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Why Treating Chronic Low-Grade Inflammation in People with the Risk Gene for Alzheimer's Disease Could Be a Viable Therapeutic Option

ARTICLE IN BRIEF

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CUMULATIVE INCIDENCE of AD, dementia, and mortality (top graph) and (bottom graph) cumulative incidence of AD by APOE2, APOE3, and APOE4 genotypes.

Researchers reported that the Alzheimer's risk gene, apolipoprotein E4, is associated with chronic inflammation and dramatically increases the risk for AD. They noted that inflammation can be detected by measuring the C-reactive protein.

Chronic low-grade inflammation may be a key driver of Alzheimer's disease in people who carry at least one copy of the apolipoprotein E4 (APOE4) gene, scientists reported based on an analysis of longitudinal data from the population-based Framingham Heart Study.

The mechanism is not clear, but the scientists say that controlling this inflammation in older people may prove a powerful treatment at preventing or reducing dementia.

Inflammation did not put others without an E4 allele at increased risk for AD, the researchers reported in the October 19 online issue of JAMA Network Open.

“Findings linking inflammation and Alzheimer's have not been consistent,” said Wendy Wei Qiao Qiu, MD, PhD, an associate professor in the psychiatry department, the pharmacology & experimental therapeutics department, and the Alzheimer's Disease Center at Boston University School of Medicine. “We looked at two to three time periods with at least five to seven years between collection of a potent inflammatory marker, C-reactive protein. This chronic low-grade inflammation was only a risk factor for dementia in people with an APOE4 allele.

“It's been a puzzle why some people with an E4 allele develop Alzheimer's and others do not,” said Dr. Qiu. “Systemic infections are far more common in older people, and we wanted to see whether chronic low-grade inflammation could explain the E4 vulnerability. We think it does.

“Our findings suggest that that APOE4 carriers should be rigorously treated with anti-inflammatories after surgery or trauma when inflammatory markers are high,” she added.

STUDY METHODS, FINDINGS

The Framingham Study, begun 70 years ago, has data on three generations of Framingham residents that have helped define risk factors for heart disease, stroke and other diseases, including Alzheimer's disease.

In this latest study, Dr. Qiu and her colleagues pulled data from 2,656 people born to the second generation of study members. They were interested in information collected since the 1970s on serum C-reactive protein (CRP) levels, brain volume, genetic risk factors, and any diagnosis of dementia. The participants were at least 20 years old between 1979 and 1983 when they had their first baseline CRP measure.

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DR. WENDY WEI QIAO QIU: “We looked at two to three time periods with at least five to seven years between collection of a potent inflammatory marker, C-reactive protein. This chronic low-grade inflammation was only a risk factor for dementia in people with an APOE4 allele.”

The researchers defined chronic low-grade inflammation as CRP levels over 3mg/L at two or more time points during the longitudinal study. The average age at the last CRP measure was 61.6 years, which meant that some people were in their 50s and others had just celebrated their 71st birthday, and they had the APOE status of study participants.

The researchers have been recording incident cases of dementia since 1979. By the fifth clinical work-up between 1991 and 1995, the scientists running the Framingham study included the Mini-Mental State Examination (MMSE) to monitor change in cognitive status. A drop of three or more points from one exam or five or more points at all clinical exams would trigger a more rigorous diagnostic workup that included assessment by at least one neurologist and one neuropsychologist.

During the 17-year follow-up period, 194 people (7.3 percent) developed dementia. Almost 79 percent of them had a diagnosis of Alzheimer's. Those with an E4 allele plus chronic inflammation were almost at three times an increased risk for developing AD earlier than those E4 carriers without any evidence of chronic inflammation.

In the absence of cardiovascular diseases, those with chronic inflammation (CRP level of 8mg/L or higher) plus APOE4 genotype had six times the risk for AD compared to those without an E4 allele, said Dr. Qiu.

Chronic inflammation did not play a role in increasing the risk for AD in those with APOE3 or APOE2 genotypes.

The Boston University team also had magnetic resonance imaging (MRI) brain scans from 1,761 people in the study who had completed their seventh examination between 1999 and 2011, and they found a strong association between APOE4 status, chronic low-grade inflammation, and atrophy in the temporal lobes and hippocampi.

The relationship between CRP and Alzheimer's has not been well understood. Dr. Qiu thinks it's because most of the studies have used a one-time measure of CRP. The Framingham data allowed them to collect data from five to seven year intervals over almost two decades to provide a true picture of chronic low-grade inflammation.

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DR. SUE T. GRIFFIN: “Our studies have shown that people with E3 alleles mount a response to neuronal stress, increasing the synthesis of three important proteins that play a role in clearing out cellular debris in the brain, the brains reaction to stress. People with E4 alleles cant mount this same protective response.”

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DR. JAMES A. MORTIMER: “The brain volume results, showing that low-grade inflammation is associated with reduced brain volume and smaller hippocampi among individuals who carry an E4 allele, support the clinical findings. The question is when is inflammation important in the disease process? Is it in the beta-amyloid phase or the tau phase of the disease?

“To our knowledge, this is the first study to use longitudinal measurements of CRP to define a chronic condition of low-grade inflammation at baseline and demonstrate that APOE4 interacting with chronic low-grade inflammation increased the risk of AD and shortened the latency for developing AD,” said Dr. Qiu. “Given the findings, we think that treating chronic low-grade inflammation could delay the onset of Alzheimer's in APOE4 carriers.”

The extensive Framingham data helped identify this link, but she said it would have been even better had there been annual CRP measurements. It's possible that they underestimated cases of chronic inflammation in people with APOE4 and dementia. She said that another limitation of the study is that the Framingham study includes mostly white people and “these findings lack generalizability to nonwhite populations.”

Dr. Qiu said that she and her colleagues would like to design a clinical trial to test whether treating chronic inflammation (measured by CRP) in APOE4 carriers would reduce the risk for AD.

EXPERT COMMENTARY

“This observation is probably relevant to the risk for atherosclerosis as well as Alzheimer's disease, potentially providing one of the first clear links to the high prevalence of comorbidity of Alzheimer's disease and vascular dementia,” said Sam Gandy, MD, PhD, professor of neurology and psychiatry and Mount Sinai Chair in Alzheimer's Disease Research, and director of the Mount Sinai Center for Cognitive Health and NFL Neurological Care.

“One of the first observations about APOE isoform structure-function relationships was made by Masaaki Miyata and Jonathan D. Smith in Nature Genetics in 1996, where they showed that the rank-order of APOE isotype risk for AD parallel the rank-order for potency as an antioxidant,” he said. One source of oxygen radicals is from the surface of inflammatory leukocytes.

“This new paper provides some of the best evidence that the observation by Dr. Miyata and Dr. Smith has clinical relevance,” Dr. Gandy said. “Oxygen radicals from inflammatory cells may well be quenched by APOE3 and APOE2 leading to protection from AD. However, APOE4 lacks the disulfide bonds present in E3 and E2, thereby rendering APOE4 as inactive in oxygen radical quenching. This in turn exposes cells in the brain and periphery to a greater sensitivity to the “bystander effect” wherein normal brain and blood vessel cells are damaged because of their proximity to inflammatory processes.”

Sue T. Griffin, PhD, professor and vice chair for research in the Donald W. Reynolds department of geriatrics at the University of Arkansas for Medical Sciences, has focused on inflammation and its role in Alzheimer's (and other neurodegenerative conditions) since the early 1980s. She is editor-in-chief of the Journal of Neuroinflammation.

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DR. AMY RENEE BORENSTEIN: “The finding is very important. If you carry an E4 allele it implies you should keep inflammation down, especially after mid-life. I would like to see the findings replicated.”

“It's very interesting, and I am not surprised by the finding about chronic low-level inflammation and APOE4 and the risk for Alzheimer's,” said Dr. Griffin. “Our studies have shown that people with E3 alleles mount a response to neuronal stress, increasing the synthesis of three important proteins that play a role in clearing out cellular debris in the brain, the brain's reaction to stress. People with E4 alleles can't mount this same protective response.”

“The finding is very important,” said Amy Renee Borenstein, PhD, MPH, professor of epidemiology in the department of family medicine and public health at University of California, San Diego. “If you carry an E4 allele it implies you should keep inflammation down, especially after mid-life. I would like to see the findings replicated.”

“Animal studies support this finding,” added James A. Mortimer, PhD, professor emeritus at the College of Public Health at the University of South Florida. “We have known that inflammation plays an important role in AD. The brain volume results, showing that low-grade inflammation is associated with reduced brain volume and smaller hippocampi among individuals who carry an E4 allele, support the clinical findings. The question is when is inflammation important in the disease process? Is it in the beta-amyloid phase or the tau phase of the disease?”

LINK UP FOR MORE INFORMATION:

• Tao Q, Ang TFA, DeCarli C, et al. Association of chronic low-grade inflammation with risk of Alzheimer disease in ApoE4 carriers https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2707427. JAMA Network Open 2018; Epub 2018 Oct 19.