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Original Investigation
April 6, 2020

Association of Factors With Elevated Amyloid Burden in Clinically Normal Older Individuals

Author Affiliations
  • 1Center for Alzheimer Research and Treatment, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts
  • 2Harvard Aging Brain Study, Departments of Neurology and Radiology, Massachusetts General Hospital, Harvard Medical School, Boston
  • 3Alzheimer Therapeutic Research Institute, Keck School of Medicine, University of Southern California, San Diego
  • 4Eli Lilly & Co, Indianapolis, Indiana
  • 5Siemers Integration LLC
JAMA Neurol. Published online April 6, 2020. doi:10.1001/jamaneurol.2020.0387
Key Points

Question  Is elevated amyloid-β deposition associated with demographic, genetic, and lifestyle factors; decreased performance on neuropsychological tests; and increased reports of recent changes in cognitive function among clinically normal older individuals?

Findings  In this cross-sectional analysis of the A4 Study screening demographic, cognitive and amyloid positron emission tomography data, elevated amyloid was significantly associated with higher age, apolipoprotein E ε4 allele, and family history but not with sex, education, marital or retirement status, or multiple self-reported lifestyle variables. Elevated amyloid was significantly associated with lower performance on the Preclinical Alzheimer Cognitive Composite and each of its components, as well as with increased reports of recent subjective declines in high-level daily cognitive function by the participant and their study partner.

Meaning  Elevated amyloid is associated with worse cognition and subtle changes in daily function, even among the restricted range of normal performance required for eligibility in this secondary prevention trial.

Abstract

Importance  The Anti-Amyloid Treatment in Asymptomatic Alzheimer disease (A4) Study is an ongoing prevention trial in clinically normal older individuals with evidence of elevated brain amyloid. The large number of participants screened with amyloid positron emission tomography (PET) and standardized assessments provides an unprecedented opportunity to evaluate factors associated with elevated brain amyloid.

Objective  To investigate the association of elevated amyloid with demographic and lifestyle factors, apolipoprotein E (APOE), neuropsychological testing, and self- and study partner reports of cognitive function.

Design, Setting, and Participants  This cross-sectional study included screening data in the Anti-Amyloid Treatment in Asymptomatic Alzheimer Disease (A4) Study collected from April 2014 to December 2017 and classified by amyloid status. Data were was analyzed from 2018 to 2019 across 67 sites in the US, Canada, Australia, and Japan and included 4486 older individuals (age 65-85 years) who were eligible for amyloid PET (clinically normal [Clinical Dementia Rating = 0] and cognitively unimpaired [Mini-Mental State Examination score, ≥25; logical memory IIa 6-18]).

Main Outcomes and Measures  Screening demographics, lifestyle variables, APOE genotyping, and cognitive testing (Preclinical Alzheimer Cognitive Composite), self- and study partner reports of high-level daily cognitive function (Cognitive Function Index). Florbetapir amyloid PET imaging was used to classify participants as having elevated amyloid (Aβ+) or not having elevated amyloid (Aβ−).

Results  Amyloid PET results were acquired for 4486 participants (mean [SD] age, 71.29 [4.67] years; 2647 women [59%]), with 1323 (29.5%) classified as Aβ+. Aβ+ participants were slightly older than Aβ−, with no observed differences in sex, education, marital or retirement status, or any self-reported lifestyle factors. Aβ+ participants were more likely to have a family history of dementia (3320 Aβ+ [74%] vs 3050 Aβ− [68%]) and at least 1 APOE ε4 allele (2602 Aβ+ [58%] vs 1122 Aβ− [25%]). Aβ+ participants demonstrated worse performance on screening Preclinical Alzheimer Cognitive Composite results and reported higher change scores on the Cognitive Function Index.

Conclusions and Relevance  Among a large group of older individuals screening for an Alzheimer disease (AD) prevention trial, elevated brain amyloid was associated with family history and APOE ε4 allele but not with multiple other previously reported risk factors for AD. Elevated amyloid was associated with lower test performance results and increased reports of subtle recent declines in daily cognitive function. These results support the hypothesis that elevated amyloid represents an early stage in the Alzheimer continuum and demonstrate the feasibility of enrolling these high-risk participants in secondary prevention trials aimed at slowing cognitive decline during the preclinical stages of AD.

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    1 Comment for this article
    EXPAND ALL
    RE: Association of factors with elevated amyloid burden in clinically normal older individuals
    Tomoyuki Kawada, MD | Nippon Medical School
    Sperling et al. conducted a cross-sectional study to investigate the risk factors of elevated amyloid burden in clinically normal older individuals, including apolipoprotein E (APOE) genotyping, neuropsychological testing, and self- and study partner reports of cognitive function (1). Amyloid positron emission tomography (PET) imaging was used to classify participants as having elevated amyloid (Aβ+) or not having elevated amyloid (Aβ-). Percentages of family history of dementia and at least 1 APOE ε4 allele were significantly higher in Aβ+ individuals than Aβ- individuals. In addition, individuals with Aβ+ presented lower levels of test performance and increased reports of subtle recent declines in daily cognitive function. Regarding the fact that Aβ+ might represent a preclinical stage of Alzheimer disease (AD), I have two concerns as follows.

    First, Biddle et al. evaluated the effect of widowhood status on the level of brain β-amyloid and cognitive decline in participants (2), and standardized regression coefficients (95% confidence intervals) of widowed participants with high β-amyloid deposition and married participants with high β-amyloid deposition were -0.33 (-0.46 to -0.19) and -0.12 (-0.18 to -0.01), respectively. These data present that the rate of cognitive decline among widowed participants was nearly 3 times faster than among married participants, if they have high levels of β-amyloid deposition. Sperling et al. could not recognize marital status as a significant risk factor of Aβ+ (1), and prospective/interventional studies might contribute to specify the causal association.

    Second, Köbe et al. conducted a cross-sectional study to assess the associations of vascular risk factors with AD pathogenesis in asymptomatic individuals with special reference to vascular medications (3). Cerebrospinal fluid Aβ1-42 and phosphorylated tau levels were also used for the analysis. There were significant associations of vascular risk factors with Aβ+, which was not observed with tau burden. These associations were found only among individuals without vascular medications, and there was a significant interaction between some vascular risk factors and vascular medications. As the frequency of vascular medications increases by aging, adjustment of comorbidities and their treatments should be made for the risk assessment of elevated amyloid burden.


    References

    1. Sperling RA, Donohue MC, Raman R, et al. Association of factors with elevated amyloid burden in clinically normal older individuals. JAMA Neurol. 2020 Apr 6. doi: 10.1001/jamaneurol.2020.0387

    2. Biddle KD, Jacobs HIL, d'Oleire Uquillas F, et al. Associations of widowhood and β-amyloid with cognitive decline in cognitively unimpaired older adults. JAMA Netw Open. 2020;3(2):e200121. doi: 10.1001/jamanetworkopen.2020.0121

    3. Köbe T, Gonneaud J, Pichet Binette A, et al. Association of vascular risk factors with β-amyloid peptide and tau burdens in cognitively unimpaired individuals and its interaction with vascular medication use. JAMA Netw Open. 2020;3(2):e1920780. doi: 10.1001/jamanetworkopen.2019.20780
    CONFLICT OF INTEREST: None Reported
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