Brain BDNF Expression May Explain Cognitive Reserve

Pauline Anderson

January 27, 2016

High expression of brain-derived neurotrophic factor (BDNF) may help explain why some patients with Alzheimer's disease (AD) pathology don't exhibit significant cognitive decline.

A new study showed not only that high levels of brain BDNF expression were independently associated with slower rates of cognitive decline but also that the relationship was strongest among patients with the most AD neuropathology.

The results suggest that boosting BDNF expression may be a therapeutic strategy to preserve cognition.

"This is a major big deal," said lead author Aron S. Buchman, MD, professor, neurological sciences, Rush University Medical Center and Rush Alzheimer's Disease Center, Chicago, Illinois.

Having a protein "to go after" is much better than telling patients to pursue higher education or have a purpose in life — two factors linked to slower cognitive decline, said Dr Buchman. "I don't know what the construct is for 'purpose in life,' and I wouldn't know how to translate that into clinical treatment, but this is something that investigators can get a hold of and look at."

The study was published online January 27 in Neurology.

BDNF, which is encoded by the BDNF gene, is a member of the neurotrophic family of growth factors. It's expressed in areas of the brain, including the hippocampus, cortex and basal forebrain, and in periphery tissues such as the kidneys, prostate, blood, and saliva.

The study included 535 persons from two clinical autopsy studies — the Religious Order Study and the Rush Memory and Aging Project — whose mean age at death was 88.5 years. They had been examined annually for an average of 6.3 years, but some for up to 20 years, and agreed to a brain autopsy upon death.

This lengthy follow-up period before death makes the study "unique," commented Dr Buchman.

"Most clinical pathology studies have just one data point when people are alive and then researchers get some pathology from the autopsy and look at the cross-sectional association. We were able to look not just at the level of cognition proximate to death, but at the rate of cognitive decline in some cases over the decade or two prior to death."

During the annual clinical examinations, researchers assessed global cognition and five cognitive components: episodic memory, semantic memory, working memory, visual spatial skills, and perceptual speed.

From the autopsies, investigators measured BDNF expression in tissue taken from the gray matter of the dorsal lateral prefrontal cortex.

They assessed AD pathology based on National Institute of Aging consensus criteria and individual amyloid or tau tangle burden. They also recorded the presence of chronic macroscopic infarcts, Lewy body disease pathology, and hippocampal sclerosis.

The study showed that high BDNF expression was associated with a slower rate of cognitive decline. The rate was reduced by almost half (48.3%) in persons with the highest level (90th percentile) of BDNF expression compared to those with the lowest (10th percentile).

The association was stronger in patients with dementia before death than in those with mild cognitive impairment or normal cognition. Brain BDNF expression levels were associated with the rate of decline in all five cognition categories.

Levels of BDNF expression showed an independent association with cognitive decline after adjustment for age, sex, education, and neuropathologies.

"This means that there's another pathway linking BDNF with cognitive decline that doesn't have to do with the pathology," said Dr Buchman.

The study also showed that those with the most AD pathology who had high BDNF expression levels had rates of cognitive decline that were about 40% slower than those with the same degree of AD pathology who had low levels of BDNF expression.

Cognitive Reserve

Researchers have long wondered why some patients with AD pathology had normal cognition before they died. If amyloid or tau tangles cause cognitive decline, there must be something that's preventing these people from becoming demented.

"This led the field to hypothesize that there are factors that provide neural reserve or cognitive reserve or resilience factors that protect against the deleterious effects of the pathology," said Dr Buchman.

Over the years, researchers have learned that acquiring higher education, having a purpose in life, and being physically active are among those protective factors.

But these aren't that easy to translate into clinical recommendations, especially for a 75- or 80-year-old. Zeroing in on BDNF may offer another way to get the same protection.

The new results could take the focus off traditional approaches of developing strategies or drugs to stop the production of amyloid or tangles or to remove these pathologies once they develop.

"What this study is saying is that we have now identified a protein that suggests an alternative," said Dr Buchman. "Even if you don't know how to get rid of the AD pathology, there may be factors you can manipulate such as BDNF that may protect against the effect of the accumulation of different pathologies that are bad for people."

But many questions remain. Other than physical activity, which research suggests may slow cognitive decline through BDNF expression, what other factors or behaviors do the same thing? How long does it take to increase BDNF to the point where it would have an effect? And are there medications that patients can take to boost BDNF?

Reasonable Strategy

In an accompanying editorial, Michal Schnaider Beeri, MD, Department of Psychiatry, The Icahn School of Medicine at Mount Sinai, New York, and Joshua Sonnen, MD, Department of Pathology, University of Utah Medical Center, Salt Lake City, said the study results promote the idea that increasing BDNF gene expression "might be a reasonable therapeutic strategy for AD in humans."

"In humans, physical activity, social interactions, and environmental enrichment (typically measured as years of formal education) have all be associated with a lower risk of dementia and AD, suggesting brain BDNF upregulation as a candidate underlying mechanism, possibly through enhancement of cognitive reserve."

BDNF gene expression or its gene products might serve as a biomarker for cognitive reserve against AD progression, they write.

"Further study is needed to confirm these findings, to better elucidate the relationship between BDNF and systemic markers of cognitive reserve, and to clarify its potential therapeutic utility," they concluded.

Asked for his opinion of the research, Dean Hartley, PhD, director of science initiatives, Alzheimer's Association, said BDNF plays a critical role in brain development, function, and health and the new study adds to the growing literature on its roles and benefits.

"This is certainly an intriguing area of research," said Dr Hartley, adding that the Alzheimer's Association recently funded several research projects looking at the function of BDNF and possible therapeutic opportunities.

Although as an associational study, it doesn't show cause and effect, just correlation. it does present some interesting findings, said Dr Hartley. "The most notable was that the decrease in BDNF expression followed the progression of the disease. BDNF was higher in cognitively healthy people in the study than cognitively impaired people. And it was higher in cognitively impaired people than those who had dementia. So, as cognitive function decreased, so too did BDNF levels."

Another interesting observation, according to Dr Hartley, was that the specific amount of BDNF predicted the severity of cognitive impairment or dementia.

However, "unfortunately," the study doesn't determine if the disease causes the reduction of BDNF , or if low BDNF causes the disease to get worse, said Dr Hartley. "This will require more research — specifically, interventional clinical trials — to determine."

This work was supported by National Institutes of Health grants, and the Illinois Department of Public Health, and the Robert C. Borwell Endowment Fund. Dr Buchman, Dr Schnaider Beeri, and Dr Sonnen have disclosed no relevant financial relationships.

Neurology. Published online January 27, 2016. Abstract Editorial


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