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    1 Comment for this article
    Immune Tolerance Disorders
    Paul Nelson, M.D., M.S. | Family Health Care, P.C.
    Finally, here is a glimmer of clear evidence for viewing the occurrence of Senile Dementia as a disorder of immune tolerance. Can we add it to the list of possible "disruptive processes" underlying the unstable-health associated with a disorder of immune tolerance? THINK: perinatal morbidity, initiating phase of new onset asthma, chronic obstructive pulmonary disease, polymyalgia rheumatica and temporal arteritis? The Nobel Prize winning team of Doctors Peter Medawar and Macfarlane Burnet at the UK University of Manchester (1940s-1960s) should be proud that their description of immune tolerance may become a broadly pervasive theme for a person's unstable-health.
    Original Investigation
    October 19, 2018

    Association of Chronic Low-grade Inflammation With Risk of Alzheimer Disease in ApoE4 Carriers

    Author Affiliations
    • 1Department of Pharmacology and Experimental Therapeutics, Boston University School of Medicine, Boston, Massachusetts
    • 2Department of Anatomy and Neurobiology, Boston University School of Medicine, Boston, Massachusetts
    • 3Department of Epidemiology, Boston University School of Public Health, Boston, Massachusetts
    • 4Alzheimer’s Disease Center, University of California Davis Medical Center, Sacramento
    • 5Department of Neurology, Boston University School of Medicine, Boston, Massachusetts
    • 6Framingham Heart Study, Boston University School of Medicine, Boston, Massachusetts
    • 7Department of Psychiatry, Boston University School of Medicine, Boston, Massachusetts
    • 8Department of Pathology and Laboratory Medicine, Boston University School of Medicine, Boston, Massachusetts
    • 9Department of Pathology, Veterans Affairs Boston Healthcare System, Boston, Massachusetts
    • 10Alzheimer’s Disease Center, Boston University School of Medicine, Boston, Massachusetts
    • 11Department of Medicine, Boston University School of Medicine, Boston, Massachusetts
    • 12Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts
    JAMA Netw Open. 2018;1(6):e183597. doi:10.1001/jamanetworkopen.2018.3597
    Key Points español 中文 (chinese)

    Question  Is interaction of chronic low-grade inflammation and the apolipoprotein E genotype associated with development of Alzheimer disease?

    Findings  In this population-based cohort study, chronic low-grade inflammation, assessed by longitudinal C-reactive protein measurements, was associated with an increased risk of Alzheimer disease only in ApoE4 carriers.

    Meaning  Clinical follow-up and treatment of high levels of C-reactive protein may be beneficial for prevention of Alzheimer disease in ApoE4 carriers.


    Importance  The association between peripheral inflammatory biomarkers and Alzheimer disease (AD) is not consistent in the literature. It is possible that chronic inflammation, rather than 1 episode of inflammation, interacts with genetic vulnerability to increase the risk for AD.

    Objective  To study the interaction between the apolipoprotein E (ApoE) genotype and chronic low-grade inflammation and its association with the incidence of AD.

    Design, Setting, and Participants  In this cohort study, data from 2656 members of the Framingham Heart Study offspring cohort (Generation 2; August 13, 1971-November 27, 2017) were evaluated, including longitudinal measures of serum C-reactive protein (CRP), diagnoses of incident dementia including AD, and brain volume. Chronic low-grade inflammation was defined as having CRP at a high cutoff level at a minimum of 2 time points. Statistical analysis was performed from December 1, 1979, to December 31, 2015.

    Main Outcomes and Measures  Development of AD and brain volumes.

    Results  Of the 3130 eligible participants, 2656 (84.9%; 1227 men and 1429 women; mean [SD] age at last CRP measurement, 61.6 [9.5] years) with both ApoE status and longitudinal CRP measurements were included in this study analysis. Median (interquartile range) CRP levels increased with mean (SD) age (43.3 [9.6] years, 0.95 mg/L [0.40-2.35 mg/L] vs 59.1 [9.6] years, 2.04 mg/L [0.93-4.75 mg/L] vs 61.6 [9.5] years, 2.21 mg/L [1.05-5.12 mg/L]; P < .001), but less so among those with ApoE4 alleles, followed by ApoE3 then ApoE2 genotypes. During the 17 years of follow-up, 194 individuals (7.3%) developed dementia, 152 (78.4%) of whom had AD. ApoE4 coupled with chronic low-grade inflammation, defined as a CRP level of 8 mg/L or higher, was associated with an increased risk of AD, especially in the absence of cardiovascular diseases (hazard ratio, 6.63; 95% CI, 1.80-24.50; P = .005), as well as an increased risk of earlier disease onset compared with ApoE4 carriers without chronic inflammation (hazard ratio, 3.52; 95% CI, 1.27-9.75; P = .009). This phenomenon was not observed among ApoE3 and ApoE2 carriers with chronic low-grade inflammation. Finally, a subset of 1761 individuals (66.3%) underwent brain magnetic resonance imaging, and the interaction between ApoE4 and chronic low-grade inflammation was associated with brain atrophy in the temporal lobe (β = –0.88, SE = 0.22; P < .001) and hippocampus (β = –0.04, SE = 0.01; P = .005), after adjusting for confounders.

    Conclusions and Relevance  In this study, peripheral chronic low-grade inflammation in participants with ApoE4 was associated with shortened latency for onset of AD. Rigorously treating chronic systemic inflammation based on genetic risk could be effective for the prevention and intervention of AD.