Medscape Medical News ~ June 24, 2013
Bret S. Stetka, MD
Reporting from The American Psychiatric Association's 2013 Annual Meeting
"Do we have any control over our brain health as we age?", Dr. Gary Small asked the crowd, a packed room of psychiatrists attending his “Brain Health and Alzheimer's Prevention ” talk at the 2013 Annual Meeting of the American Psychiatric Association (APA) in San Francisco, California. Nearly everyone raised their hands. “If the answer is yes,” he followed, “then what can we do to forestall the symptoms of Alzheimer's disease (AD)?” For the next hour, conference-goers found out or, perhaps, given their line of work, brushed up.
Dr. Small is Professor of Psychiatry and Director of the UCLA Longevity Center at the Semel Institute for Neuroscience & Human Behavior. As session chair Dr. Brent Forester pointed out in his introduction, Small's list of achievements is humbling: renowned clinician, cutting-edge researcher, author of over 400 scientific publications and 7 popular books, including his latest, The Alzheimer's Prevention Program. His research has contributed to brain imaging methods capable of detecting AD years before symptoms are present; his healthy lifestyle and memory training programs are widely used throughout the United States. In 2002, Scientific American Magazine named Small one of the world's top innovators in science and technology.
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Up went an image of Madame Jeanne Calment, a French supercentenarian who lived to 122 years. "At 94, Calment sold her apartment to a businessman who agreed to pay her rent for the rest of her life. He died 10 years later," said Small to the chuckling crowd. He was introducing the idea that certain lifestyles are associated with both longevity and brain health, a term encompassing our various neurologic faculties like memory, thinking, reasoning, mood, and stress responses. There are certain regions in the world -- so-called "blue zones" -- with abnormally high clusters of centenarians, most notably Sardinia, Italy; Loma Linda, California; and Okinawa, Japan. These regions share a number of characteristics thought to contribute to collective longevity and prolonged brain health on which Small would later expand: Namely, their inhabitants tend to be physically active, socially engaged, and eat a healthy diet high in omega-3 fats, just like the fish-heavy fare most likely enjoyed by Ms. Calment in the south of France.
With such striking epidemiologic examples, numerous lifestyle factors are now being taken seriously by researchers and clinicians as potential avenues for AD prevention, particularly given the current lack of disease-modifying treatments -- in other words, the lack of a cure. Couple these insights with advances in neuroimaging and other biomarker tests that allow for early disease identification, and it appears we have at least some control over our brain health. But is lifestyle modification enough to actually prevent or significantly delay AD? Will adopting healthy habits heed results, or are other factors such as genetic influences standing in the way?
Background and Biomarkers
AD is an epidemic, affecting over 5 million Americans and nearly 40 million people worldwide. AD afflicts 1 in 8 people aged 65 years or older and nearly half of those 85 years and older.  The reason for the staggering prevalence is simply that we're living longer. “The major risk factor for AD is advanced age,” noted Small. According to the Centers for Disease Control and Prevention, life expectancy in 1900 in the United States was around 47 years; in 2013, it's nearly 80 years. [3,4]
"So what is Alzheimer's disease?” asked Small rhetorically, before a brief history lesson. In 1906, German psychiatrist and neuropathologist Alois Alzheimer presented the first case of the condition that would bear his name. His initial patient died 4 years after her symptoms began, and on autopsy her brain contained the waxy protein fragments and twisted fibers now known to be amyloid plaque and tau tangle protein accumulations. Assumed to be a rare form of dementia, it wasn't until decades later that more progress was made. A 1968 paper  by Blessed, Tomlinson, and Roth correlated plaques and tangles with "senility," pathologizing cognitive dysfunction previously thought to be a normal part of aging and igniting AD awareness.
Diagnosing and monitoring AD initially proved tricky. The AD brain exhibits gross atrophy and prominent collections of plaques and tangles. But the "normal" brain can too, in lower concentrations. Plaques and tangles build up gradually as we age. Moreover, until recently, detecting such changes was difficult in living patients. Over the years, numerous potential AD biomarkers have been considered with varying degrees of success. Serum, blood, and cerebrospinal fluid (CSF) assays have proved useful, particularly in research settings, as have genomics, vascular risk factor assessments, and neuroimaging. The American Academy of Neurology now recommends a CT or MRI scan in cases of suspected AD to rule out other causes of impaired cognition such as stroke or tumor, as findings associated with AD such as generalized atrophy can be nonspecific. However, structural imaging [6,7] can contribute to AD identification. The hippocampus undergoes significant atrophy as dementia progresses, and though hippocampal volume reduction cannot confirm AD in an individual, it can distinguish AD in an aggregate patient sample.
Better yet, the application of PET scan technology in AD research has advanced the functional characterization of the AD-afflicted brain. Work by Small, Mosconi, and others [8-10] using PET with a radiolabeled glucose analogue (fluorodeoxyglucose [FDG]-PET) helped correlate specific patterns of glucose metabolism with different causes of dementia. These findings were, in 2004, enough to convince the Centers for Medicare & Medicaid Services that PET was useful in dementia diagnosis, making reimbursement possible. Other radio-tracers have since been developed that allow for the visualization of specific protein targets in the brain, namely Pittsburgh compound B (PiB) and the recently approved florbetapir, which bind to amyloid, and FDDNP, which binds to both amyloid and tau. FDDNP studies have correlated cognitive decline with the degree and location of amyloid and tau accumulation; amyloid preferentially accumulates in the lateral temporal region with tau more prominent in the medial temporal lobes.
Combining diagnostic markers may prove the most useful approach to AD diagnosis. A 2013 study  by Prestia and colleagues assessed for hippocampal atrophy, decreased CSF amyloid, and decreased brain glucose metabolism in 73 patients with mild cognitive impairment. Among those with no positive biomarkers, just 4% went on to develop AD; in patients positive for all 3, 100% ultimately progressed to AD. Still, while AD biomarker profiles are increasingly common in academic and research settings, the limited efficacy of current therapies has largely kept them from the clinic. At the moment, a more accurate AD diagnosis provides limited benefits to the patient.
"People come in wanting these fancy scans, and we can do that," noted Small. "But the question is: 'How is this going to change the course of treatment?' We need to find biomarkers that predict treatment responses, but we're not quite there yet."
Adding to the improved understanding of AD are genetic advances. Early genetic studies looked at families with autosomal dominant inheritance patterns, namely involving presenilin and APP gene mutations that result in early-onset disease. Though these patients represent less than 1% of those who develop AD, those with a family history of AD can be tested for the mutations and receive genetic counseling. The ongoing Dominantly Inherited Alzheimer Network is a multicenter, international initiative studying families with a rare genetic variant causing early-onset AD. The hope is to uncover insights into what causes AD and how the disease develops preclinically.
The APOE e4 risk gene is far more common, present in over 1 in 5 people, and typically results in late-onset AD. But, as Small pointed out, it is "neither necessary nor sufficient to get the disease." A study out of Washington University  found that people with APOE e4 were not demented and had less amyloid in their brain if they had a history of exercise. "So genetics is not the whole story," Small commented.
Genome-wide association studies have helped identify a number of other genes associated with late-onset AD, including BIN1, CLU, PICALM, and CR1. Also among them is TREM2; the mutation is uncommon but, when present, triples AD risk. Of note, the TREM2 protein is expressed on the surface of microglia, supporting a growing school of thought that AD pathogenesis involves inflammatory hyperactivity. As Small pointed out, many of the behaviors associated with AD prevention -- exercise, diet, healthy sleep habits -- are actually anti-inflammatory strategies. Inflammation is a normal physiologic process that helps repair and protect us from harmful stimuli such as trauma or infection. But with aging, our inflammatory systems become overly active, representing a potential pathophysiologic target in treating cognitive decline.
Small then presented data  his group had gleaned by combining genetic and imaging tests, again speaking to the value of combining diagnostic markers. FDG-PET scans found that in older people with APOE e4, glucose metabolism in some brain regions may be reduced by nearly 20%. Another functional MRI study found that the brains of those with this genetic risk for AD actually work harder on memory tests to complete the same task. 
What Interventions Work?
"The goal is to protect the healthy brain rather than repair a damaged brain," Small continued, moving on to prevention and treatment strategies, "and to develop disease-modifying drugs," noting that, unfortunately, currently available medications are primarily symptomatic. Still, drugs like donepezil, memantine, and rivastigmine do benefit patients and can slow clinical progression. "If you take patients off of the drug too early they will get worse faster," said Small. Medications that clear amyloid from the brain are thought to be a potential disease-modifying approach, one that has received a great deal of research attention. However, this work has yet to pan out. Studies are also underway looking at various other preventive strategies in AD, including anti-tau and anti-inflammatory treatments, cholesterol-lowering drugs, and an insulin nasal spray, developed as a result of the association between diabetes and AD.
Anti-inflammatory therapies may hold particular promise in slowing AD progression. A study by Small and colleagues from 2008  found that anti-inflammatory treatment increases cognition and brain function in normal aging; however, at the moment he doesn't recommend anti-inflammatories for brain health given the limited data and side effects.
The MacArthur Studies of Successful Aging  suggests that genetics may account for only a third of AD risk, with the rest dependent on nongenetic factors, suggesting a major role for lifestyle modification in preventing AD. Small spent the remainder of his talk reviewing the lifestyle factors thought to influence brain health and aging: (1) physical conditioning; (2) mental stimulation; (3) stress management; and (4) nutrition.
Of all lifestyle approaches that might contribute to AD prevention, the strongest evidence exists for exercise. Active animals have larger hippocampi, while older people who walk regularly -- even as little as 15 minutes a day -- have a lower risk for AD. People who routinely exercise exhibit better cognitive abilities and actually have larger brains. Regular exercise also results in lower PiB and FDDNP binding in the brain, reduced CSF tau, and increased CSF amyloid, all markers of decreased AD risk. 
Read, write, and do a crossword: Mentally stimulating activities and certain brain-training programs are in the long term associated with lower brain amyloid levels and a decreased risk for AD, as are graduating from college or engaging in life-long learning. [18,19] However as Small pointed out, data such as these are caveated by the chicken or egg conundrum: "Are people with good brain genes more often going onto college, or is it the mental enrichment that [is effective]?" wondered Small. "I think it's probably a combination."
Many worry that our increasing reliance on technology hinders our mental stimulation -- that digital dependence will in fact hasten neurologic deterioration. Small cited a recent cover story in the Atlantic, "Is Google Making Us Stoopid [sic]." His group at UCLA set to find out. Their study, "Your Brain On Google,"  looked at brain activity in Internet-naive research volunteers, people who had literally never used the Internet. "They were hard to find, and I quickly learned that I could not recruit them online," joked Small.
Using functional MRI, his research team compared brain activity in the internet-naive with Internet-experienced controls when each was asked to search online vs reading information from a book. The Internet-naive subjects had minimal activity in expected brain regions when reading a book and similar brain activity when searching online for the first time. When the Internet-savvy people searched online, there was a 2-fold increase in activity throughout the brain compared with interpreting a book and compared with the Internet-naive volunteers. And after just a week of searching online, the Internet-naive subjects demonstrated significant increases in brain activity in areas responsible for working memory and decision-making, likely due to the decision-making and engagement required to navigate the Internet. At least in this case, engaging with technology actually increased mental stimulation. However, like many tasks, once one gets more proficient at searching online, activity decreases as the brain becomes more efficient at the activity.
Small and colleagues use a number of mental stimulation and compensatory techniques at UCLA's Longevity Center. Their memory fitness programs and brain boot camps can be licensed out for use and show significant effects on memory and brain efficiency. A simpler approach recommended by Small is called "Look, Snap, Connect," which encourages patients to take "mental snapshots" and create meaningful associations. Among his series of examples was an attorney named Sue Bangal -- "She has bangs and could 'sue' me." It might sound silly, but it works. He then flashed 8 words and asked the audience to create a visual story in their head to help remember them: beach, professor, horse, teddy bear, cigar, nun, palm tree, and pasta.
Eat Right and Relax
Stress is a known contributor to cognitive impairment and decline. Animal work by Sapolsky and others  has linked stress states with memory impairment and decreased brain size; specifically, glucocorticoids released during stress appear to impair neuronal plasticity and lead to dendritic atrophy, particularly in the hippocampus. A 2012 study in rats  found that stress hormones impair prefrontal cortical functioning, affecting mental flexibility and attention.
Human studies show that chronic stress leads to an increased risk for dementia,  AD,  and depression.  In another APA 2013 session -- incidentally chaired by Dr. Small -- Helen Lavretsky, MD, also of UCLA's Semel Institute, presented data  showing that in addition to just inducing relaxation, meditation affects biomarkers of inflammation and telomerase activity. Small recommends managing stress with psychotherapy and personalized relaxation approaches.
Weight management and nutrition also play major roles in brain health. Several studies support an association between being overweight and increased dementia risk, including a recent twin study  controlled for sex, education, diabetes, hypertension, stroke, and heart disease. Concurrent work found that cognitive function improved significantly in obese patients who underwent bariatric surgery. 
Mediterranean diets high in omega-3 fatty acids improve working memory  and reduce risk for mild cognitive impairment  -- per DSM-5, minor neurocognitive disorder -- and AD.  Antioxidant-rich fruits and vegetables improve cognition while refined sugars and trans-fats impair it.  Moderate alcohol -- defined in many studies as up to 1 drink per day for women and up to 2 drinks per day for men -- is also associated with better brain health, possibly due to both relaxation effects and, in the case of red wine, high levels of the antiaging compound resveratrol. Resveratrol supplements are now available; however, it is uncertain whether the compound delivered in this way actually crosses the blood-brain barrier: "So if you are taking resveratrol capsules, make sure you wash them down with a nice Bordeaux," joked Small.
Other Approaches and Conclusions
Small's group is running a trial looking at whether curcumin, an anti-inflammatory compound found in turmeric, slows amyloid and tau build-up in the brain. Areas with turmeric and curry-heavy diets such as India have a lower rate of AD. Another study at UCLA is looking at pomegranate extract, as daily consumption is associated with improved verbal memory.
Other lifestyle approaches that may benefit cognition include avoiding activities potentially traumatic to the head, avoiding smoking, having a positive outlook, and appropriate treatment of age-related illnesses like hypertension and hypercholesterolemia. Head trauma in particular is a major focus of study as progressive cognitive and psychiatric dysfunction among athletes due to chronic traumatic encephalopathy (CTE) has become increasingly evident. In a study published this year,  Small's group looked at FDDNP binding patterns in the brains of retired NFL players. Tau accumulations were found in a pattern similar to that seen in CTE on autopsy, suggesting a potential screen for the condition.
In closing, Small returned to the question, "So can we control our brain health and prevent Alzheimer's disease? If you think of the term 'prevention' as meaning 'cure,' the answer is no. But if we set a more modest goal of forestalling symptoms, I think the evidence suggests that we can," Small concluded, citing the various healthy lifestyle and compensatory strategies he'd spent the last hour reviewing.
He then asked the audience if they could remember the 8 words he'd presented earlier based on their story. One brave psychiatrist approached the microphone: "I was at the beach last week in La Jolla when a UCLA Alzheimer's disease professor appeared riding a horse and holding his teddy bear transitional object. He revealed that there was one additional finding to the nun study, which included the fact that if people hang from palm trees while smoking a cigar wrapped with spaghetti, they have an excellent chance of surviving from Alzheimer's."
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