By Franklin Faust and Genevieve Wanucha
The Adult Changes in Thought study’s longstanding commitment to epidemiological research, and collaborations with the ADRC, have helped to build a large body of work on brain health, aging, and disease that is relevant to public health policy. The fruits of that labor are now on the record in the Lancet Commission 2020 Report on Dementia Prevention, Intervention, and Care. Created by an international team of researchers, including UW’s Eric Larson and former ADRC leader Linda Teri, PhD, the report is a comprehensive synthesis of the current science of preventing dementia. It provides policy makers, doctors, researchers, and the general public with evidence-based strategies for reducing dementia risk, and the authors recognize the barriers that many people face in accessing the vital components that support brain health at every age.
The report suggests that 40% of all dementia cases worldwide may be prevented by addressing a group of risk factors: high blood pressure, obesity, hearing loss, late-life depression, diabetes, physical inactivity, smoking, social isolation, lower levels of education, alcohol consumption over 14 drinks a week, traumatic brain injury, and air pollution. “It's not a single thing that's going to lead to late-life dementia,” says Eric Larson. “In the report, we emphasized this idea of the life course, with elements ranging from early life to late life that influence risk.” Fortunately, existing public health interventions and personal lifestyle changes can directly address these risks. Some help preserve the mind by reducing damage to brain cells from pathology or inflammation; some help by constructing a cognitive “buffer” that keeps the mind functional in spite of the presence of disease in the brain; or, a combination of both fortuitous pathways. Behind the list of preventable risk factors in the 2020 Lancet Report is a history of ACT contributions to our modern understanding of aging and brain health. Highlighted below are some of the most significant findings about what’s helpful and what’s not.
- Receiving coverage in the Washington Post in 1989, one of Larson’s first major studies of the local community population investigated the effect of hearing loss on brain health. Larson worked with UW School of Medicine’s Richard F. Uhlmann MD, MPH on a study that found that a hearing loss of at least 30dB, equivalent to the volume of a whisper, was twice as common in people with dementia symptoms, and that the greater the hearing loss, the higher the odds of having dementia. This finding has stood the test of time, foreshadowing current evidence of a strong link between hearing loss and odds of dementia. The team speculated, as do modern-day researchers, that hearing loss could lead to disorientation, especially in socially isolated individuals, and it may predispose a person to loneliness and depression, which in turn can impair cognition, including perception, memory and judgment. Uhlmann RF et al. Relationship of Hearing Impairment to Dementia and Cognitive Dysfunction in Older Adults.
- Larson worked with a team led by UW Otolaryngology’s George Gates, MD for many years on hearing loss research. In 2011, they discovered that hearing loss caused by dysfunction of the auditory processing centers in the brain is a precursor to Alzheimer’s disease-type dementia. They recommended that doctors consider referring older patients with hearing loss for neurological evaluation. Gates GA et al. Central auditory dysfunction as a harbinger of Alzheimer dementia
Exercise & Fitness
- People who get their heart rate up, or strengthen or stretch their muscles, for at least 15 minutes 3 times per week may be about 40% less likely to develop dementia than those who move their body less frequently, suggests a 2006 study led by Larson. “ACT was the first study to show the benefits of habitual exercise,” says Larson. “And it didn't take much exercise to see the reduction in risk. It’s really just about avoiding no exercise. This finding has held up over time.” Larson EB et al. Exercise is associated with reduced risk for incident dementia among persons 65 years of age and older
- When a VA Puget Sound team scored the physical performance of the study’s participants–based on fitness in walking, standing up, balancing, and grip strength–they found that those with low scores were roughly 3 times more likely to develop dementia and Alzheimer’s disease during a 6-year follow up period than those who were more physically fit. The 2006 study suggests that the first signs of dementia in older people may be changes in physical function, which often appear before noticeable mental decline. Wang L et al. Performance-based physical function and future dementia in older people
- More exercise and activity research is on the horizon. Modern activity monitor technology now allows researchers to gather accurate data on sedentary activity, light exercise, and even circadian rhythms and sleep time from participants in the ACT Activity Monitor (ACT-AM) Study. A new goal of ACT-AM: search the “24-hour cycles” of participants for elements of daily activity tied to risk or resilience to dementia. Amidst the SARS-COV2 pandemic, Dori Rosenberg, PhD, MPH, leader of ACT-AM, is considering the investigation of how trends of isolation have affected the 24-hour activities of seniors. “With these new measurements, I think the ACT study is well positioned to help identify the key features of exercise that are beneficial to cognitive health,” said Marilyn Albert, PhD of John’s Hopkins University in her keynote at the 2020 ACT Symposium. “Is the benefit just from aerobic activity? How much activity makes a difference, and at what age? I think ACT can help us communicate to the public about the factors critically important to brain health.”
Vitamin Supplements & Nutrition
- The ACT study has repeatedly refuted connections between antioxidant supplements and brain health benefits. In 2008, a team led by UW School of Pharmacy’s Shelly Gray, PharmD, MS looked into the use of vitamins E and C, which were thought to be neuroprotective thanks to their antioxidant effects. They found no link to suggest that supplementation of E and C, whether taken alone or together, reduced the risk of dementia. Gray S et al. Antioxidant Vitamin Supplement Use and Risk of Dementia or Alzheimer's Disease in Older Adults
- Findings from the Kame Project, an ACT-associated effort that followed the brain health of Japanese Americans in King County, showed that those who drank fruit or vegetable juices at least three times a week might be less likely to develop Alzheimer’s disease than those who drank such juices less often. However, these brain benefits were not observed in those who only took antioxidant-rich vitamin supplements (vitamins E, C, and beta-carotene). The study suggested that supplements may lack some neuroprotective chemical present in the juice, suggesting that supplements don’t necessarily capture all of the benefits one can gain from including common, healthy foods in their diet. Dai Q et al. Fruit and vegetable juices and Alzheimer's disease: the Kame Project
- Researchers in the new EyeACT project think of the eyes as an “under explored window to the brain.” ACT’s unique access to participants’ ophthalmology records allows researchers to examine the link between eye disorders, corrective surgeries, and dementia risk. The team recently found that individuals with diabetic retinopathy, a deterioration of eyesight caused by diabetes, have an increased risk of microscopic strokes in the brain. Lee CS et al. Ophthalmology-Based Neuropathology Risk Factors: Diabetic Retinopathy is Associated with Deep Microinfarcts in a Community-Based Autopsy Study
- Cataract surgery, a quick outpatient procedure, prevents blindness, and it may also benefit the brain. At the 2020 Alzheimer’s Association International Conference, UW Medicine’s Cecilia S. Lee, MS, MD reported emerging findings that cataract surgery is associated with decreased risk of dementia, suggesting a benefit to addressing cataracts as early as possible. Lee CS et al. Cataract surgery is associated with reduced risk for Alzheimer’s disease. AAIC 2020 presentation.
- When a 2007 study showed that the use of non-steroidal anti-inflammatory drugs (NSAIDs), such as aspirin, could help prevent dementia, NSAIDs and dementia became a hot research topic with over thirty observational studies coming out in the following years. Most of these studies confirmed that NSAIDs seemed to lower dementia risk, but a handful of studies raised questions. The VA Geriatric Research Education and Clinical Center’s John C. S. Breitner, MD sought to clear up the confusion with one of the best resources available—a wealth of ACT study medication data that can often be traced back 10 to 15 years for each participant. He and his colleagues found that a history of sustained NSAID usage was associated with an increased risk of dementia and Alzheimer’s disease in elderly individuals, calling the drug’s status as a common preventative treatment into question. Breitner JC et al. Risk of dementia and AD with prior exposure to NSAIDs in an elderly community-based cohort
- To Larson, ACT’s most important finding concerning medication use emerged from a large study led by Gray in 2015. The study found a link between a significantly increased risk for developing dementia, including Alzheimer’s, and taking commonly used medications with anticholinergic effects at higher doses or for a longer period of time. Many older people take such medications—nonprescription diphenhydramine (Benadryl), for instance. Gray’s team backed up a similar finding of a French team with evidence from ACT’s gold standard drug-use dataset. “It's now widely recognized that anticholinergics are a risk factor for late-life dementia,” says Larson. Gray SL et al. Cumulative Use of Strong Anticholinergics and Incident Dementia: A Prospective Cohort Study
- Examination of brains from research participants led to the first finding of a link between heavy cigarette smoking and reduced Lewy Body related neuropathology, supporting previous observational studies that showed a link between cigarette smoking and a reduced risk of Parkinson’s disease. The study found no relationship between smoking and Alzheimer’s pathology in postmortem brain tissue. Still, the Lancet Commission Report lists stopping smoking cigarettes as one of the most significant ways to help prevent the clinical syndrome of dementia, as well as cardiovascular disease. Tsuang D et al. Association between lifetime cigarette smoking and lewy body accumulation
- A 2010 ADRC study of the ACT population became the first to show a link between smoking and oxidative damage to the brain, a type of cellular damage caused by reactive oxygen sources that is linked to Alzheimer’s disease and vascular brain injury. The use of antioxidant supplements does not seem to change oxidative brain damage caused by smoking, vascular injury, or Alzheimer’s disease, suggesting that such supplements do not compensate for the risks that smoking poses to the brain. Sonnen JA et al. Free radical damage to cerebral cortex in Alzheimer's disease, microvascular brain injury, and smoking
Traumatic Head Injury
- Using self-reported data from ACT participants, Kristen Dams-O’Connor, PhD, Director of the Brain Injury Research Center of Mount Sinai, and ADRC collaborators were the first to show that traumatic brain injury (TBI) with a loss of consciousness increases the chance of another TBI later in life. This study’s discovery of the risk of repeated injury supported the need to monitor older adults who sustain head trauma. Today, we know that preventing blows to the head is important, as repetition of injury seems to compound the risk of dementia. Much of our knowledge in this area comes from non-ACT work led by ADRC member Elaine Peskind, MD who uses cerebrospinal fluid and brain imaging to study the link between repeated mild TBI, neurodegeneration, and dementia in American veterans. Dams-O'Connor K et al. Risk for late-life re-injury, dementia and death among individuals with traumatic brain injury: a population-based study
- A 2016 study led by ACT co-PI Paul Crane examined the relationship between TBI with a loss of consciousness and neuropathology in ACT and other longitudinal cohort studies of aging. The team found that this severity of TBI is linked to greater risk for Lewy body accumulation, as well as the progression of Parkinson’s disease and associated movement abnormalities, but they were surprised to find that the TBI link did not extend to Alzheimer’s disease. “These conditions are very common by the end of life, so we had enough power with our large population to find an Alzheimer’s story and we didn’t,” says Crane. “We found no association at all between head injury during life and Alzheimer-type dementia or the plaques and tangles of Alzheimer disease in the brain. It is a pretty strong negative study and contrary to what the field has found.” Crane PK et al. Association of Traumatic Brain Injury With Late-Life Neurodegenerative Conditions and Neuropathologic Findings
- The science of TBI and dementia is complicated. To learn more, the ACT study collaborates with the Allen Brain Atlas’ Aging, Dementia, and TBI Project to better understand the long-term implications of traumatic brain injury. “So far, we haven’t found any signal of a significant link between one TBI with loss of consciousness and Alzheimer's disease,” says C. Dirk Keene, MD, PhD, Lead of the ADRC Precision Neuropathology Core. “It's important to keep in mind that the ACT study enrolls people who make it to the age of 65 without developing dementia. The bottom line is that people who reach 65, and who have had a serious whack to the head earlier in life, have the same risk of Alzheimer's disease as someone without a TBI. I think that’s good news. However, we could be missing something in all that data, and we are still working on analyzing other measures.” Edlow BL et al. Multimodal Characterization of the Late Effects of Traumatic Brain Injury: A Methodological Overview of the Late Effects of Traumatic Brain Injury Project
- Slipping and falling at home might lead to hitting the head. In 2004, the ACT Study looked at shoe surfaces and falls among elderly people and showed that falls are more likely in those who wear stocking feet or slippers around their house. Opting for a pair of hard-sole shoes while getting around at home seems to be a simple way to lower one’s risk for falls. Koepsell TD. Footwear style and risk of falls in older adults
- High blood pressure can put strain on the heart, and it seems that it may put a strain on the brain as well. A 2007 finding showed that high systolic blood pressure—the first and larger number you’re shown when your blood pressure is taken—was associated with a greater risk of dementia in people aged 65 to 74. Li G et al. Age‐Varying Association Between Blood Pressure and Risk of Dementia in Those Aged 65 and Older: A Community‐Based Prospective Cohort Study
- Two years later, a new association between high systolic blood pressure and cerebrovascular damage in untreated older adults aged 65 to 80 suggested that controlling high blood pressure with antihypertensives may reduce dementia risk by minimizing microvascular injury to the brain. “ACT is one of the first studies to demonstrate the association of vascular pathology to dementia risk, including Alzheimer's disease,” says Larson. “Over the years, that information has encouraged people to control their blood pressure, avoid smoking, increase exercise, and do other things that reduce vascular risk that have also turned out to be valuable for brain health.” Wang LY et al. Blood pressure and brain injury in older adults: findings from a community-based autopsy study.
Cholesterol comes in two varieties: “good” and “bad”. Specifically, “good” HDL cholesterol can lower your risk for heart disease and stroke, while “bad” non-HDL cholesterol raises these risks. In 2017, ACT researchers took advantage of the consistently collected cholesterol data obtained from patient visits to investigate how “good” and “bad” cholesterol might impact the brain. The study was the first to look at differences in neuropathological outcomes based on a snapshot of cholesterol levels at age 70. This led to the finding that higher levels of non-HDL cholesterol at this age were associated with Lewy Body pathology in the brain at autopsy. However, they found no association between HDL or non-HDL cholesterol and Alzheimer’s disease pathology. Bettcher B et al. Association between Cholesterol Exposure and Neuropathological Findings: The ACT Study
- In 2018, a team led by UW School of Pharmacy’s Zachary Marcum, PhD found that levels of “bad”, non-HDL cholesterol produced a “U-shaped” Alzheimer’s risk relationship in patients aged 60 to 79, where both higher and lower levels of non-HDL cholesterol led to heightened risk. The study found no association between “good” HDL cholesterol and Alzheimer’s-type dementia. Marcum Z. et al. Serum Cholesterol and Incident Alzheimer's Disease: Findings from the Adult Changes in Thought Study
- ACT’s frequent linking of heart health to brain health hints at a potentially powerful route to preventing dementia. Current epidemiological studies show that the ages of onset for Alzheimer’s disease have pushed out about five years later than the generation 30 years ago experienced, and UW Biostatistics’ Ellen Wijsman, PhD, Lead of the ADRC Data Management and Statistics Core, thinks that gains to public heart health over that time might be pushing that trend. “The difference in the cardiovascular risk prevention profiles of those generations has made huge changes in overall health and has extended life expectancy,” says Wijsman. “It’s possible that the delayed onset of Alzheimer’s that we’re seeing is coming from the benefits of cardiovascular risk prevention.”
- Diabetes is a known risk factor for Alzheimer’s disease that jeopardizes the ability of the body to maintain safe, stable levels of blood sugar. In 2013, Crane led a study published in the New England Journal of Medicine that looked at blood sugar levels and dementia risk among ACT participants that found an association between higher blood sugar levels and Alzheimer’s disease in people with and without diabetes, suggesting that lowering blood sugar to safe levels through diet, exercise, or medical treatment, might lower the risk of Alzheimer’s disease. Crane PK et al. Glucose levels and risk of dementia
- Crane has just recently expanded off of this 2013 study with new, not yet published, research presented at the 2020 ACT Symposium that further solidifies his previous findings. His team has verified that the link between high blood sugar and dementia is consistent among people with differences in blood pressure and antihypertensive drug usage. Next up, Crane and other ACT researchers aim to see if the link between heightened blood sugar and dementia is consistent among people with different levels of cholesterol and classes of cholesterol medications.
Early Life Factors & Socioeconomic Health
- ACT research conducted in the early 2000’s pointed to early-life experiences having old-age consequences for the risk of dementia. Researchers hunted down birth records, census records, and other public records of their participants to find early-life data. When the data was compared to the rates of dementia in those participants later on, the researchers found that having more siblings, growing up in a non-suburban neighborhood, living in a household size of seven or more, and having a father employed in manual labor were all linked to the development of Alzheimer’s disease later in life. This early research raised awareness about the connections between socioeconomic status and the risk of developing Alzheimer’s disease. “Early life socioeconomic wellbeing probably lays down brain reserve,” says Larson, “so that when you get into the late part of life, you have more reserve to draw on before you develop cognitive decline that impairs function.” Moceri VM. Early-life Risk Factors and the Development of Alzheimer's Disease
- Socioeconomic deprivation and racial discrimination lead to worse outcomes in physical and mental health. Over the past 34 years, King County’s socioeconomic and racial diversity has grown, and the ACT study is taking action to achieve a pool of participants that better represents our local population. This year, the study aims to increase its active cohort from 2,000 to 3,000 people, add 2 clinics serving socioeconomically diverse areas, and adopt a recruitment outreach plan that emphasizes racial diversity. With a more representative population, ACT discoveries of risk, resilience, and precision medicine will better serve and include all of Seattle’s vibrant communities.
- Larson and UCSF Memory and Aging Center’s Kristine Yaffe, MD are spearheading the new Systematic Multi-Domain Alzheimer’s Risk Reduction Trial (SMARRT) as another key part of ACT’s efforts to make this needed change. SMARRT directly oversamples from the racial and ethnic communities that are underrepresented in the ACT study of today. The goal is to see how lifestyle changes might be implemented to address the dementia risk factors that ACT has helped illuminate. SMARRT will test the effect of coaching interventions in preventing cognitive decline in a group of 200 older individuals. The personalized coaching will be focused on tackling the specific dementia risk factors present for each participant. Backed by decades of ACT contributions, SMARRT’s prescription for dementia prevention is on track to bring brain-healthy changes into all King County neighborhoods.
- In 1991, ACT research found that more years of education predicted a higher score on the Mini Mental State Examination, a common test used to screen Alzheimer’s dementia. Later in 2002, UW School of Public Health’s Walter Kukull, PhD led a team that found that attaining a higher level of education was linked to a lower risk of dementia. Subjects who had more than 15 years of education were at nearly half the risk of subjects with less than 12 years of education. These studies brought to light a difficulty in interpreting results about education and dementia risk. Cognitive screening tests are likely to have a favorable bias towards highly educated people. Education might support the health of neural connections that ultimately preserve a person’s test-taking ability, or it might engender cognitive flexibility or strategies that help them to perform well on tests despite the development of thinking and memory impairments in daily life. These studies remind researchers to consider that observed positive effects of education might reflect a failure of cognitive tests to detect early signs of dementia in highly educated participants. Kukull WA et al. Dementia and Alzheimer Disease Incidence: A Prospective Cohort Study
- After following 2,168 non-demented elderly participants for six years, a 2005 study found that lower level of education was associated with a rapid pattern of cognitive decline in individuals with two copies of the APOE4 allele, a genetic variant that increases Alzheimer’s risk. The researchers did not discover such a connection in people with only one copy of the risky genetic variant. The study, published in 2005, showed that lower levels of education could be particularly risky in people already genetically at-risk for Alzheimer’s disease. Shadlen M et al. Education modifies the effect of apolipoprotein epsilon 4 on cognitive decline •
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