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Chronic Inflammation Linked to Higher Alzheimer’s Risk in APOE4 Carriers


Chronic inflammation was associated with an increased risk of early-onset Alzheimer's disease (AD) in carriers of the apolipoprotein E4 (APOE4) gene, according to a population-based cohort study published online in JAMA Network Open on October 19.

Low-grade inflammation — defined by a C-reactive protein (CRP) level of 8 mg/L or higher — was linked to an elevated risk of AD only in APOE4 carriers, especially in the absence of cardiovascular diseases ([hazard ratio] HR 6.63, 95% CI 1.80-24.50, p=0.005).

In addition, APOE4 carriers with chronic low-grade inflammation had an elevated risk of earlier disease onset than APOE4 carriers without inflammation (HR 3.52, 95% CI 1.27-9.75, p=0.009).

Among the elderly, infection and inflammation are common. Previous research reported inflammation triggered AD pathologic characteristics only in mice who carried the APOE4 gene. The APOE4 gene is a major genetic risk factor for late-onset AD, but not all APOE4 carriers develop AD.

The researchers, led by Qiushan Tao, MD, of the department of pharmacology and experimental therapeutics at Boston University School of Medicine, wrote that their findings "may explain why ApoE4 carriers have increased risk for AD at an old age and suggest that treating chronic low-grade inflammation may delay the onset of AD in ApoE4 carriers."

The researchers analyzed data from 2,656 participants of the Framingham Offspring Study (generation 2) — a cohort of children from the Framingham Heart. They defined chronic inflammatory status as having at least two longitudinal serum CRP measurements above pre-specified levels. Typically, a CRP level lower than 3 mg/L is considered normal, but in this study, the researchers defined any CRP measurement above 3 mg/L as low-grade inflammation, using cutoff levels to indicate severity. Participants with only one CRP measurement equal to or higher than 3 mg/L were not considered to have chronic low-grade inflammation.

On average, patients were about 61 years old at their last CRP measurement.

During the 17 years of follow-up, 194 participants developed dementia, 152 of these participants were diagnosed with AD.

The findings revealed APOE4 carriers with low-grade inflammation had an increased risk of overall AD and earlier onset. However, APOE3 and APOE2 carriers with chronic low-grade inflammation did not have the same risk. The researchers noted while APOE2 carriers had higher CRP levels as they aged, it was not tied to AD risk.

Lastly, in a subset of 1,761 participants who underwent brain magnetic resonance imaging, the researchers found the interaction between APOE4 and chronic low-grade inflammation was associated with brain atrophy in the temporal lobe (beta = –0.88, SE = 0.22; p< .001) and hippocampus (beta = –0.04, SE = 0.01; p= .005).

"Our results indicate that chronic low-grade inflammation may play an early role leading to AD in ApoE4 carriers," the researchers concluded.

The team suggested rigorously treating chronic inflammation based on an individual's genetic risk could effectively prevent and treat AD.

Study limitations included the irregularity of CRP assessments, which may have led some cases of sustained inflammatory status to be misclassified or missed, and the inability to prove causality. The Framingham Heart Study cohort lacked ethnic diversity. This means the findings may not be generalizable to non-white populations.

The study was funded by the National Heart, Lung, and Blood Institute and by grants from the National Institute of Neurological Disorders and Stroke and the National Institute on Aging.

The researchers reported no conflicts of interest.


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; Epub 2018 Oct 19.