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Association of Chronic Low-grade Inflammation With Risk of Alzheimer Disease in ApoE4 Carriers
Open accessAbstract
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.
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“As some proinflammatory proteins in blood impact APOE genotypes differently for AD risk [4, 20]”
From Blood PCSK9 Impacts Alzheimer's Disease Risk in an APOE Genotype‐Dependent Manner: A Prospective Cohort Study (2026) · cites this paper as [20]
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“Our findings of an inflammatory phenotype in resting APOE4 iAstrocytes could explain the mechanistic link between chronic inflammation and AD pathogenesis in APOE4 carriers (Tao et al., 2018).”
From APOE2, E3, and E4 differentially modulate cellular homeostasis, cholesterol metabolism, and inflammatory response in isogenic iPSC-derived astrocytes (2022) · cites this paper as Tao et al., 2018
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“In APOE4 carriers, chronic inflammation has been linked to an accelerated onset of AD symptoms [77].”
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“For instance, it is known that periodontitis can induce an elevation in systemic inflammation [2,3], and such conditions would increase the risk of brain diseases [4,5].”
Backgroundde Moraes, R. C. M., Roth, J. R., Mao, H., Crawley, S. R., Xu, B. P., Watson, J. C., & Melkani, G. C. (2024) · Genes · doi:10.3390/genes15111376 · Cited by 6
Linking alcohol use to Alzheimer’s disease: Interactions with aging and APOE along immune pathways
Monnig, M. A., & Shah, K. (2024) · Medical Research Archives · doi:10.18103/mra.v12i8.5228 · Cited by 6
“In clinical research, chronic low-grade inflammation increased risk and hastened onset of AD in ɛ 4 carriers, but not non-carriers 81 .”
Bornemann, E. A., Kamma, H. K., Alabbas, M., Elashahab, M., Abid, N., Manaye, S., Cheran, K., Murthy, C., Giva, S., & Penumetcha, S. S. (2025) · Cureus · doi:10.7759/cureus.84057 · Cited by 4
Associations of circulating c-reactive protein levels with central Alzheimer’s disease biomarkers
Choi, H., Byun, M. S., Yi, D., Ahn, H., Jung, G., Park, S., Jung, J. H., Keum, M., Sohn, B. K., Kim, Y., et al. (2025) · The Journal of Prevention of Alzheimer s Disease · doi:10.1016/j.tjpad.2025.100368 · Cited by 4
“However, other previous studies have reported that circulating CRP levels have no significant association or a negative association with the risk of AD dementia, as well as greater cognitive and functional decline [9 – 11].”
Neuroinflammation in Dementia—Therapeutic Directions in a COVID-19 Pandemic Setting
Łuc, M., Woźniak, M., & Rymaszewska, J. (2022) · Cells · doi:10.3390/cells11192959 · Cited by 4
Alzheimer’s Disease as a Disease of Evolutionary Mismatch, with a Focus on Reproductive Life History
Fox, M. M. (2022) · Cambridge University Press eBooks · doi:10.1017/9781009030564.019 · Cited by 4
Evolutionary Selection of APOEɛ4 Encourages Increased Focus on Immunity in Alzheimer’s Disease
Wheeler, C. J. (2023) · Journal of Alzheimer s Disease · doi:10.3233/jad-230390 · Cited by 4
Marr, C., McDowell, B., Holmes, C., Edwards, C. J., Cardwell, C. R., McHenry, M., Meenagh, G., Teeling, J. L., & McGuinness, B. (2024) · Journal of Alzheimer s Disease · doi:10.3233/jad-231329 · Cited by 4
Is the Relationship Between Cardiovascular Disease and Alzheimer’s Disease Genetic? A Scoping Review
Moore, A. K., & Ritchie, M. D. (2024) · Genes · doi:10.3390/genes15121509 · Cited by 5
Dafnis, I., Mountaki, C., Fanarioti, Ε., Mastellos, D. C., Karvelas, M., Karathanos, V. Τ., Tzinia, A. K., Dermon, C. R., & Chroni, A. (2022) · Molecular Neurobiology · doi:10.1007/s12035-022-03047-3 · Cited by 4
“Moreover, a chronic low-grade inflammation has been associated with earlier disease onset in carriers of the apolipoprotein E (apoE) ε4 allele, which is the major genetic risk factor for late-onset AD [8].”
BackgroundIdentification of an APOE ε4–specific blood‐based molecular pathway for Alzheimer's disease risk
Tao, Q., Zhang, C., Mercier, G., Lunetta, K. L., Ang, T. F. A., Akhter‐Khan, S. C., Zhang, Z., Taylor, A. W., Killiany, R., Alosco, M. L., et al. (2023) · Alzheimer s & Dementia Diagnosis Assessment & Disease Monitoring · doi:10.1002/dad2.12490 · Cited by 3
“Based on our previous findings indicating that CRP is associated with AD risk in ε 4 carriers in humans, 5,6 the goal of this study was to determine which other proteins in the biological pathway containing CRP would also modify the association of APOE genotype with AD-related traits including A β…”
BackgroundSelf-citationAlbar, N. Y., Hassaballa, H., Shikh, H., Albar, Y., Ibrahim, A. S., Mousa, A. H., Alshanberi, A. M., Elgebaly, A. S., & Bahbah, E. I. (2024) · Postgraduate Medicine · doi:10.1080/00325481.2024.2360887 · Cited by 4
“Some of these factors encompass aging, cardiovascular conditions, type 2 diabetes (T2DM), metabolic syndrome (MS), obesity, depression, post-menopausal stage in women, cognitive stagnancy, poor lipid levels, smoking, drug misuse, and unhealthy diets [2,11,14–16].”
RetractedFissler, P., Mavioğlu, R. N., Wenzel, M., Filippi, M., Stoewer, S., Wolff, W., Karabatsiakis, A., Pruessner, J. C., Kolassa, I., & Krähenmann, R. (2022) · PsyArXiv (OSF Preprints) · doi:10.31234/osf.io/b3qf5 · Cited by 4
Huang, J., Wang, Y., Stein, T. D., Ang, T. F. A., Zhu, Y., Tao, Q., Lunetta, K. L., Mez, J. B., Au, R., Farrer, L. A., et al. (2023) · Research Square · doi:10.21203/rs.3.rs-3376348/v1 · Cited by 4
“Page 4/26 using the Framingham Heart Study (FHS), we found that within carriers of the AD risk genotype, apolipoprotein E4 (APOE 4), elevated blood C-reactive protein (CRP) levels are associated with increased AD risk.(2) This phenomenon is not observed among APOE 2 and APOE 3 carriers.”
MethodSelf-citationVitamin E and cognitive function: A systematic review of clinical evidence
Amin, A. M., & Mostafa, H. M. A. (2025) · Nutrition Research · doi:10.1016/j.nutres.2025.11.009 · Cited by 4
Genetic modifiers of APOE-ε4-associated cognitive decline
Contreras, A. G., Walters, S., Eissman, J. M., Archer, D. B., Regelson, A. N., Durant, A., Clifton, M. J., Mukherjee, S., Lee, M. L., Choi, S.-E., et al. (2026) · Nature Communications · doi:10.1038/s41467-026-68933-z · Cited by 4
“Inter-estingly, APOE - ε 4 carriers are susceptible to chronic in fl ammatory diseases, and our results suggest some shared genetic architecture with such in fl ammatory traits and cognitive decline among carriers 40 .”
Self-citationSheikh, M. A., Moon, M. P., Wright, C. B., Gutierrez, J., Liu, M., Rundek, T., Cheung, K., Hornig, M., & Elkind, M. S. V. (2024) · Brain Behavior & Immunity - Health · doi:10.1016/j.bbih.2024.100937 · Cited by 3
Highlights of 2024: Beyond lipids: immune dysfunction in APOE4‐associated Alzheimer's disease
McEwan, I., Thomson, S., Issar, J. K., & Finney, C. A. (2025) · Immunology and Cell Biology · doi:10.1111/imcb.70025 · Cited by 3
An overview on the impact of viral pathogens on Alzheimer's disease
AmeliMojarad, M., AmeliMojarad, M., & Cui, X. (2024) · Ageing Research Reviews · doi:10.1016/j.arr.2024.102615 · Cited by 4
Burke, J., Gibbon, S., Low, A., Hamid, C., Reid‐Schachter, M., Terrera, G. M., Ritchie, C. W., Dhillon, B., O'Brien, J. T., KING, S. E., et al. (2025) · Alzheimer s & Dementia Diagnosis Assessment & Disease Monitoring · doi:10.1002/dad2.70075 · Cited by 4
“38 The APOE ε 4 variant is a major risk factor for AD, 23 and has been associated with a wide range of negative health-related outcomes or features including cardiovascular disease, 39 blood–brain barrier dysfunction, 40 inflammation, 41 and autonomic dysfunction.”
Alzheimer’s Disease: Epidemiology, Etiology, Risk Factors, and Future Predictions
Jojo, G. M., Johnson, J., Kuppusamy, G., & Karri, V. V. S. R. (2024) · Springer eBooks · doi:10.1007/978-981-96-0259-9_3 · Cited by 3
Li, J., Li, J., Yu, Y., Sun, Y., Fu, Y.-Q., Cai, L., Shen, W.-Q., Tan, X., Wang, N., Lu, Y.-L., et al. (2025) · Diabetes, obesity and metabolism · doi:10.1111/dom.16292 · Cited by 2
“37,38 These findings implied a pivotal role of systemic inflammation in the development of dementia.”
Merchant, A. T., Zhao, L., Bawa, E. M., Yaseri, A. F., Lohman, M. C., Zhang, J., Clay‐Gilmour, A., Newman‐Norlund, R., & Fridriksson, J. (2025) · Journal of Alzheimer s Disease Reports · doi:10.1177/25424823251370770 · Cited by 4
Bei, J., Miranda-Morales, E. G., Gan, Q., Qiu, Y., Husseinzadeh, S., Liew, J. Y., Chang, Q., Krishnan, B., Gaitas, A., Yuan, S., et al. (2023) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2023.04.03.535441 · Cited by 3
Self-citationReyes‐Reyes, E. M., Brown, J. A., Trial, M., Chinnasamy, D., Wiegand, J., Bradford, D. R., Brinton, R. D., & Rodgers, K. E. (2024) · Experimental Brain Research · doi:10.1007/s00221-023-06763-x · Cited by 2
“This sex–APOE4 genotype interaction significantly influences a range of AD-related outcomes (Christensen et al. 2010; Altmann et al. 2014; Kanekiyo et al. 2014; Tao et al. 2018; Duarte-Guterman et al. 2020; Farmer et al. 2021; Polsinelli et al. 2023).”
BackgroundLehman, C., & Peebles, R. S. (2025) · doi:10.37349/eaa.2025.100967 · Cited by 2
Shi, Y., He, X., Liu, W. J., Hu, J., Qiu, W. Q., Zhang, X., & Fan, Z. (2025) · Frontiers in Endocrinology · doi:10.3389/fendo.2025.1506560 · Cited by 3
Self-citationHuang, J., Wang, Y., Stein, T. D., Ang, T. F. A., Zhu, Y., Tao, Q., Lunetta, K. L., Mez, J., Au, R., Farrer, L. A., et al. (2025) · Translational Psychiatry · doi:10.1038/s41398-025-03542-w · Cited by 8
Self-citationCross‐tissue immune profiling of APOE ε4 reveals early dysregulation in Alzheimer's disease
Shvetcov, A., Thomson, S., Graham, M. E., Hauger, B. M., Keller, J. E., Smoyer, C. J., Tague, S. E., Cho, A., Imam, F. B., Krish, V. S., et al. (2026) · Alzheimer s & Dementia · doi:10.1002/alz.71714 · Cited by 6
“While prior studies of APOE ε 4 immunopathology largely focused on peripheral immune cells, 3–7, 42– 45, 62, 64, 65 post mortem brain tissue, 8, 66 or Future large-scale organoid studies, however, would benefit from gen-eratingiPSCsfromdonorswithdiffering APOE genotypestostudytheir respective…”
Hegde, K. U., Mehak, S. F., Gangadharan, G., & Pillai, V. G. (2023) · Elsevier eBooks · doi:10.1016/b978-0-323-95698-7.00001-2 · Cited by 2
Ma, X., Ma, J., Guo, R., Du, J., Feng, B., Liu, X., Du, X., Ma, Z., & Cui, H. (2021) · Stem Cell Research · doi:10.1016/j.scr.2021.102450 · Cited by 2
Tao, Q., Ang, T. F. A., Huang, J., Itchapurapu, I. S., Mez, J., Alosco, M., Au, R., Farrer, L. A., Zhang, X., Qiu, W. Q., et al. (2026) · Health Science Reports · doi:10.1002/hsr2.71810 · Cited by 1
“As some proinflammatory proteins in blood impact APOE genotypes differently for AD risk [4, 20], PCSK9, a lipid related protein, also showed different or opposite associations with AD risk depending on APOE genotypes, e.g blood PCSK9 could be a protector for AD in APOE ɛ4 noncarriers but did not…”
Self-citationC-Reactive Protein, the Gliovascular Unit, and Alzheimer’s Disease
Straistă, M., & SLEVIN, M. A. (2024) · Cureus · doi:10.7759/cureus.67969 · Cited by 1
“The Framingham Heart Study offspring cohort revealed that chronically elevated levels of CRP can raise the risk of AD in ApoE4 positive patients [13].”
BackgroundAmeliMojarad, M., & AmeliMojarad, M. (2025) · Journal of NeuroVirology · doi:10.1007/s13365-025-01282-7 · Cited by 2
Fink, A., Reinke, C., Aretz, B., Heneka, M. T., & Doblhammer, G. (2025) · Journal of Alzheimer s Disease · doi:10.1177/13872877251386480 · Cited by 1
Lee, P.-L., Huang, C., & Ou, L.-C. (2025) · Scandinavian Journal of Psychology · doi:10.1111/sjop.70051 · Cited by 1
Klinger, H. M., Coughlan, G., Hayden, K. M., Manson, J. E., Wild, R. A., Jung, S. Y., Casanova, R., Liu, L., Shadyab, A. H., Wactawski‐Wende, J., et al. (2026) · Journal of Clinical and Experimental Neuropsychology · doi:10.1080/13803395.2025.2608340 · Cited by 1
“This interaction may amplify neuroinflammation cascades that compromise blood-brain barrier integrity, accelerate tau pathology, and impair neuronal function (Tao et al., 2018).”
Cell-type-specific APOE4 cascade across the Alzheimer’s disease continuum
Shostak, D. M., Liang, Z., & Huang, Y. (2026) · Neuron · doi:10.1016/j.neuron.2026.04.024 · Cited by 1
Naler, L. B., Hsieh, Y.-P., Geng, S., Zhou, Z., Li, L., & Lu, C. (2021) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2021.03.28.437377 · Cited by 1
Metadata
- Authors
- Tao, Q., Ang, T. F. A., DeCarli, C., Auerbach, S. H., Devine, S., Stein, T. D., Zhang, X., Massaro, J., Au, R., & Qiu, W. Q.
- Affiliations
- Boston University (US)
- University of California Davis Medical Center (US)
- Corresponding author
- Au, Rhoda
- Qiu, Wei Qiao
- ORCID
- Venue
- JAMA Network Open
- Publisher
- American Medical Association (AMA)
- Published
- 2018-10-19
- Volume
- 1
- Issue
- 6
- Pages
- e183597
- ISSN
- 2574-3805 (ISSN-L)
- PMC
- PMC6324596
- OpenAlex
- W2896917224
- Cited by
- 239
- References
- 34
- Citations by year
- 2026: 19 · 2025: 38 · 2024: 40 · 2023: 33 · 2022: 38 · 2021: 32 · 2020: 26 · 2019: 13
- FWCI
- 13.87
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- cc-by
- Locations
- JAMA Network Open (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (n01hc25195-41-0-1)
- National Institute on Aging (P30AG010129, K24AG050842, U01AG052409, R01AG054076)
- National Heart, Lung, and Blood Institute (N01‐HC25195)
- National Institute of Neurological Disorders and Stroke (R01NS017950)
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- Alzheimer's disease, low-grade inflammation, apolipoprotein E, APOE ε4 carriers, C-reactive protein, inflammatory markers, dementia incidence, brain volume, cardiovascular disease, Framingham Offspring cohort, APOE3, APOE2
- MeSH terms
- Adult, Aged, Aged, 80 and over, Alzheimer Disease, Brain, C-Reactive Protein, Chronic Disease, Female, Humans, Inflammation, Longitudinal Studies, Magnetic Resonance Imaging, Male, Middle Aged, Risk Factors, Cohort Studies, Apolipoprotein E4
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