Among patients with the apolipoprotein E (APOE) genotype, peripheral chronic low-grade inflammation is associated with a shortened latency for Alzheimer disease (AD) onset, according to a study published in JAMA Network Open.

Study investigators obtained Generation 2 individual data from the Framingham Heart Study offspring cohort (n=2656). Included participants underwent measurements for serum C-reactive protein (CRP), incident dementia including AD, and brain volume. Additionally, the researchers assessed participants for the presence of low-grade inflammation, defined as a CRP >3 mg/L and ≥2 longitudinal CRP values above the stipulated cutoff levels. For the purposes of their analysis, researchers evaluated the association between the APOE genotype and chronic low-grade inflammation with AD development.

The mean (SD) age of the cohort at the time of the last CRP measurement was 61.6 (9.5) years. The median (interquartile range [IQR]) levels of CRP increased with mean (SD) age (43.3 [9.6] years; 0.95 mg/L [IQR, 0.40-2.35 mg/L] vs 59.1 [9.6] years, 2.04 mg/L [IQR, 0.93-4.75 mg/L] vs 61.6 [9.5] years, 2.21 mg/L [IQR, 1.05-5.12 mg/L]; P <.001). A total of 194 (7.3%) participants developed dementia during a 17-year follow-up period, and 78.4% of these individuals had AD.

Patients who were carriers of the APOE Ɛ4 allele with  a CRP level of ≥8 mg/L (ie, chronic low-grade inflammation), had an increased risk for AD (hazard ratio [HR] 6.63; 95% CI, 1.80-24.50; P =.005). Additionally, the presence of APOE Ɛ4 and chronic low-grade inflammation was associated with an increased risk for earlier AD onset vs APOE Ɛ4 carriers without evidence of chronic inflammation (HR 3.52; 95% CI, 1.27-9.75; P =.009). In a subset of 1761 individuals who underwent brain MRI, the presence of APOE Ɛ4 and chronic low-grade inflammation was associated with atrophy in the temporal lobe of the brain (β = –0.88, SE = 0.22; P <.001) as well as in the hippocampus (β = –0.04, SE = 0.01; P =.005).

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The lack of frequent and/or annual measurements of CRP in this cohort, which may have led to misclassification or missed inflammation statuses, represents a potential limitation of the study.

Based on these results, the investigators suggest “specifically targeting a subset of patients based on APOE genotypes and inflammation status may be an important consideration for future clinical trial study design.”


Tao Q, Ang TFA, DeCarli C, et al. Association of chronic low-grade inflammation with risk of Alzheimer disease in APOE4 carriers. JAMA Network Open. 2018;1(6):e183597.