Elsevier

Neurobiology of Aging

Volume 95, November 2020, Pages 46-55
Neurobiology of Aging

Regular article
Impact of APOE-ε4 carriage on the onset and rates of neocortical Aβ-amyloid deposition

https://doi.org/10.1016/j.neurobiolaging.2020.06.001Get rights and content

Highlights

  • APOE-ε4 carriers reached abnormal levels of Aβ ~15 years earlier than noncarriers.

  • APOE-ε4 carriers and noncarriers had no differences in Aβ deposition rates beyond the threshold.

  • Primary and secondary prevention trials should target APOE-ε4 carriers aged between 60 and 66.

  • Primary and secondary prevention trials should target APOE-ε4 non-carriers aged between 76 and 84.

Abstract

Neocortical Aβ-amyloid deposition, one of the hallmark pathologic features of Alzheimer's disease (AD), begins decades prior to the presence of clinical symptoms. As clinical trials move to secondary and even primary prevention, understanding the rates of neocortical Aβ-amyloid deposition and the age at which Aβ-amyloid deposition becomes abnormal is crucial for optimizing the timing of these trials. As APOE-ε4 carriage is thought to modulate the age of clinical onset, it is also important to understand the impact of APOE-ε4 carriage on the age at which the neocortical Aβ-amyloid deposition becomes abnormal. Here, we show that, for 455 participants with over 3 years of follow-up, abnormal levels of neocortical Aβ-amyloid were reached on average at age 72 (66.5–77.1). The APOE-ε4 carriers reached abnormal levels earlier at age 63 (59.6–70.3); however, noncarriers reached the threshold later at age 78 (76.1–84.4). No differences in the rates of deposition were observed between APOE-ε4 carriers and noncarriers after abnormal Aβ-amyloid levels had been reached. These results suggest that primary and secondary prevention trials, looking to recruit at the earliest stages of disease, should target APOE-ε4 carriers between the ages of 60 and 66 and noncarriers between the ages of 76 and 84.

Introduction

Alzheimer's disease (AD), the most common form of dementia, is characterized pathologically by the extracellular accumulation of Aβ-amyloid and intracellular accumulation of tau in the neocortex (Jack et al., 2018). Neocortical accumulation of Aβ-amyloid is a key part of the cascade of pathologic changes leading to the onset of clinical symptoms in AD (Hardy and Selkoe, 2002; Karran et al., 2011) and is a process that initiates decades prior to clinical manifestation of the disease (Jack et al., 2013a; Villemagne et al., 2013). Increased understanding of the onset and rates of neocortical Aβ-amyloid deposition would provide improved disease staging criteria particularly for preclinical AD. This is increasingly important with clinical trials aimed at preventative treatment.

Carriage of an APOE-ε4 allele is a well-established risk factor for AD (Harold et al., 2009), reported to impact the levels of neocortical Aβ-amyloid (Liu et al., 2013; Reiman et al., 2009; Rowe et al., 2010; Villemagne et al., 2011); however, the nature of this impact is unclear. The literature appears to agree that APOE-ε4 carriage is associated with the deposition of neocortical Aβ-amyloid at an earlier age (Bilgel et al., 2019; Fleisher et al., 2013; Mishra et al., 2018) as well as an earlier onset of disease (Corder et al., 1995). Some contributions report that APOE-ε4 carriage is associated with an increased rate of neocortical Aβ-amyloid deposition (Bilgel et al., 2019; Jack et al., 2013a; Mishra et al., 2018; Toledo et al., 2019), others only report a difference in those with low neocortical Aβ-amyloid burden (Lim et al., 2017), while others report no difference in neocortical Aβ-amyloid accumulation rates between carriers and noncarriers (Corder et al., 1995; Resnick et al., 2015; Saunders, 2000). Accounting for the temporal relationship between neocortical Aβ-amyloid deposition and disease stage/progression may provide a clearer understanding of the impact of APOE-ε4 carriage on neocortical Aβ-amyloid deposition.

In this study, we evaluate the age at which abnormal levels of neocortical Aβ-amyloid deposition can be detected and test our hypotheses that carriage of an APOE-ε4 allele would be associated with a) a younger age of onset and b) faster rates of neocortical Aβ-amyloid deposition. For that purpose, natural history modeling in conjunction with survival analyses is used to jointly consider the onset and rates of neocortical Aβ-amyloid accumulation in reference to disease stage and progression.

Section snippets

AIBL cohort

The Australian Imaging, Biomarker and Lifestyle (AIBL) cohort study of aging combines data from neuroimaging, biomarkers, lifestyle, clinical, and neuropsychological assessments. Two study centers in Melbourne, VIC, and Perth, WA, Australia recruit mild cognitively impaired (MCI) individuals and individuals with AD from primary-care physicians or tertiary Memory Disorders Clinics. Cognitively healthy normal controls (NCs) were recruited through advertisement or from spouses of participants in

Data Availability

All ADNI and a subset of the AIBL data including images are shared through the LONI Image & Data Archive (http://adni.loni.usc.edu), a secure research data repository. Applications for access to the entirety of the AIBL data can be made via application through the AIBL website (https://aibl.csiro.au/).

Demographics

There were a significantly higher proportion of NC participants in the AIBL APOE-ε4 noncarriers compared with carriers (p = 0.001), for the ADNI participants this relationship held as a trend (p = 0.057). Within AIBL, there were significantly more males among the APOE-ε4 carriers compared with noncarriers (p = 0.026), a finding not observed in the ADNI participants (p = 0.683). The ADNI APOE-ε4 noncarriers were significantly older than carriers (p = 0.005), no differences were observed for age

Discussion

Survival analyses indicated the average age that AIBL and ADNI participants reached abnormal levels of neocortical Aβ-amyloid was 70 years of age, with CI ranging from 66 to 77 years of age. Stratifying the survival analyses by APOE-ε4 carriage suggested that on average APOE-ε4 carriers reached the abnormal threshold in their early sixties, 15 (CI: 6–24) years earlier than noncarriers who reached the threshold late in their seventies. Further, evaluation of the natural history of deposition of

CRediT authorship contribution statement

Samantha C. Burnham: Conceptualization, Investigation, Methodology, Data curation, Funding acquisition, Writing - original draft. Simon M. Laws: Data curation, Formal analysis. Charley A. Budgeon: Methodology, Software. Vincent Doré: Data curation, Formal analysis. Tenielle Porter: Data curation, Formal analysis. Pierrick Bourgeat: Data curation, Formal analysis. Rachel F. Buckley: Writing - review & editing. Kevin Murray: Methodology, Software. Kathryn A. Ellis: Project administration, Data

Acknowledgements

We thank the participants who took part in the study and their families.

ADNI Acknowledgement list: Michael W. Weiner, MD; Paul Aisen, MD; Ronald Petersen, MD, PhD; Clifford R. Jack, Jr., MD; William Jagust, MD; John Q. Trojanowki, MD, PhD; Arthur W. Toga, PhD; Laurel Beckett, PhD; Robert C. Green, MD, MPH; Andrew J. Saykin, PsyD; John Morris, MD; Leslie M. Shaw Zaven Khachaturian, PhD; Greg Sorensen, MD; Maria Carrillo, PhD; Lew Kuller, MD; Marc Raichle, MD; Steven Paul, MD; Peter Davies, MD;

References (33)

  • P. Bougeat et al.

    Comparison of MR-less PiB SUVR quantification methods

    Neurobiol. Aging

    (2015)
  • C.A. Budgeon et al.

    Constructing longitudinal disease progression curves using sparse, short-term individual data with an application to Alzheimer's disease

    Stat. Med.

    (2017)
  • K. Chen et al.

    Improved power for characterizing longitudinal amyloid-b PET changes and evaluating amyloid-modifying treatments with a cerebral white matter reference region

    J. Nucl. Med.

    (2015)
  • E. Corder et al.

    Apolipoprotein E, survival in Alzheimer's disease patients, and the competing risks of death and Alzheimer's disease

    Neurology

    (1995)
  • E. Corder et al.

    Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer’s disease in late onset families

    Science

    (1993)
  • S. Craft et al.

    Cerebrospinal fluid and plasma insulin levels in Alzheimer's disease relationship to severity of dementia and apolipoprotein E genotype

    Neurology

    (1998)
  • Cited by (32)

    • Interactions between apolipoprotein E, sex, and amyloid-beta on cerebrospinal fluid p-tau levels in the European prevention of Alzheimer's dementia longitudinal cohort study (EPAD LCS)

      2022, eBioMedicine
      Citation Excerpt :

      This risk increases in a dose-dependent manner4 and varies by sex, with meta-analytic evidence of a stronger effect in females aged 55-70.5,6 The APOE ε4 allele is associated with the pathological hallmarks of AD such as accelerated Aβ deposition,7 disruption of Aβ clearance,8 and acceleration of tau spread.9 These pathological hallmarks can also be measured in vivo in the cerebrospinal fluid (CSF), with reduced levels of Aβ (reflecting deposition in the brain) and increased levels of phosphorylated tau (p-tau) and total tau (t-tau) indicating an AD-like CSF biomarker profile.10

    • Rates of β-amyloid deposition indicate widespread simultaneous accumulation throughout the brain

      2022, Neurobiology of Aging
      Citation Excerpt :

      However, studies of longitudinal Aβ accumulation rates in ε4 carriers and noncarriers are inconsistent, with some finding no significant difference in accumulation rates and others showing higher accumulation rates in ε4 carriers than noncarriers. ( Burnham et al., 2020; Lim and Mormino, 2017; Mishra et al., 2018; Resnick et al., 2015). It is unclear if ε4 carriers simply develop Aβ earlier than noncarriers, but accumulate at the same rate, or if accumulation rate itself is faster in carriers versus noncarriers.

    View all citing articles on Scopus

    Funding: Core funding for the AIBL study was provided by the CSIRO Flagship Collaboration Fund and the Science and Industry Endowment Fund (SIEF) in partnership with the CRC for Mental Health, Edith Cowan University (ECU), Mental Health Research institute (MHRI), Alzheimer's Australia (AA), National Ageing Research Institute (NARI), Austin Health, Macquarie University, CogState Ltd, Hollywood Private Hospital, and Sir Charles Gairdner Hospital. The study also received funding from the National Health and Medical Research Council (NHMRC), Dementia Collaborative Research Centres program (DCRC), and McCusker Alzheimer's Research Foundation, and operational infrastructure support from the Government of Victoria. Funding for this study was provided by the NHMRC (Grant Number 1156891). Data collection and sharing for this project was funded by the 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: AbbVie, Alzheimer's Association; Alzheimer's Drug Discovery Foundation; Araclon Biotech; BioClinica, Inc; Biogen; Bristol-Myers Squibb Company; CereSpir, Inc; Cogstate; Eisai Inc; Elan Pharmaceuticals, Inc; Eli Lilly and Company; EuroImmun; F. Hoffmann-La 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.; Lumosity; Lundbeck; Merck & Co, Inc; Meso Scale Diagnostics, LLC.; NeuroRx Research; Neurotrack Technologies; Novartis Pharmaceuticals Corporation; Pfizer Inc; Piramal Imaging; Servier; Takeda Pharmaceutical Company; and Transition Therapeutics. 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 California Institute for Research and Education, and the study is coordinated by the Alzheimer's Therapeutic Research Institute at the University of Southern California. ADNI data are disseminated by the Laboratory for Neuro Imaging at the University of Southern California.

    Competing interest: Samantha C. Burnham: Reports speaker honoraria from Novartis outside the scope of the submitted work. Simon Laws: Personal fees from Alzhyme outside the scope of the submitted work. Charley Budgeon: Declares no conflicts of interest. Vincent Doré: Declares no conflicts of interest. Tenielle Porter: Declares no conflicts of interest. Pierrick Bourgeat: Declares no conflicts of interest. Rachel Buckley: Declares no conflicts of interest. Kevin Murray: Declares no conflicts of interest. Kathryn Ellis: Declares no conflicts of interest. Berwin Turlach: Declares no conflicts of interest. Olivier Salvado: Reports a patent PCT/AU2012001536 pending to CSIRO. David Ames: Reports receipt of financial assistance to his employer in order to assist with an international drug trail of an anti-Alzheimer's agent owned by Eli Lilly. Ralph N Martins: Declares no conflicts of interest. Dorene Rentz: Declares no conflicts of interest. Colin Masters: Reports personal fees from Prana Biotechnology, Eli Lilly, and Actinogen outside the scope of the submitted work. Christopher C. Rowe: Reports speaker honoraria from GE Healthcare and Avid Radiopharmaceuticals, consulting fees from Avid Radiopharmaceuticals, AstraZeneca, and Piramal Imaging, and research grants from Avid Radiopharmaceuticals, GE Healthcare, and Piramal Imaging all outside the scope of the submitted work. Victor L. Villemagne: Reports speaker honoraria from GE Healthcare, Piramal Imaging, and Avid Radiopharmaceuticals, and consulting fees from Lundbeck, Abbvie, Shanghai Green Valley Co and Hoffmann La Roche, all outside the scope of the submitted work.

    1

    Alzheimer's Disease Neuroimaging Initiative (ADNI): Data used in preparation of this article were obtained from the ADNI database (adni.loni.usc.edu). As such, the investigators within the ADNI contributed to the design and implementation of ADNI and/or provided data but did not participate in analysis or writing of this report. A complete listing of ADNI investigators can be found at: http://adni.loni.usc.edu/wp-content/uploads/how_to_apply/ADNI_Acknowledgement_List.pdf.

    2

    AIBL Research Group: https://aibl.csiro.au/about/aibl-research-team/.

    View full text