[Skip to Content]
Access to paid content on this site is currently suspended due to excessive activity being detected from your IP address 35.175.191.72. Please contact the publisher to request reinstatement.
[Skip to Content Landing]
1.
Strittmatter  WJ, Saunders  AM, Schmechel  D,  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 U S A. 1993;90(5):1977-1981. doi:10.1073/pnas.90.5.1977PubMedGoogle ScholarCrossref
2.
Tanzi  RE.  A genetic dichotomy model for the inheritance of Alzheimer’s disease and common age-related disorders.  J Clin Invest. 1999;104(9):1175-1179. doi:10.1172/JCI8593PubMedGoogle ScholarCrossref
3.
Stephensen  CB, Gildengorin  G.  Serum retinol, the acute phase response, and the apparent misclassification of vitamin A status in the third National Health and Nutrition Examination Survey.  Am J Clin Nutr. 2000;72(5):1170-1178. doi:10.1093/ajcn/72.5.1170PubMedGoogle ScholarCrossref
4.
Desikan  RS, Schork  AJ, Wang  Y,  et al; Inflammation working group, IGAP and DemGene Investigators.  Polygenic overlap between C-reactive protein, plasma lipids, and Alzheimer disease.  Circulation. 2015;131(23):2061-2069. doi:10.1161/CIRCULATIONAHA.115.015489PubMedGoogle ScholarCrossref
5.
Song  IU, Chung  SW, Kim  YD, Maeng  LS.  Relationship between the hs-CRP as non-specific biomarker and Alzheimer’s disease according to aging process.  Int J Med Sci. 2015;12(8):613-617. doi:10.7150/ijms.12742PubMedGoogle ScholarCrossref
6.
O’Bryant  SE, Waring  SC, Hobson  V,  et al.  Decreased C-reactive protein levels in Alzheimer disease.  J Geriatr Psychiatry Neurol. 2010;23(1):49-53. doi:10.1177/0891988709351832PubMedGoogle ScholarCrossref
7.
Sundelöf  J, Kilander  L, Helmersson  J,  et al.  Systemic inflammation and the risk of Alzheimer’s disease and dementia: a prospective population-based study.  J Alzheimers Dis. 2009;18(1):79-87. doi:10.3233/JAD-2009-1126PubMedGoogle ScholarCrossref
8.
Royall  DR, Al-Rubaye  S, Bishnoi  R, Palmer  RF.  Few serum proteins mediate APOE’s association with dementia.  PLoS One. 2017;12(3):e0172268. doi:10.1371/journal.pone.0172268PubMedGoogle ScholarCrossref
9.
Wilson  PW, Nam  BH, Pencina  M, D’Agostino  RB  Sr, Benjamin  EJ, O’Donnell  CJ.  C-reactive protein and risk of cardiovascular disease in men and women from the Framingham Heart Study.  Arch Intern Med. 2005;165(21):2473-2478. doi:10.1001/archinte.165.21.2473PubMedGoogle ScholarCrossref
10.
Kannel  WB, Feinleib  M, McNamara  PM, Garrison  RJ, Castelli  WP.  An investigation of coronary heart disease in families: the Framingham offspring study.  Am J Epidemiol. 1979;110(3):281-290. doi:10.1093/oxfordjournals.aje.a112813PubMedGoogle ScholarCrossref
11.
Rost  NS, Wolf  PA, Kase  CS,  et al.  Plasma concentration of C-reactive protein and risk of ischemic stroke and transient ischemic attack: the Framingham study.  Stroke. 2001;32(11):2575-2579. doi:10.1161/hs1101.098151PubMedGoogle ScholarCrossref
12.
Seshadri  S.  Elevated plasma homocysteine levels: risk factor or risk marker for the development of dementia and Alzheimer’s disease?  J Alzheimers Dis. 2006;9(4):393-398. doi:10.3233/JAD-2006-9404PubMedGoogle ScholarCrossref
13.
DeCarli  C, Massaro  J, Harvey  D,  et al.  Measures of brain morphology and infarction in the Framingham Heart Study: establishing what is normal.  Neurobiol Aging. 2005;26(4):491-510. doi:10.1016/j.neurobiolaging.2004.05.004PubMedGoogle ScholarCrossref
14.
Jefferson  AL, Himali  JJ, Beiser  AS,  et al.  Cardiac index is associated with brain aging: the Framingham Heart Study.  Circulation. 2010;122(7):690-697. doi:10.1161/CIRCULATIONAHA.109.905091PubMedGoogle ScholarCrossref
15.
DeCarli  C, Reed  T, Miller  BL, Wolf  PA, Swan  GE, Carmelli  D.  Impact of apolipoprotein E epsilon4 and vascular disease on brain morphology in men from the NHLBI twin study.  Stroke. 1999;30(8):1548-1553. doi:10.1161/01.STR.30.8.1548PubMedGoogle ScholarCrossref
16.
Miklossy  J.  Chronic inflammation and amyloidogenesis in Alzheimer’s disease—role of spirochetes.  J Alzheimers Dis. 2008;13(4):381-391. doi:10.3233/JAD-2008-13404PubMedGoogle ScholarCrossref
17.
Marottoli  FM, Katsumata  Y, Koster  KP, Thomas  R, Fardo  DW, Tai  LM.  Peripheral inflammation, apolipoprotein E4, and amyloid-β interact to induce cognitive and cerebrovascular dysfunction.  ASN Neuro. 2017;9(4):1759091417719201. doi:10.1177/1759091417719201PubMedGoogle ScholarCrossref
18.
Yarchoan  M, Louneva  N, Xie  SX,  et al.  Association of plasma C-reactive protein levels with the diagnosis of Alzheimer’s disease.  J Neurol Sci. 2013;333(1-2):9-12. doi:10.1016/j.jns.2013.05.028PubMedGoogle ScholarCrossref
19.
Schuitemaker  A, Dik  MG, Veerhuis  R,  et al.  Inflammatory markers in AD and MCI patients with different biomarker profiles.  Neurobiol Aging. 2009;30(11):1885-1889. doi:10.1016/j.neurobiolaging.2008.01.014PubMedGoogle ScholarCrossref
20.
Licastro  F, Pedrini  S, Davis  LJ,  et al.  Alpha-1-antichymotrypsin and oxidative stress in the peripheral blood from patients with probable Alzheimer disease: a short-term longitudinal study.  Alzheimer Dis Assoc Disord. 2001;15(1):51-55. doi:10.1097/00002093-200101000-00007PubMedGoogle ScholarCrossref
21.
Dik  MG, Jonker  C, Comijs  HC,  et al.  Memory complaints and APOE-epsilon4 accelerate cognitive decline in cognitively normal elderly.  Neurology. 2001;57(12):2217-2222. doi:10.1212/WNL.57.12.2217PubMedGoogle ScholarCrossref
22.
Jefferson  AL, Massaro  JM, Wolf  PA,  et al.  Inflammatory biomarkers are associated with total brain volume: the Framingham Heart Study.  Neurology. 2007;68(13):1032-1038. doi:10.1212/01.wnl.0000257815.20548.dfPubMedGoogle ScholarCrossref
23.
Gu  Y, Manly  JJ, Mayeux  RP, Brickman  AM.  An inflammation-related nutrient pattern is associated with both brain and cognitive measures in a multiethnic elderly population.  Curr Alzheimer Res. 2018;15(5):493-501. doi:10.2174/1567205015666180101145619PubMedGoogle ScholarCrossref
24.
Kamer  AR, Pirraglia  E, Tsui  W,  et al.  Periodontal disease associates with higher brain amyloid load in normal elderly.  Neurobiol Aging. 2015;36(2):627-633. doi:10.1016/j.neurobiolaging.2014.10.038PubMedGoogle ScholarCrossref
25.
Wilson  D, Peters  R, Ritchie  K, Ritchie  CW.  Latest advances on interventions that may prevent, delay or ameliorate dementia.  Ther Adv Chronic Dis. 2011;2(3):161-173. doi:10.1177/2040622310397636PubMedGoogle ScholarCrossref
26.
Wang  TJ, Nam  BH, Wilson  PW,  et al.  Association of C-reactive protein with carotid atherosclerosis in men and women: the Framingham Heart Study.  Arterioscler Thromb Vasc Biol. 2002;22(10):1662-1667. doi:10.1161/01.ATV.0000034543.78801.69PubMedGoogle ScholarCrossref
27.
D’Mello  C, Swain  MG.  Liver-brain interactions in inflammatory liver diseases: implications for fatigue and mood disorders.  Brain Behav Immun. 2014;35:9-20. doi:10.1016/j.bbi.2013.10.009PubMedGoogle ScholarCrossref
28.
Jeukendrup  AE, Vet-Joop  K, Sturk  A,  et al.  Relationship between gastro-intestinal complaints and endotoxaemia, cytokine release and the acute-phase reaction during and after a long-distance triathlon in highly trained men.  Clin Sci (Lond). 2000;98(1):47-55. PubMedGoogle ScholarCrossref
29.
Gordienko  AI.  Levels of serum antibodies to enterobacterial lipopolysaccharides and their relationship with concentration of C-reactive protein in diabetes mellitus patients  [in Ukrainian].  Ukr Biochem J. 2015;87(3):98-106. doi:10.15407/ubj87.03.098PubMedGoogle ScholarCrossref
30.
Monnet  E, Lapeyre  G, Poelgeest  EV,  et al.  Evidence of NI-0101 pharmacological activity, an anti-TLR4 antibody, in a randomized phase I dose escalation study in healthy volunteers receiving LPS.  Clin Pharmacol Ther. 2017;101(2):200-208. doi:10.1002/cpt.522PubMedGoogle ScholarCrossref
31.
Zhao  Y, Cong  L, Lukiw  WJ.  Lipopolysaccharide (LPS) accumulates in neocortical neurons of Alzheimer’s disease (AD) brain and impairs transcription in human neuronal-glial primary co-cultures.  Front Aging Neurosci. 2017;9:407. doi:10.3389/fnagi.2017.00407PubMedGoogle ScholarCrossref
32.
ADAPT-FS Research Group.  Follow-up evaluation of cognitive function in the randomized Alzheimer’s Disease Anti-inflammatory Prevention Trial and its follow-up study.  Alzheimers Dement. 2015;11(2):216-225. doi:10.1016/j.jalz.2014.03.009PubMedGoogle 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
    1 Comment for this article
    EXPAND ALL
    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.
    CONFLICT OF INTEREST: None Reported
    READ MORE
    Original Investigation
    Geriatrics
    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.

    Abstract

    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.

    ×