New Approaches to Mitigating Cognitive Decline
by Bridget M. Kuehn, MSJ for JAMA:
Pathology is not destiny. So say the more than 1200 brains autopsied so far as part of the Rush Memory and Aging Project and the Religious Orders Study, a pair of massive prospective studies that have tracked the cognitive status of nearly 3000 elders for about 2 decades (Bennett DA et al. Curr Alzheimer Res. 2012;9[6]:646-663, and Bennett DA et al. Curr Alzheimer Res. 2012;9[6]:628-645).
Autopsies showed that some mentally spry participants had extensive signs of cellular neuropathologies such as Lewy bodies or those related to Alzheimer or vascular disease. But others with substantial cognitive decline in their later years had few signs of these cellular abnormalities, explained David Bennett, MD, director of the Rush Alzheimer’s Disease Center at Rush University in Chicago and lead investigator of the studies. In fact, these overt cellular pathologies accounted for only about half of the cognitive decline documented, revealing a disconnect with the study participants’ cognitive status. (Boyle PA et al. Ann Neurol. 2013;74[3]:478-489).
Instead, certain behavioral factors appeared to modify the association between cellular pathologies and cognitive decline, explaining some of the discrepancy. Other work has since similarly implicated behavioral modifiers such as exercise, social interaction, conscientiousness, and sense of purpose in cognitive resilience (Wilson RS et al. Neurology. 2013;81[4]:314-321, Wilson RS et al. Psychol Aging. 2015;30[1]:74-80, and Windsor TD et al. Dev Psychol. 2015;51[7]:975-986).
“The data suggest we need to think more broadly about potential therapeutic targets,” Bennett said during an interview. Currently, the vast majority of public and private funding is spent on therapeutic trials for cognitive decline in Alzheimer disease, but even if successful treatments were developed, only about one-third of age-related cognitive decline would be eliminated, noted Bennett.
Instead, he argued the focus should be on prevention that taps into the brain’s own defense mechanisms. The National Institutes of Health and the National Institute on Aging have committed $12 million to boosting research into brain resilience in 2016 and recently issued a call for proposals.
“Identifying drugs that target protective mechanisms agnostic of [disease] pathology is of the highest value,” he said.
A Social Solution
Studies are beginning to explain the underlying biology that allows behavioral and other social factors to mediate the risk of cognitive decline even when signs of pathology are present.
New results from the Framingham Heart Study presented at the recent American Neurological Association meeting showed that social support for elders increases levels of the protein called brain-derived neurotrophic factor (BDNF) and reduces their risk of dementia and stroke. The converse also holds true for elders without social support, according to work by Sudha Seshadri, MD, a professor of neurology at Boston University, and her colleagues. Bennett’s soon-to-be published study also reports that higher BDNF expression is associated with slower cognitive decline in the face of brain pathology.
Increased BDNF levels have been implicated in a whole host of behaviors that protect the brain, including eating a lower-calorie diet and exercise, Seshadri noted. Studies have shown that BDNF is involved in learning and memory and is released in response to neural activity (Park H and Poo MM. Nat Rev Neurosci. 2013;14[1]:7-23), which could explain why social activities and other behavioral modifiers enhance BDNF levels. Research suggests behavior-induced spikes in BDNF may encourage new neuron growth and support the formation of synapses, connections that allow neurons to communicate with one another. Seshadri explained that BDNF also appears to protect neurons from dying. These molecular findings may explain why studies have found that higher BDNF levels appear to be protective against Alzheimer disease and dementia (Weinstein G. JAMA Neurol. 2014;71[1]:55-61).
The Heart Of The Matter
Another promising line of inquiry emphasizes the importance of cardiovascular health in maintaining brain function throughout life. Poor cardiovascular health has been linked to cognitive decline in a number of large studies, including the massive Framingham Heart Study, which began in 1948 and has since followed 3 generations of participants to identify risk factors for heart disease.
Maintaining good heart health is important—not because it may prevent Alzheimer disease—but because it protects the brain from damage resulting from a stroke or heart attack, Bennett explained. In fact, he advises young family members of patients with Alzheimer disease to maintain healthy blood pressure, cholesterol, weight, and activity levels as way to protect the brain.
A protein called vascular endothelial growth factor (VEGF), which promotes brain development and blood vessel growth, also may play a role in the protective effects of heart health on the brain. “There has been a lot of work [in humans and animals] suggesting it may be protective,” explained Timothy Hohman, PhD, an assistant professor of neurology at Vanderbilt University, in an interview.
Hohman and his colleagues have examined blood VEGF levels, cognitive performance, and magnetic resonance imaging in 300 older adults with mild cognitive impairment, Alzheimer disease, or normal cognition (Hohman TJ et al. JAMA Neurol. 2015;72[5]:520-529). The study, which is part of the Alzheimer’s Disease Neuroimaging Initiative, found that higher VEGF levels in the cerebrospinal fluid were associated with healthier brain aging. This was particularly true for those who had early biomarkers in the cerebrospinal fluid for tau and β amyloid, key aggregate-prone proteins associated with Alzheimer disease, suggesting that VEGF may help stave off cognitive decline in individuals showing early signs of disease.
Exactly how VEGF protects the brain isn’t clear. But Hohman speculated that vascular tissue around amyloid plaques may deteriorate, starving surrounding neurons of oxygen and causing further tissue death. Having higher levels of VEGF may protect against this cascade of damage by promoting the growth of new blood vessels.
“There may be subsets of individuals who can endure [Alzheimer pathology] because they have some compensatory mechanism that kicks in,” Hohman said.
Exercise is known to boost VEGF, so the findings may offer the extra encouragement patients need to commit to a healthier lifestyle.
“Many people know about lifestyle risk and protective factors as things that reduce the risk of heart attack and dying from a stroke,” Seshadri said. “The fact that we are also showing a protective effect for your brain might be motivational.”
Ancient Defenses
Other defenses may have ancient origins. Some research shows that cognitive resilience may have evolved from mechanisms of innate immunity that have protected the brain against infection and injury for millennia.
For example, a variant of the gene encoding the CD33 receptor, expressed on innate immune cells such as monocytes, has been linked to Alzheimer pathology and cognitive decline in humans. The variation increases the number of CD33 receptors on the surface of monocytes in young and older individuals (Bradshaw EM et al. Nat Neurosci. 2013:16[7]: 848-850). Using positron emission tomography imaging of older adults and autopsy tissue from older adult brains, the researchers showed that people with the variant have less functional immune cells that cannot clear amyloid well. The result is an accumulation of plaques.
Another variant, in the triggering receptor expressed on myeloid cells 1 (TREM1) gene, is linked with reduced expression of these receptors, which normally help amplify inflammatory immune responses (Repogle JM et al. Ann Neurol. 2015;77[3]:469-477). This variant also was associated with more plaques and tangles and a faster rate of cognitive decline. Together, the results suggest variants that suppress the innate immune system accelerate cognitive decline and Alzheimer-related pathology.
Better understanding how the immune system does double duty in the brain is critical to developing treatments that promote neuroprotection and cognitive resilience.
Clinical Potential?
This growing body of biological evidence implicating molecular-cellular factors in brain resilience presents the possibility of developing drugs targeting these factors to mitigate cognitive decline.
“If you are able to show a biological basis, it increases probability that it is causal and that you can intervene and have a positive effect,” Seshadri said. “One of the attractive things about BDNF is that there are drugs, such as certain antidepressants and some experimental drugs, that increase BDNF levels.” However, research already suggests BDNF is not the only biological mechanism mediating the neuroprotective benefits of certain behavioral interventions. What’s more, although higher BDNF levels may allow the brain to compensate for awhile, once the pathology progresses to a certain point, it’s not enough, Seshadri explained. Multiple pathways are likely involved, as are complex genetic and epigenetic interactions.
“We’re in an initial exciting phase,” she said. “We need to understand this pathway better; we need to find additional pathways and understand the gene and environment interactions better.”
Thus far, a home-run clinical therapy that harnesses brain resilience mechanisms has remained elusive. One drug called davunetide, a peptide derived from a neurotrophic factor implicated in neuronal resilience and protection, showed early promise as a brain-boosting agent in preclinical models of neurodegenerative diseases and improved some measures of memory in patients with mild cognitive impairment. However, because a recent larger clinical trial involving patients with progressive supranuclear palsy, a neurodegenerative tauopathy, failed to show any benefit from davunetide, further development and testing of the drug have been shelved (Boxer AL et al. Lancet Neurol. 2014;13:676-685).
Such challenges underscore the need for a more comprehensive understanding of resilience pathways and gene-environment interactions, which likely will be critical to designing future clinical trials of brain resilience boosting factors, Seshadri said. For example, she noted that a clinical trial of exercise to prevent cognitive decline was negative (Sink KM et al. JAMA. 2015;314[8]:781-790). She explained that perhaps only certain subgroups will benefit from particular interventions. Both lifestyle and drug interventions may need to be carefully targeted to subpopulations most likely to benefit.
Large-scale genomic, proteomic, and epigenomic studies have also begun in earnest to help tease out the multitude of factors that contribute to cognitive decline or that protect against decline in the face of pathology, Bennett said. For example, he and his colleagues published new evidence showing that patients with the CD33 risk allele for Alzheimer disease also have higher expression of TREM2, another triggering receptor expressed on myeloid cells that functions to counteract TREM1 (Chan G et al. Nat Neurosci. 2015;18:1556-1558). The finding suggests that TREM1, TREM2, and CD33 pathways may converge to additively suppress the immune response to Alzheimer pathology.
Epigenomic studies in particular might help further elucidate risk factors for cognitive decline. One study found that epigenetic changes are associated with amyloid plaque burden independently of Alzheimer risk genes (Chibnik LB et al. Ann Clin Trans Neurol. 2015;2[6]:636-647).
Although these epigenomic changes have not yet been linked to any particular behavioral intervention, Bennet is optimistic that the epigenome might provide additional insights on how behaviors and life experiences may protect the brain from dementia. “A better understanding of [this] biology will help us provide more targeted interventions that are more likely to be effective and adopted,” Seshadri added.
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