Inflammation in Midlife Linked to Later Cognitive Decline

February 14, 2019

Higher blood levels of inflammatory markers in midlife were associated with greater cognitive decline many years later in the decades leading up to older adulthood, according to a new study.

"Our results suggest that maintaining health and thereby reducing inflammation in middle age can have positive effects on brain health in older adulthood," lead author Keenan Walker, PhD, Department of Neurology, Johns Hopkins University, Baltimore, Maryland, commented to Medscape Medical News.

The study was published online February 13 in Neurology.   

Walker noted that there is previous evidence that Alzheimer’s disease and dementia are linked to higher levels of inflammatory markers in the blood and cerebrospinal fluid, and to brain tissue on autopsy. However, the vast majority of this work has been done in older people.

"We wanted to investigate whether inflammatory markers much earlier in life are related to cognitive decline in older years," he said. "This gives us a temporal relationship and is much more suggestive of causality."  

In the current study, the researchers measured several inflammatory markers in blood samples from cognitively normal individuals in mid-adulthood, in their 40s and 50s. They then followed these people for the next two decades and measured cognitive decline.

They found that those with higher levels of inflammatory markers in midlife had steeper rates of cognitive decline over the next 20 years.

Walker believes this is one of the first studies to look at this association starting so early in life; it also has one of the longest follow up periods.

"The most impactful thing about this study is that it suggests that inflammation may have a detrimental effect on later cognition much earlier in life than we have previously thought. Things that we do in our 40s and 50s seem to affect our cognitive heath in our 70s and 80s," he said.  

"The neat thing about this study is that as well as showing a temporal relationship, we compared cognitive function in people to their own baseline, so we eliminate much of the bias that can occur in observational studies," Walker added.

He says that while it is not possible to conclusively confirm that inflammation causes memory decline from these data, it is very suggestive that this is the case.

"The fact we are seeing inflammation occurring at higher levels many years before memory decline leads me to believe there is a causal link here."

Walker points out that major causes of inflammation include heart disease, diabetes, obesity, and hypertension — and avoiding these conditions can lower levels of inflammation in the body.

It is also known that exercise and diet are important. "Exercise lowers inflammation and we know certain foods — like saturated fats and sugar — cause inflammation. The Mediterranean diet has been shown to lower inflammation and has also been linked to reduced risk of dementia," he noted.

"We’re not yet at the stage of recommending anti-inflammatory medication as a preventative strategy for cognitive decline as we haven’t got trial data on this," Walker said, "but I think we can say it is a good idea to lead a healthy lifestyle and try to avoid becoming hypertensive or diabetic or obese and that should lower our risk of developing dementia later in life."

It's known that avoiding diabetes, hypertension, and obesity reduces the risk of developing vascular disease, but now evidence is mounting that this may also stave off cognitive decline, he added. "That's an extra reason to make those lifestyle changes as soon as possible."  

For the study, the researchers analyzed blood samples taken from 12,336 people (21% black, 56% women) participating in the Atherosclerosis Risk in Communities (ARIC) cohort study (average age at baseline 56 years at 1987–1989).

Participants were evaluated in person over five visits until 2011–2013 and received a serial cognitive assessment using measures of memory, executive function, and language at visits 2, 4, and 5 spanning 20 years.

An inflammation composite score was created using four blood biomarkers measured at visit 1 (fibrinogen, white blood cell count, von Willebrand factor, and factor VIII); and C-reactive protein (CRP) was measured at visit 2.

Results showed that after adjusting for demographic variables, vascular risk factors, and comorbidities, each standard deviation (SD) increase in midlife inflammation composite score was associated with an additional 20-year decline of −0.035 SD on the cognitive composite score.

They found a similar association between each SD increase in midlife CRP level and additional 20-year cognitive decline (−0.038 SD).

Having an inflammation composite score in the 2nd, 3rd, and 4th quartile was associated with cognitive declines that were 7.5%, 7.7%, and 8.9% steeper, respectively, than that of the 1st quartile.

A CRP level in the top 2nd, 3rd, and 4th quartile was associated with 9.7%, 8.5%, and 12.3% steeper decline on the cognitive composite score, respectively, compared with participants with CRP in the 1st quartile.

In cognitive domain specific analyses, elevated midlife inflammatory markers were most consistently associated with declines in memory.

The authors note that the additional absolute level of cognitive change associated with systemic inflammation was modest overall, but comparable to that which has been associated with vascular risk factors such as hypertension and diabetes.

The study authors point out: "Given that neuropathologic processes associated with dementia, such as β-amyloid deposition, are believed to begin during midlife, decades before the onset of clinical symptoms, the current findings provide support for the idea that systemic inflammation may have an early pathologic role in driving or accelerating some of the pathologic processes underlying late-life cognitive decline."

However, they caution that it is also possible that systemic inflammation during midlife is a marker, not a cause, of neurodegenerative disease.

The ARIC study was supported by the National Heart, Lung, and Blood Institute; the National Institute on Aging; and the National Institute of Diabetes and Digestive and Kidney Diseases. Walker has disclosed no relevant financial relationships.

Neurology. Published online February 13, 2019. Abstract

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