 is associated with increased tau pathology in primary tauopathy.  Nat Commun. 2018;9(1):4388. doi:10.1038/s41467-018-06783-0PubMedGoogle ScholarCrossref
41.
Deming  Y, Li  Z, Kapoor  M,  et al; Alzheimer’s Disease Neuroimaging Initiative; Alzheimer Disease Genetic Consortium.  Genome-wide association study identifies four novel loci associated with Alzheimer’s endophenotypes and disease modifiers.  Acta Neuropathol. 2017;133(5):839-856. doi:10.1007/s00401-017-1685-yPubMedGoogle ScholarCrossref
42.
Ossenkoppele  R, Schonhaut  DR, Schöll  M,  et al.  Tau PET patterns mirror clinical and neuroanatomical variability in Alzheimer’s disease.  Brain. 2016;139(pt 5):1551-1567. doi:10.1093/brain/aww027PubMedGoogle ScholarCrossref
43.
Jack  CR  Jr, Wiste  HJ, Lesnick  TG,  et al.  Brain β-amyloid load approaches a plateau.  Neurology. 2013;80(10):890-896. doi:10.1212/WNL.0b013e3182840bbePubMedGoogle ScholarCrossref
44.
Hohman  TJ, Dumitrescu  L, Oksol  A, Wagener  M, Gifford  KA, Jefferson  AL; Alzheimer’s Disease Neuroimaging Initiative.  APOE allele frequencies in suspected non-amyloid pathophysiology (SNAP) and the prodromal stages of Alzheimer’s disease.  PLoS One. 2017;12(11):e0188501. doi:10.1371/journal.pone.0188501PubMedGoogle Scholar
45.
Bell  WR, An  Y, Kageyama  Y,  et al.  Neuropathologic, genetic, and longitudinal cognitive profiles in primary age-related tauopathy (PART) and Alzheimer’s disease.  Alzheimers Dement. 2019;15(1):8-16. doi:10.1016/j.jalz.2018.07.215PubMedGoogle ScholarCrossref
46.
Farfel  JM, Yu  L, De Jager  PL, Schneider  JA, Bennett  DA.  Association of APOE with tau-tangle pathology with and without β-amyloid.  Neurobiol Aging. 2016;37:19-25. doi:10.1016/j.neurobiolaging.2015.09.011PubMedGoogle ScholarCrossref
47.
La Joie  R, Bourakova  V, Visani  A,  et al. Does APOE E4 have an a(beta)-independent effecton tau pathology? neuroimaging investigations in cognitively normal elders and patients with Alzheimer’s disease. In: Proceedings from the 142nd Annual Meeting of the American Neurological Association; October 15-17, 2017; San Diego, CA. Abstract M183.
48.
Ulrich  JD, Ulland  TK, Mahan  TE,  et al.  ApoE facilitates the microglial response to amyloid plaque pathology.  J Exp Med. 2018;215(4):1047-1058. doi:10.1084/jem.20171265PubMedGoogle ScholarCrossref
49.
Heneka  MT, Carson  MJ, El Khoury  J,  et al.  Neuroinflammation in Alzheimer’s disease.  Lancet Neurol. 2015;14(4):388-405. doi:10.1016/S1474-4422(15)70016-5PubMedGoogle ScholarCrossref
50.
Mielke  MM, Wiste  HJ, Weigand  SD,  et al.  Indicators of amyloid burden in a population-based study of cognitively normal elderly.  Neurology. 2012;79(15):1570-1577. doi:10.1212/WNL.0b013e31826e2696PubMedGoogle ScholarCrossref
51.
Holland  D, Desikan  RS, Dale  AM, McEvoy  LK; Alzheimer’s Disease Neuroimaging Initiative.  Higher rates of decline for women and apolipoprotein E epsilon4 carriers.  AJNR Am J Neuroradiol. 2013;34(12):2287-2293. doi:10.3174/ajnr.A3601PubMedGoogle ScholarCrossref
52.
Mazure  CM, Swendsen  J.  Sex differences in Alzheimer’s disease and other dementias.  Lancet Neurol. 2016;15(5):451-452. doi:10.1016/S1474-4422(16)00067-3PubMedGoogle ScholarCrossref
53.
Ferretti  MT, Iulita  MF, Cavedo  E,  et al; Women’s Brain Project and the Alzheimer Precision Medicine Initiative.  Sex differences in Alzheimer disease—the gateway to precision medicine.  Nat Rev Neurol. 2018;14(8):457-469. doi:10.1038/s41582-018-0032-9PubMedGoogle ScholarCrossref
54.
Hoenig  MC, Bischof  GN, Hammes  J,  et al.  Tau pathology and cognitive reserve in Alzheimer’s disease.  Neurobiol Aging. 2017;57:1-7. doi:10.1016/j.neurobiolaging.2017.05.004PubMedGoogle ScholarCrossref
55.
Hoenig  MC, Bischof  GN, Onur  OA,  et al; Alzheimer’s Disease Neuroimaging Initiative.  Level of education mitigates the impact of tau pathology on neuronal function.  Eur J Nucl Med Mol Imaging. 2019;46(9):1787-1795. doi:10.1007/s00259-019-04342-3PubMedGoogle ScholarCrossref
56.
Arenaza-Urquijo  EM, Przybelski  SA, Lesnick  TL,  et al.  The metabolic brain signature of cognitive resilience in the 80+: beyond Alzheimer pathologies.  Brain. 2019;142(4):1134-1147. doi:10.1093/brain/awz037PubMedGoogle ScholarCrossref
57.
Kuczynski  B, Jagust  W, Chui  HC, Reed  B.  An inverse association of cardiovascular risk and frontal lobe glucose metabolism.  Neurology. 2009;72(8):738-743. doi:10.1212/01.wnl.0000343005.35498.e5PubMedGoogle ScholarCrossref
58.
Rabin  JS, Yang  HS, Schultz  AP,  et al.  Vascular risk and β-amyloid are synergistically associated with cortical tau.  Ann Neurol. 2019;85(2):272-279. doi:10.1002/ana.25399PubMedGoogle ScholarCrossref
59.
Leuzy  A, Chiotis  K, Lemoine  L,  et al.  Tau PET imaging in neurodegenerative tauopathies-still a challenge.  Mol Psychiatry. 2019;24(8):1112-1134. doi:10.1038/s41380-018-0342-8PubMedGoogle ScholarCrossref
60.
Nelson  PT, Dickson  DW, Trojanowski  JQ,  et al.  Limbic-predominant age-related TDP-43 encephalopathy (LATE): consensus working group report.  Brain. 2019;142(6):1503-1527. doi:10.1093/brain/awz099PubMedGoogle ScholarCrossref
61.
Wilson  RS, Yu  L, Lamar  M, Schneider  JA, Boyle  PA, Bennett  DA.  Education and cognitive reserve in old age.  Neurology. 2019;92(10):e1041-e1050. doi:10.1212/WNL.0000000000007036PubMedGoogle ScholarCrossref
62.
Knopman  DS.  Lowering of amyloid-beta by β-secretase inhibitors—some informative failures.  N Engl J Med. 2019;380(15):1476-1478. doi:10.1056/NEJMe1903193PubMedGoogle ScholarCrossref
Limit 200 characters
Limit 25 characters
Conflicts of Interest Disclosure

Identify all potential conflicts of interest that might be relevant to your comment.

Conflicts of interest comprise financial interests, activities, and relationships within the past 3 years including but not limited to employment, affiliation, grants or funding, consultancies, honoraria or payment, speaker's bureaus, stock ownership or options, expert testimony, royalties, donation of medical equipment, or patents planned, pending, or issued.

Err on the side of full disclosure.

If you have no conflicts of interest, check "No potential conflicts of interest" in the box below. The information will be posted with your response.

Not all submitted comments are published. Please see our commenting policy for details.

Limit 140 characters
Limit 3600 characters or approximately 600 words
    Original Investigation
    Neurology
    October 23, 2019

    Association of Apolipoprotein E ɛ4, Educational Level, and Sex With Tau Deposition and Tau-Mediated Metabolic Dysfunction in Older Adults

    Author Affiliations
    • 1Department of Neurology, Mayo Clinic–Rochester, Rochester, Minnesota
    • 2Department of Health Sciences Research, Mayo Clinic–Rochester, Rochester, Minnesota
    • 3Department of Radiology, Mayo Clinic–Rochester, Rochester, Minnesota
    JAMA Netw Open. 2019;2(10):e1913909. doi:10.1001/jamanetworkopen.2019.13909
    Key Points español 中文 (chinese)

    Question  Are the apolipoprotein E ɛ4 allele, educational levels, and sex associated with tau deposition and tau-mediated metabolic dysfunction in older adults?

    Findings  In a population-based cohort study, regional tau deposition was most significantly associated with global amyloid burden without any main associations of apolipoprotein E ɛ4, education, or sex. Via interaction models, women displayed a higher degree of tau-mediated metabolic dysfunction in the entorhinal cortex compared with men.

    Meaning  These findings suggest that in older adults, tau deposition is most significantly associated with amyloidosis, but other factors, including sex, may be associated with differential resilience to tau pathology.

    Abstract

    Importance  While amyloidosis is an early event in the Alzheimer disease (AD) biomarker cascade, a complex interplay among the apolipoprotein E (APOE) ɛ4 allele, educational levels, and sex may be associated with an individual’s resilience to dementia.

    Objective  To assess whether APOE ɛ4, educational levels, and sex are associated with regional tau deposition and tau-mediated metabolic dysfunction in older adults.

    Design, Setting, and Participants  Population-based cohort study of individuals aged 65 years and older enrolled between January 1, 2004, and May 1, 2018, in the Mayo Clinic Study of Aging, a prospective longitudinal study of cognitive aging in Olmsted County, Minnesota.

    Main Outcomes and Measures  The primary outcomes were cross-sectional tau burden and the fluorodeoxyglucose (FDG) to tau ratio (as a measure of tau-mediated metabolic dysfunction) assessed by positron emission tomography for 43 atlas-defined regions, with specific focus on the entorhinal, inferior temporal, and posterior cingulate cortices.

    Exposures  Using linear regression, APOE ɛ4 status and years of education were the primary exposure variables, with sex additionally investigated through interaction models.

    Results  The sample included 325 individuals (173 [53%] male; mean [SD] age, 76.1 [7.2] years; 291 [90%] cognitively unimpaired). Although APOE ɛ4 was nominally associated with higher tau deposition (β = 0.05 [95% CI, 0.02-0.09]; P = .001; Cohen d = 0.40) and lower FDG to tau ratio (β = −0.05 [95% CI, −0.08 to −0.01]; P = .008; Cohen d = 0.33) in the entorhinal cortex, these associations were completely attenuated after controlling for global amyloid burden. Education was not associated with regional tau burden or FDG to tau ratio. In the 3 regions of interest, global amyloid burden accounted for the largest proportion of variance in tau deposition among the candidate variables assessed. In the entorhinal cortex, significant interactions were identified between APOE ɛ4 and global amyloid burden on tau (β = 0.25; SE = 0.06; P < .001) and between sex and tau burden on FDG metabolism (β = 0.10; SE = 0.05; P = .049).

    Conclusions and Relevance  These results suggest that (1) tau deposition is most significantly associated with amyloidosis; (2) in the presence of abundant amyloidosis, APOE ɛ4 may be associated with accelerated entorhinal cortex tau deposition; and (3) women may have lower resilience to tau, manifested by a higher degree of metabolic dysfunction in the entorhinal cortex in response to tau pathology.

    ×