Defending the Aging Brain

The disconnect between cognitive decline and pathology is one of the mysteries of later life. Some people whose brains are heavily marked by the plaques and tangles of Alzheimer’s disease (AD) or damaged by stroke remain cognitively intact throughout long lives, while others with limited evidence of disease are seriously demented.

“If you account for all the pathology you can measure in the brain—Alzheimer’s-, Parkinson’s-, and vascular-related—it explains less than half of the decline in cognition that an individual experiences,” says Philip De Jager, professor of neurology at Columbia University.

It’s a matter of resilience, the innate ability of all physiological systems to continue functioning despite injury and disease. Unlike such organs as the lungs or kidneys, there’s no second brain should the first falter, nor can the brain regenerate like the liver. “The brain is the ultimate high-rent district,” says David Bennett, professor of neuroscience at Rush Medical School and director of the Rush Alzheimer’s Disease Center. But it also boasts unique ways to keep on keeping on, such as the neuroplasticity that allows intact areas to take over functions lost by diseased or injured tissue.

“The brain doesn’t want to be demented,” Bennett says, “and it has means to protect itself.”

In the Brain’s Defense

Interest in factors that may promote self-protection has increased in recent years. According to Bennett’s 2014 review paper, lifestyle factors including education, continued intellectual activity, and social interaction appear to enhance “cognitive reserve,” reducing the rate of cognitive decline and risk of dementia. The role of physical activity and diet also has research support.

Now, an important study just reported in PLoS Medicine provides evidence that another part of the story is in the genes.

“There’s a lot of biology [of resilience] we still don’t understand,” says De Jager, senior author of the study. “That was the genesis of our project, to try to identify new leads.”

“We seem to have identified two, maybe three genes that function in this area,” he says. “Two entry points into the biology.”

The study used genetic, cognitive, lifestyle, and pathological data from two large studies. Begun in the mid-’90s, the Religious Orders Study (ROS) and the Rush Memory and Aging Project (RMAP) have enrolled more than 3,000 healthy people, for the most part in their 60s and 70s, following their lives, tracking their cognitive function, and subjecting the brains of those who die to close examination.

“These are the only two studies in the world to enroll people without dementia and study risk factors for Alzheimer’s and other dementias, where everyone is an organ donor,” says Bennett, who is principal investigator for both studies and a co-author of the PLoS paper.

The PLoS study analyzed data on nearly 1,000 members of ROS and RMAP. For each brain, the researchers tabulated the total damage due to the amyloid plaques and neurofibrillary tangles of Alzheimer’s, the Lewy bodies of Parkinson’s disease and Lewy body dementia, and the cell death of stroke.

Using cognitive assessments made closest to the time of death, they calculated “residual cognition,” the level of function that could not be accounted for by damage and demographics. “The measure reflects how well you’re functioning, given the amount of pathology in your brain,” says De Jager. “It goes both ways: some people fared better than expected, some worse.”

The genetic investigation was a three-step process specially devised for the study. The researchers conducted a genome-wide analysis for each sample, to identify candidate genes, then refined the field with epigenetic analysis, which measured the degree to which each was modified by methylation. Finally, they calculated RNA transcription, a stage on the way from gene to protein.

All three measures converged in two genes, UNC5C and ENC1. “Specific alleles of these genes are associated with measures of residual cognition,” De Jager says. Variation in each, in other words, appeared to influence the brain’s ability to function in the face of disease.

A third gene, TMEM106B, was supported by weaker evidence but also associated with residual cognition, and had been identified in earlier studies for a possible protective role in certain kinds of dementia.

“These genes are connected to the kinds of phenomena that affect cognitive aging,” De Jager says: ENC1 with depression, UNC5C with synaptic composition, and TMEM106B with certain abnormal proteins.

A Global View

“What makes this paper so interesting, I think, is that it takes a quantitative approach to the disconnect between how much brain pathology you have and how well you do,” says ElizabethMormino, assistant professor of neurology at Stanford University. “Using quantitative data on both the genetic and pathology side takes it beyond things like education.”

A recent paper to which Mormino contributed explored the relationships between brain imaging measures of AD related pathology (tau protein and amyloid deposits), cognitive reserve (as measured by verbal IQ), and cognitive function in 156 older people, some with mild cognitive impairment (MCI) or AD. The researchers found that as tau levels went up, cognitive performance went down. But its impact was lessened by cognitive reserve.

She sees such findings and the PLoS work as “complementary. It’s very difficult to define what reserve is and useful to acknowledge it might have multiple etiologies; it may be influenced by physical activity, social activity and genetics, and they may be related to each other.

“The [PLoS authors] note that 53 percent of variance [in the relationship between cognitive function and pathology] is still not explained,” Mormino observes. “A good chunk of this could represent interactions between genetics and environment and behavior.

“After reading the paper, I want to apply it to some data sets we have,” she says. “Now we can use [genetic variations] they identified and see if they contribute to cognitive decline.”

The paper’s focus on total brain pathology rather than pathways associated with single disorders like Alzheimer’s represents another strength, she says. “This speaks to the complexity of cognitive aging. It’s very much in line with what the data are telling us: pretty much everyone has multiple pathologies that impact on the risk of dementia.”

Indeed, a paper by Bennett in the same issue of PLoS Medicine as his study expands on the idea that “there’s so much mixed pathology in the brain that resilience itself can be a therapeutic target.”

“Attempts to mitigate disease processes underlying specific disorders have been disappointing,” he says. “We know about 450 failed clinical trials in AD in the last 11 years.”  Aiming instead to enhance the brain’s ability to protect itself and offset the effects of all pathologies “to me, has been kind of a Holy Grail.”

Functions of the three genes identified in the study suggest potential targets for such research, De Jong says.

“Particularly the UNC5C gene, which has been associated with AD and with synaptic density,” he says. (Reduced synaptic density in some brain regions appears linked to cognitive decline.) “One hypothesis is that if you manipulate UNC5C expression levels, you can alter synaptic density.”

He emphasizes the preliminary nature of his research. “We don’t want to oversell these results, but they are intriguing,” says De Jong. “We’re in a great spot to generate a bunch of hypotheses to be explored further.”

A mechanism to facilitate such explorations is in place. The study is part of a broader initiative to develop novel drugs and approaches to dementia, the AcceleratingMedicines Partnership for Alzheimer’s Disease [AMP-AD], which combines the efforts of government agencies, non-profit foundations, academia, and industry.

Data is shared among all members, so further investigations, to determine whether proteins associated with these genes represent feasible drug targets, for example, could be readily pursued by diverse researchers, including pharmaceutical companies.

“We have a drug discovery pipeline,” Bennett says.