Chronic Inflammation May Underlie Higher Alzheimer’s Risk in ApoE4 Carriers, Study Shows

Chronic, low-level inflammation enhances the risk of Alzheimer’s disease among ApoE4 gene carriers, the major genetic risk factor for the late-onset form of the disorder, a study shows.

The study, “Association of Chronic Low-grade Inflammation With Risk of Alzheimer Disease in ApoE4 Carriers,” was published in the journal JAMA Network Open.

People who carry two copies of the apolipoprotein E4 (ApoE4) gene have a significantly higher risk of developing Alzheimer’s disease after the age of 65 than the rest of the population. However, not all of these carriers will develop Alzheimer’s, even those who are 90 or older.

Researchers at the Boston University School of Medicine (BUSM) hypothesized that a complex interaction of genetic vulnerabilities with environmental risk factors may influence the risk of developing Alzheimer’s disease among certain ApoE4 carriers.

“Finding out what mediating factors for ApoE4 increase AD risk is important for developing intervention and prevention of the disease,” Wendy Qiu, MD, PhD, associate professor at BUSM and the study’s lead author, said in a press release.

Chronic inflammation is common among the elderly, leading researchers to hypothesize that it may influence the risk of Alzheimer’s disease.

“Since many elders have chronic low-grade inflammation after suffering from common diseases like cardiovascular diseases, diabetes, pneumonia and urinary tract infection, or after having surgeries, rigorously treating chronic systemic inflammation in ApoE4 carriers could be effective for prevention of Alzheimer’s dementia,” Qiu said.

C-reactive protein (CRP) is a marker of whole-body inflammation, and its levels are known to increase with age. Moreover, preclinical studies suggest that CRP plays a role in the ApoE4-mediated risk of Alzheimer’s disease.

Researchers used data from the Framingham Heart Study, a large population-based cohort study in Massachusetts, to assess how the levels of CRP in the blood were associated with the onset of Alzheimer’s among ApoE4 carriers.

They evaluated data from 2,656 participants in the study, 1,227 men and 1,429 women, all carrying two copies of the ApoE4 gene. Data included the levels of CRP in the blood, clinical diagnosis of dementia, including Alzheimer’s, and brain volume.

After 17 years of follow-up, 194 individuals (7.3%) developed dementia, among whom 152 (78.4%) were diagnosed with Alzheimer’s disease.

The analysis revealed that ApoE4 carriers with chronic low inflammation, defined by CRP levels in the blood of 8 mg/L or higher, had an up to six times increased risk of Alzheimer’s disease compared with ApoE4 carriers without chronic inflammation.

Moreover, ApoE4 carriers with chronic inflammation had a 3.5 times increased risk of earlier disease onset.

ApoE4 and chronic low-grade inflammation was also associated with a reduction in the volume of the brain (atrophy), namely of the temporal lobe (an area of the brain that helps process pain and auditory stimuli) and the hippocampus, a region of the brain that plays a major role in learning and memory.

These results suggest that chronic, low-grade inflammation may be behind the higher risk of Alzheimer’s disease among ApoE4 carriers.

“Rigorously treating chronic systemic inflammation based on genetic risk could be effective for the prevention and intervention of AD [Alzheimer’s disease],” the researchers concluded.