CoChat
Sign Up
Cited by 151Dementia and Cognitive Impairment ResearchAlzheimer's disease research and treatmentsAmyotrophic Lateral Sclerosis Research

Longitudinal brain imaging in preclinical Alzheimer disease: impact of APOE ε4 genotype

Open access
Mishra, Shruti, Blazey, Tyler M, Holtzman, David M, Cruchaga, Carlos, Su, Yi, Morris, John C, Benzinger, Tammie L S, Gordon, Brian A·2018·Brain
DOI 10.1093/brain/awy103PMC PMC5972633
Open this paper in CoChat — free accountOpen PDF

Abstract

While prior work reliably demonstrates that the APOE ɛ4 allele has deleterious group level effects on Alzheimer disease pathology, the homogeneity of its influence across the lifespan and spatially in the brain remains unknown. Further it is unclear what combinations of factors at an individual level lead to observed group level effects of APOE genotype. To evaluate the impact of the APOE genotype on disease trajectories, we examined longitudinal MRI and PET imaging in a cohort of 497 cognitively normal middle and older aged participants. A whole-brain regional approach was used to evaluate the spatial effects of genotype on longitudinal change of amyloid-β pathology and cortical atrophy. Carriers of the ɛ4 allele had increased longitudinal accumulation of amyloid-β pathology diffusely through the cortex, but the emergence of this effect across the lifespan differed greatly by region (e.g. age 49 in precuneus, but 65 in the visual cortex) with the detrimental influence already being evident in some regions in middle age. This increased group level effect on accumulation was due to a greater proportion of ɛ4 carriers developing amyloid-β pathology, on average doing so at an earlier age, and having faster amyloid-β accumulation even after accounting for baseline amyloid-β levels. APOE ɛ4 carriers displayed faster rates of structural loss in primarily constrained to the medial temporal lobe structures at around 50 years, although this increase was modest and proportional to the elevated disease severity in APOE ɛ4 carriers. This work indicates that influence of the APOE gene on pathology can be detected starting in middle age.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1093/brain/awy103

Cites

15 of 15 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • There is a strong positive correlation between the APOE ε4 allele and Aβ pathology in human AD brains, with the highest Aβ burden in homozygous APOE ε4 carriers.

    “there is a strong positive correlation between the APOE ε4 allele and Aβ pathology in human AD brains with the highest Aβ burden found in homozygous APOE ε4 carriers”

    From ApoE4 reduction: An emerging and promising therapeutic strategy for Alzheimer's disease (2022) · cites this paper as Mishra et al 2018

    The Results report earlier and greater rates of amyloid-β accumulation in APOE ε4 homozygotes than heterozygotes, supporting a genotype-related difference. But the Discussion describes the homozygote analysis as exploratory and based on a very small sample; the study examined cognitively normal adults, not brains of people with diagnosed AD. Greater accumulation rates do not establish the claim that homozygotes had the highest Aβ burden. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Cites

Flagged first, then by citations

Research works printed but not linked: 73

  1. Bateman RJ, Xiong C, Benzinger TLS, Fagan AM, Goate A, Fox NC, et al. Clinical and biomarker changes in dominantly inherited Alzheimer's disease. N Engl J Med 2012; 367: 795-804.
  2. Benzinger TLS, Blazey T, Jack CR, Koeppe RA, Su Y, Xiong C, et al. Regional variability of imaging biomarkers in autosomal dominant Alzheimer's disease. Proc Natl Acad Sci USA 2013; 110: E4502-9.
  3. Bilgel M, An Y, Zhou Y, Wong DF, Prince JL, Ferrucci L, et al. Individual estimates of age at detectable amyloid onset for risk factor assessment. Alzheimers Dement 2016; 12: 373-9.
  4. Buckner RL, Head D, Parker J, Fotenos AF, Marcus D, Morris JC, et al. A unified approach for morphometric and functional data analysis in young, old, and demented adults using automated atlas-based head size normalization: reliability and validation against manual measurement of total intracranial volume. Neuroimage 2004; 23: 724-38.
  5. Carpenter B, Lee D, Brubaker MA, Riddell A, Gelman A, Goodrich B, et al. Stan: a probabilistic programming language. J Stat Softw 2017; 76. Chen K, Reiman EM, Alexander GE, Caselli RJ, Gerkin R, Bandy D, et al. Correlations between apolipoprotein E "4 gene dose and whole brain atrophy rates. Am J Psychiatry 2007; 164: 916-21.
  6. Cohen AD, Mowrey W, Weissfeld LA, Aizenstein HJ, McDade E, Mountz JM, et al. Classification of amyloid-positivity in controls: comparison of visual read and quantitative approaches. Neuroimage 2013; 71: 207-15.
  7. Cohen RM, Small C, Lalonde F, Friz J, Sunderland T. Effect of apo- lipoprotein E genotype on hippocampal volume loss in aging healthy women. Neurology 2001; 57: 2223-8.
  8. Corder E, Saunders A, Strittmatter W, Schmechel D, Gaskell P, Small G, et al. Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families. Science 1993; 261: 921-3.
  9. Du AT, Schuff N, Chao LL, Kornak J, Jagust WJ, Kramer JH, et al. Age effects on atrophy rates of entorhinal cortex and hippocampus. Neurobiol Aging 2006; 27: 733-40.
  10. Fan M, Liu B, Zhou Y, Zhen X, Xu C, Jiang T. Cortical thickness is associated with different apolipoprotein E genotypes in healthy eld- erly adults. Neurosci Lett 2010; 479: 332-6.
  11. Fischl B. FreeSurfer. Neuroimage 2012; 62: 774-81.
  12. Fischl B, Dale AMM. Measuring the thickness of the human cerebral cortex from magnetic resonance images. Proc Natl Acad Sci USA 2000; 97: 11050-5.
  13. Fleisher AS, Chen K, Liu X, Ayutyanont N, Roontiva A, Thiyyagura P, et al. Apolipoprotein E "4 and age effects on florbetapir positron emission tomography in healthy aging and Alzheimer disease. Neurobiol Aging 2013; 34: 1-12.
  14. Fouquet M, Besson FL, Gonneaud J, La Joie R, Che ´telat G. Imaging brain effects of APOE4 in cognitively normal individuals across the lifespan. Neuropsychol Rev 2014; 24: 290-9.
  15. Galasko D, Chang L, Motter R, Clark CM, Kaye J, Knopman D, et al. High cerebrospinal fluid Tau and low amyloid b42 levels in the clinical diagnosis of Alzheimer disease and relation to apolipopro- tein E genotype. Arch Neurol 1998; 55: 937-45.
  16. Gelman A, Rubin DB. Inference from iterative simulation using mul- tiple sequences linked references are available on JSTOR for this article: inference from iterative simulation using multiple sequences. Stat Sci 1992; 7: 457-72.
  17. Geroldi C, Pihlajama ¨ki M, Laakso MP, Decarli C, Beltramello A, Bianchetti A, et al. APOE-epsilon4 is associated with less frontal and more medial temporal lobe atrophy in AD. Neurology 1999; 53: 1825-32.
  18. Gordon BA, Blazey T, Benzinger TL. Regional variability in Alzheimer's disease biomarkers. Future Neurol 2014; 9: 131-4.
  19. Gordon BA, Najmi S, Hsu P, Roe CM, Morris JC, Benzinger TLS. The effects of white matter hyperintensities and amyloid deposition on Alzheimer dementia. Neuroimage Clin 2015; 8: 246-52.
  20. Gottesman RF, Schneider ALC, Zhou Y, Chen X, Green E, Gupta N, et al. The ARIC-PET amyloid imaging study. Neurology 2016; 87: 473-80.
  21. Grimmer T, Tholen S, Yousefi BH, Alexopoulos P, Frschler A, Frstl H, et al. Progression of cerebral amyloid load is associated with the apolipoprotein e e4 genotype in Alzheimer's disease. Biol Psychiatry 2010; 68: 879-84.
  22. Holtzman D, Herz J. Apolipoprotein E and apolipoprotein receptors: normal biology and roles in Alzheimer's disease. Cold Spring Harb Perspect Med 2012; 2: a006312.
  23. Hostage CA, Choudhury KR, Doraiswamy PM, Petrella JR. Mapping the effect of the apolipoprotein E genotype on 4-year atrophy rates in an Alzheimer disease-related brain. Radiology 2014; 271: 211- 19.
  24. Hostage CA, Roy Choudhury K, Doraiswamy PM, Petrella JR, Simmons A. Dissecting the gene dose-effects of the APOE "4 and "2 alleles on hippocampal volumes in aging and Alzheimer's disease. PLoS One 2013; 8: e54483.
  25. Jack CR, Holtzman DM. Biomarker modeling of alzheimer's disease. Neuron 2013; 80: 1347-58.
  26. Jack CR, Knopman DS, Jagust WJ, Petersen RC, Weiner MW, Aisen PS, et al. Tracking pathophysiological processes in Alzheimer's dis- ease: an updated hypothetical model of dynamic biomarkers. Lancet Neurol 2013a; 12: 207-16.
  27. Jack CR, Lowe VJ, Weigand SD, Wiste HJ, Senjem ML, Knopman DS, et al. Serial PIB and MRI in normal, mild cognitive impairment and Alzheimer's disease: implications for sequence of pathological events in Alzheimer's disease. Brain 2009; 132: 1355-65.
  28. Jack CR, Petersen RC, Xu YC, Obrien PC, Waring SC, Tangalos EG, et al. Hippocampal atrophy and apolipoprotein e genotype are in- dependently associated with alzheimers-disease. Ann Neurol 1998; 43: 303-10.
  29. Jack CR, Wiste HJ, Lesnick TG, Weigand SD, Knopman DS, Vemuri P, et al. Brain b-amyloid load approaches a plateau. Neurology 2013b; 80: 890-6.
  30. Jack CR, Wiste HJ, Weigand SD, Knopman DS, Vemuri P, Mielke MM, et al. Age, sex, and APOE "4 effects on memory, brain struc- ture, and b-amyloid across the adult life span. JAMA Neurol 2015; 72: 511-19.
  31. Jagust WJ, Landau SM; Alzheimer's Disease Neuroimaging Initiative. Apolipoprotein E, not fibrillar b-amyloid, reduces cerebral glucose metabolism in normal aging. J Neurosci 2012; 32: 18227-33.
  32. Jansen WJ, Ossenkoppele R, Knol DL, Tijms BM, Scheltens P, Verhey FRJ, et al. Prevalence of cerebral amyloid pathology in persons with- out dementia: a meta-analysis. JAMA 2015; 313: 1924-38.
  33. Johnson KAA, Sperling RAA, Gidicsin CMM, Carmasin JSS, Maye JEE, Coleman REE, et al. Florbetapir (F18-AV-45) PET to assess amyloid burden in Alzheimer's disease dementia, mild cognitive im- pairment, and normal aging. Alzheimers Dement 2013; 9: S72-83.
  34. Kruschke JK. Doing Bayesian data analysis: a tutorial with R, JAGS, and Stan. 2nd edn. Amsterdam: Academic Press; 2014.
  35. Lehmann M, Ghosh PM, Madison C, Karydas A, Coppola G, O'Neil JP, et al. Greater medial temporal hypometabolism and lower cor- tical amyloid burden in ApoE4-positive AD patients. J Neurol Neurosurg Psychiatry 2013; 85: 266-73.
  36. Lemaitre H, Crivello F, Dufouil C, Grassiot B, Tzourio C, Alperovitch A, et al. No e4 gene dose effect on hippocampal atrophy in a large MRI database of healthy elderly subjects. Neuroimage 2005; 24: 1205-13.
  37. Leung KK, Bartlett JW, Barnes J, Manning EN, Ourselin S, Fox NC. Cerebral atrophy in mild cognitive impairment and Alzheimer dis- ease: rates and acceleration. Neurology 2013; 80: 648-54.
  38. Lewandowski D, Kurowicka D, Joe H. Generating random correlation matrices based on vines and extended onion method. J Multivar Anal 2009; 100: 1989-2001.
  39. Liu Y, Paajanen T, Westman E, Wahlund LO, Simmons A, Tunnard C, et al. Effect of APOE "4 allele on cortical thicknesses and volumes: the AddNeuroMed Study. J Alzheimers Dis 2010; 21: 947-66.
  40. Lu PH, Thompson PM, Leow A, Lee GJ, Lee A, Yanovsky I, et al. NIH public access. J Alzheimers Dis 2011; 23: 433-42.
  41. Mahoney-Sanchez L, Belaidi AA, Bush AI, Ayton S. The complex role of apolipoprotein E in Alzheimer's disease: an overview and update. J Mol Neurosci 2016; 60: 325-35.
  42. Manning EN, Barnes J, Cash DM, Bartlett JW, Leung KK, Ourselin S, et al. APOE "4 is associated with disproportionate progressive hip- pocampal atrophy in AD. PLoS One 2014; 9: e97608.
  43. Mathis CA, Kuller LH, Klunk WE, Snitz BE, Price JC, Weissfeld LA, et al. In vivo assessment of amyloid-b deposition in nondemented very elderly subjects. Ann Neurol 2013; 73: 751-61.
  44. Mintun MA, Larossa GN, Sheline YI, Dence CS, Lee SY, Mach RH, et al. [11C]PIB in a nondemented population: potential antecedent marker of Alzheimer disease. Neurology 2006; 67: 446-52.
  45. Mishra S, Gordon BA, Su Y, Christensen J, Friedrichsen K, Jackson K, et al. AV-1451 PET imaging of tau pathology in preclinical Alzheimer disease: defining a summary measure. Neuroimage 2017; 161: 171-8.
  46. Moffat SD, Szekely CA, Zonderman AB, Kabani NJ, Resnick SM. Longitudinal change in hippocampal volume as a function of apoli- poprotein E genotype. Neurology 2000; 55: 134-6.
  47. Mori E, Lee K, Yasuda M, Hashimoto M, Kazui H, Hirono N, et al. Accelerated hippocampal atrophy in Alzheimer's disease with apoli- poprotein E epsilon4 allele. Ann Neurol 2002; 51: 209-14.
  48. Morra JH, Tu Z, Apostolova LG, Green AE, Avedissian C, Madsen SK, et al. Automated mapping of hippocampal atrophy in 1-year repeat MRI data from 490 subjects with Alzheimer's disease, mild cognitive impairment, and elderly controls. Neuroimage 2009; 45: S3-15.
  49. Murphy KR, Landau SM, Choudhury KR, Hostage CA, Shpanskaya KS, Sair HI, et al. Mapping the effects of ApoE4, age and cognitive status on 18F-florbetapir PET measured regional cortical patterns of beta-amyloid density and growth. Neuroimage 2013; 78: 474-80.
  50. Reiman EM, Caselli RJ, Yun LS, Chen K, Bandy D, Minoshima S, et al. Preclinical evidence of alzheimer's disease in persons homozy- gous for the. N Engl J Med 1996; 334: 752-8.
  51. Resnick SM, Bilgel M, Moghekar A, An Y, Cai Q, Wnag MC, et al. Changes in Ab biomarkers and assocications with APOE genotype in two longitudinal cohorts. Neurobiol Aging 2015; 36: 2333-9.
  52. Risacher SL, Kim S, Nho K, Foroud T, Shen L, Petersen RC, et al. APOE effect on Alzheimer's disease biomarkers in older adults with significant memory concern. Alzheimers Dement 2015; 11: 1417-29.
  53. Risacher SL, Shen L, West JD, Kim S, McDonald BC, Beckett LA, et al. Longitudinal MRI atrophy biomarkers: relationship to conver- sion in the ADNI cohort. Neurobiol Aging 2010; 31: 1401-18.
  54. Rodrigue KM, Kennedy KM, Devous MD, Rieck JR, Hebrank AC, Diaz- Arrastia R, et al. b-Amyloid burden in healthy aging: regional distri- bution and cognitive consequences. Neurology 2012; 78: 387-95.
  55. Rousset OG, Ma Y, Evans AC. Correction for partial volume effects in PET: principle and validation. J Nucl Med 1998; 39: 904-11.
  56. Roussotte FF, Gutman BA, Madsen SK, Colby JB, Narr KL, Thompson PM. The apolipoprotein E epsilon 4 allele is associated with ventricular expansion rate and surface morphology in dementia and normal aging. Neurobiol Aging 2014; 35: 1309-17.
  57. Rowe CC, Ellis KA, Rimajova M, Bourgeat P, Pike KE, Jones G, et al. Amyloid imaging results from the Australian Imaging, Biomarkers and Lifestyle (AIBL) study of aging. Neurobiol Aging 2010; 31: 1275-83.
  58. Saunders AM, Strittmatter WJ, Schmechel D, George-Hyslop PH, Pericak-Vance MA, Joo SH, et al. Association of apolipoprotein E allele 4 with late-onset familial and sporadic Alzheimer's disease. Neurology 1993; 43: 1467-72.
  59. Scheinin NM, Wikman K, Jula A, Perola M, Vahlberg T, Rokka J, et al. Cortical 11C-PIB uptake is associated with age, APOE geno- type, and gender in 'healthy aging'. J Alzheimers Dis 2014; 41: 193-202.
  60. Schmechel DE, Saunders AM, Strittmatter WJ, Crain BJ, Hulette CM, Joo SH, et al. Increased amyloid beta-peptide deposition in cerebral cortex as a consequence of apolipoprotein E genotype in late-onset Alzheimer disease. Proc Natl Acad Sci USA 1993; 90: 9649-53.
  61. Schuff N, Woerner N, Boreta L, Kornfield T, Shaw LM, Trojanowski JQ, et al. MRI of hippocampal volume loss in early Alzheimer's disease in relation to ApoE genotype and biomarkers. Brain 2009; 132: 1067-77.
  62. Soininen H, Partanen K, Pitkanen A, Hallikainen M, Tanninen T, Helisalmi S, et al. Decreased hippocampal volume asymmetry on MRIs in nondemented elderly subjects carrying the apolipoprotein E e4 allele. Neurology 1995; 45: 391-2.
  63. Sorensen T, Vasishth S. Bayesian linear mixed models using Stan: a tutorial for psychologists, linguists, and cognitive scientists. Tutor Quant Methods Psychol 2016; 12: 175-200.
  64. Sperling RA, Rentz DM, Johnson KA, Karlawish J, Donohue M, Salmon DP, et al. The A4 study: stopping AD before symptoms begin? Sci Transl Med Med 2014; 6: 228fs13.
  65. Strittmatter WJ, Saunders AM, Schmechel D, Pericak-Vance M, Enghild J, Salvesen GS, et al. Apolipoprotein E: high-avidity binding to beta-amyloid and increased frequency of type 4 allele in late-onset familial Alzheimer disease. Proc Natl Acad Sci USA 1993; 90: 1977- 81.
  66. Sunderland T, Mirza N, Putnam KT, Linker G, Bhupali D, Durham R, et al. Cerebrospinal fluid b-amyloid1-42 and tau in control subjects at risk for Alzheimer's disease: the effect of APOE "4 allele. Biol Psychiatry 2004; 56: 670-6.
  67. Sutphen CL, Jasielec MS, Shah AR, Macy EM, Xiong C, Vlassenko AG, et al. Longitudinal cerebrospinal fluid biomarker changes in preclinical Alzheimer disease during middle age. JAMA Neurol 2015; 72: 1029-42.
  68. Taylor JL, Scanlon BK, Farrell M, Hernandez B, Adamson MM, Ashford JW, et al. Neurobiology of aging APOE-epsilon4 and aging of medial temporal lobe gray matter in healthy adults older than 50 years. Neurobiol Aging 2014; 35: 2479-85.
  69. Tosun D, Schuff N, Shaw LM, Trojanowski JQ, Weiner MW. Relationship between CSF biomarkers of Alzheimer's disease and rates of regional cortical thinning in ADNI data. Adv Alzheimers Dis 2011; 2: 127-40.
  70. Van De Pol LA, Van Der Flier WM, Korf ESC, Fox NC, Barkhof F, Scheltens P. Baseline predictors of rates of hippocampal atrophy in mild cognitive impairment. Neurology 2007; 69: 1491-7.
  71. Villemagne VL, Burnham S, Bourgeat P, Brown B, Ellis KA, Salvado O, et al. Amyloid b deposition, neurodegeneration, and cognitive decline in sporadic Alzheimer's disease: a prospective cohort study. Lancet Neurol 2013; 12: 357-67.
  72. Villemagne VL, Rowe CC. Long night's journey into the day: amyloid- beta imaging in Alzheimer's disease. J Alzheimers Dis 2013; 33: S349-59.
  73. Vlassenko AG, Mintun MA, Xiong C, Sheline YI, Goate AM, Benzinger TLS, et al. Amyloid-beta plaque growth in cognitively normal adults: longitudinal [11C]Pittsburgh compound B data. Ann Neurol 2011; 70: 857-61.

Cited by

Sorted by citations

Authors
Mishra, S., Blazey, T. M., Holtzman, D. M., Cruchaga, C., Su, Y., Morris, J. C., Benzinger, T. L. S., & Gordon, B. A.
Affiliations
Washington University in St. Louis (US)
Corresponding author
Gordon, Brian A
ORCID
Venue
Brain
Publisher
Oxford University Press (OUP)
Published
2018-04-17
Volume
141
Issue
6
Pages
1828-1839
ISSN
  • 0006-8950 (ISSN-L)
  • 1460-2156
DOI
10.1093/brain/awy103
PMC
PMC5972633
OpenAlex
W2801042920
Cited by
151
References
15
Citations by year
2026: 14 · 2025: 24 · 2024: 22 · 2023: 20 · 2022: 22 · 2021: 18 · 2020: 17 · 2019: 10 · 2018: 4
FWCI
9.32
Type
journal article
Language
en
Open access
Licence
academic.oup.com/journals/pages/about_us/legal/notices (vor)
Locations
  • Brain (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • NIH (P01 AG003991, P50 AG005681, P01 AG026276, P30 NS098577, 1S10RR022984-01A1, 1S10OD018091, R01 EB009352)
  • Barnes-Jewish Hospital Foundation
Topics
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
Keywords
APOE ε4, preclinical Alzheimer's disease, amyloid-beta deposition, cortical atrophy, longitudinal neuroimaging, magnetic resonance imaging, PET, medial temporal lobe, disease trajectories, middle age (human life stage), genetic risk factors
MeSH terms
Adult, Aged, Aged, 80 and over, Alzheimer Disease, Aniline Compounds, Brain, Cross-Sectional Studies, Female, Genotype, Humans, Longitudinal Studies, Magnetic Resonance Imaging, Male, Middle Aged, Thiazoles, Amyloid beta-Peptides, Positron-Emission Tomography, Apolipoprotein E4

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review