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  1. Email Facebook Twitter Pinterest Pocket Reddit Print By Cassandra Willyard 11 hours ago The internet is rife with advice for keeping the brain sharp as we age, and much of it is focused on the foods we eat. Headlines promise that oatmeal will fight off dementia. Blueberries improve memory. Coffee can slash your risk of Alzheimer’s disease. Take fish oil. Eat more fiber. Drink red wine. Forgo alcohol. Snack on nuts. Don’t skip breakfast. But definitely don’t eat bacon. One recent diet study got media attention, with one headline claiming, “Many people may be eating their way to dementia.” The study, published last December in Neurology, found that people who ate a diet rich in anti-inflammatory foods like fruits, vegetables, beans and tea or coffee had a lower risk of dementia than those who ate foods that boost inflammation, such as sugar, processed foods, unhealthy fats and red meat. Sign Up For the Latest from Science News Headlines and summaries of the latest Science News articles, delivered to your inbox E-mail Address* But the study, like most research on diet and dementia, couldn’t prove a causal link. And that’s not good enough to make recommendations that people should follow. Why has it proved such a challenge to pin down whether the foods we eat can help stave off dementia? First, dementia, like most chronic diseases, is the result of a complex interplay of genes, lifestyle and environment that researchers don’t fully understand. Diet is just one factor. Second, nutrition research is messy. People struggle to recall the foods they’ve eaten, their diets change over time, and modifying what people eat — even as part of a research study — is exceptionally difficult. For decades, researchers devoted little effort to trying to prevent or delay Alzheimer’s disease and other types of dementia because they thought there was no way to change the trajectory of these diseases. Dementia seemed to be the result of aging and an unlucky roll of the genetic dice. While scientists have identified genetic variants that boost risk for dementia, researchers now know that people can cut their risk by adopting a healthier lifestyle: avoiding smoking, keeping weight and blood sugar in check, exercising, managing blood pressure and avoiding too much alcohol — the same healthy behaviors that lower the risk of many chronic diseases. Diet is wrapped up in several of those healthy behaviors, and many studies suggest that diet may also directly play a role. But what makes for a brain-healthy diet? That’s where the research gets muddled. Despite loads of studies aimed at dissecting the influence of nutrition on dementia, researchers can’t say much with certainty. “I don’t think there’s any question that diet influences dementia risk or a variety of other age-related diseases,” says Matt Kaeberlein, who studies aging at the University of Washington in Seattle. But “are there specific components of diet or specific nutritional strategies that are causal in that connection?” He doubts it will be that simple. Worth trying In the United States, an estimated 6.5 million people, the vast majority of whom are over age 65, are living with Alzheimer’s disease and related dementias. Experts expect that by 2060, as the senior population grows, nearly 14 million residents over age 65 will have Alzheimer’s disease. Despite decades of research and more than 100 drug trials, scientists have yet to find a treatment for dementia that does more than curb symptoms temporarily (SN: 7/3/21 & 7/17/21, p. 8). “Really what we need to do is try and prevent it,” says Maria Fiatarone Singh, a geriatrician at the University of Sydney. Forty percent of dementia cases could be prevented or delayed by modifying a dozen risk factors, according to a 2020 report commissioned by the Lancet. The report doesn’t explicitly call out diet, but some researchers think it plays an important role. After years of fixating on specific foods and dietary components — things like fish oil and vitamin E supplements — many researchers in the field have started looking at dietary patterns. That shift makes sense. “We do not have vitamin E for breakfast, vitamin C for lunch. We eat foods in combination,” says Nikolaos Scarmeas, a neurologist at National and Kapodistrian University of Athens and Columbia University. He led the study on dementia and anti-inflammatory diets published in Neurology. But a shift from supplements to a whole diet of myriad foods complicates the research. A once-daily pill is easier to swallow than a new, healthier way of eating. Where diet fits Up to 40 percent of dementia cases could be prevented or delayed by modifying 12 risk factors. Targeting some of these risks reduces nerve cell loss in the brain; other interventions protect the brain’s ability to function and adapt even if some nerve loss has occurred, a concept called cognitive reserve. Diet plays a role in at least four of these risk factors. Twelve modifiable risk factors for dementia Reduce nerve cell damage Minimize diabetes Treat hypertension Prevent head injury Stop smoking Reduce air pollution Reduce midlife obesity Increase or maintain cognitive reserve Maintain frequent exercise Reduce depression Avoid excessive alcohol Treat hearing impairment Maintain frequent social contact Attain high level of education Source: G. Livingston et al/Lancet 2020 Earning points Suspecting that inflammation plays a role in dementia, many researchers posit that an anti-inflammatory diet might benefit the brain. In Scarmeas’ study, more than 1,000 older adults in Greece completed a food frequency questionnaire and earned a score based on how “inflammatory” their diet was. The lower the score, the better. For example, fatty fish, which is rich in omega-3 fatty acids, was considered an anti-inflammatory food and earned negative points. Cheese and many other dairy products, high in saturated fat, earned positive points. During the next three years, 62 people, or 6 percent of the study participants, developed dementia. People with the highest dietary inflammation scores were three times as likely to develop dementia as those with the lowest. Scores ranged from –5.83 to 6.01. Each point increase was linked to a 21 percent rise in dementia risk. Such epidemiological studies make connections, but they can’t prove cause and effect. Perhaps people who eat the most anti-inflammatory diets also are those least likely to develop dementia for some other reason. Maybe they have more social interactions. Or it could be, Scarmeas says, that people who eat more inflammatory diets do so because they’re already experiencing changes in their brain that lead them to consume these foods and “what we really see is the reverse causality.” To sort all this out, researchers rely on randomized controlled trials, the gold standard for providing proof of a causal effect. But in the arena of diet and dementia, these studies have challenges. Dementia is a disease of aging that takes decades to play out, Kaeberlein says. To show that a particular diet could reduce the risk of dementia, “it would take two-, three-, four-decade studies, which just aren’t feasible.” Many clinical trials last less than two years. As a work-around, researchers often rely on some intermediate outcome, like changes in cognition. But even that can be hard to observe. “If you’re already relatively healthy and don’t have many risks, you might not show much difference, especially if the duration of the study is relatively short,” says Sue Radd-Vagenas, a nutrition scientist at the University of Sydney. “The thinking is if you’re older and you have more risk factors, it’s more likely we might see something in a short period of time.” Yet older adults might already have some cognitive decline, so it might be more difficult to see an effect. Many researchers now suspect that intervening earlier will have a bigger impact. “We now know that the brain is stressed from midlife and there’s a tipping point at 65 when things go sour,” says Hussein Yassine, an Alzheimer’s researcher at the Keck School of Medicine of the University of Southern California in Los Angeles. But intervene too early, and a trial might not show any effect. Offering a healthier diet to a 50- or 60-year-old might pay off in the long run but fail to make a difference in cognition that can be measured during the relatively short length of a study. And it’s not only the timing of the intervention that matters, but also the duration. Do you have to eat a particular diet for two decades for it to have an impact? “We’ve got a problem of timescale,” says Kaarin Anstey, a dementia researcher at the University of New South Wales in Sydney. And then there are all the complexities that come with studying diet. “You can’t isolate it in the way you can isolate some of the other factors,” Anstey says. “It’s something that you’re exposed to all the time and over decades.” Food as medicine? In a clinical trial, researchers often test the effectiveness of a drug by offering half the study participants the medication and half a placebo pill. But when the treatment being tested is food, studies become much more difficult to control. First, food doesn’t come in a pill, so it’s tricky to hide whether participants are in the intervention group or the control group. Imagine a trial designed to test whether the Mediterranean diet can help slow cognitive decline. The participants aren’t told which group they’re in, but the control group sees that they aren’t getting nuts or fish or olive oil. “What ends up happening is a lot of participants will start actively increasing the consumption of the Mediterranean diet despite being on the control arm, because that’s why they signed up,” Yassine says. “So at the end of the trial, the two groups are not very dissimilar.” Second, we all need food to live, so a true placebo is out of the question. But what diet should the control group consume? Do you compare the diet intervention to people’s typical diets (which may differ from person to person and country to country)? Do you ask the comparison group to eat a healthy diet but avoid the food expected to provide brain benefits? (Offering them an unhealthy diet would be unethical.) And tracking what people eat during a clinical trial can be a challenge. Many of these studies rely on food frequency questionnaires to tally up all the foods in an individual’s diet. An ongoing study is assessing the impact of the MIND diet (which combines part of the Mediterranean diet with elements of the low-salt DASH diet) on cognitive decline. Researchers track adherence to the diet by asking participants to fill out a food frequency questionnaire every six to 12 months. But many of us struggle to remember what we ate a day or two ago. So some researchers also rely on more objective measures to assess compliance. For the MIND diet assessment, researchers are also tracking biomarkers in the blood and urine — vitamins such as folate, B12 and vitamin E, plus levels of certain antioxidants. Weighty survey Lengthy food frequency questionnaires (a snapshot of some questions below) are a common tool for assessing an individual’s eating habits over time. But the accuracy of results depends on how well participants can recall what they ate and how often. NIH Another difficulty is that these surveys often don’t account for variables that could be really important, like how the food was prepared and where it came from. Was the fish grilled? Fried? Slathered in butter? “Those things can matter,” says dementia researcher Nathaniel Chin of the University of Wisconsin–Madison. Plus there are the things researchers can’t control. For example, how does the food interact with an individual’s medications and microbiome? “We know all of those factors have an interplay,” Chin says. The few clinical trials looking at dementia and diet seem to measure different things, so it’s hard to make comparisons. In 2018, Radd-Vagenas and her colleagues looked at all the trials that had studied the impact of the Mediterranean diet on cognition. There were five at the time. “What struck me even then was how variable the interventions were,” she says. “Some of the studies didn’t even mention olive oil in their intervention. Now, how can you run a Mediterranean diet study and not mention olive oil?” Another tricky aspect is recruitment. The kind of people who sign up for clinical trials tend to be more educated, more motivated and have healthier lifestyles. That can make differences between the intervention group and the control group difficult to spot. And if the study shows an effect, whether it will apply to the broader, more diverse population comes into question. To sum up, these studies are difficult to design, difficult to conduct and often difficult to interpret. Kaeberlein studies aging, not dementia specifically, but he follows the research closely and acknowledges that the lack of clear answers can be frustrating. “I get the feeling of wanting to throw up your hands,” he says. But he points out that there may not be a single answer. Many diets can help people maintain a healthy weight and avoid diabetes, and thus reduce the risk of dementia. Beyond that obvious fact, he says, “it’s hard to get definitive answers.” A better way In July 2021, Yassine gathered with more than 30 other dementia and nutrition experts for a virtual symposium to discuss the myriad challenges and map out a path forward. The speakers noted several changes that might improve the research. One idea is to focus on populations at high risk. For example, one clinical trial is looking at the impact of low- and high-fat diets on short-term changes in the brain in people who carry the genetic variant APOE4, a risk factor for Alzheimer’s. One small study suggested that a high-fat Western diet actually improved cognition in some individuals. Researchers hope to get clarity on that surprising result. “I get the feeling of wanting to throw up your hands.” Matt Kaeberlein Another possible fix is redefining how researchers measure success. Hypertension and diabetes are both well-known risk factors for dementia. So rather than running a clinical trial that looks at whether a particular diet can affect dementia, researchers could look at the impact of diet on one of these risk factors. Plenty of studies have assessed the impact of diet on hypertension and diabetes, but Yassine knows of none launched with dementia prevention as the ultimate goal. Yassine envisions a study that recruits participants at risk of developing dementia because of genetics or cardiovascular disease and then looks at intermediate outcomes. “For example, a high-salt diet can be associated with hypertension, and hypertension can be associated with dementia,” he says. If the study shows that the diet lowers hypertension, “we achieved our aim.” Then the study could enter a legacy period during which researchers track these individuals for another decade to determine whether the intervention influences cognition and dementia. One way to amplify the signal in a clinical trial is to combine diet with other interventions likely to reduce the risk of dementia. The Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability, or FINGER, trial, which began in 2009, did just that. Researchers enrolled more than 1,200 individuals ages 60 to 77 who were at an elevated risk of developing dementia and had average or slightly impaired performance on cognition tests. Half received nutritional guidance, worked out at a gym, engaged in online brain-training games and had routine visits with a nurse to talk about managing dementia risk factors like high blood pressure and diabetes. The other half received only general health advice. After two years, the control group had a 25 percent greater cognitive decline than the intervention group. It was the first trial, reported in the Lancet in 2015, to show that targeting multiple risk factors could slow the pace of cognitive decline. Now researchers are testing this approach in more than 30 countries. Christy Tangney, a nutrition researcher at Rush University in Chicago, is one of the investigators on the U.S. arm of the study, enrolling 2,000 people ages 60 to 79 who have at least one dementia risk factor. The study is called POINTER, or U.S. Study to Protect Brain Health Through Lifestyle Intervention to Reduce Risk. The COVID-19 pandemic has delayed the research — organizers had to pause the trial briefly — but Tangney expects to have results in the next few years. This kind of multi-intervention study makes sense, Chin says. “One of the reasons why things are so slow in our field is we’re trying to address a heterogeneous disease with one intervention at a time. And that’s just not going to work.” A trial that tests multiple interventions “allows for people to not be perfect,” he adds. Maybe they can’t follow the diet exactly, but they can stick to the workout program, which might have an effect on its own. The drawback in these kinds of studies, however, is that it’s impossible to tease out the contribution of each individual intervention. Embracing complexity To untangle the role of diet in dementia, researchers are designing trials that intervene earlier in life and last longer. Some studies combine multiple interventions, like diet, exercise and brain training, as well as measure a wider range of outcomes. Dementia and diet studies are due a makeover Then Now Target one risk factor at a time Target multiple risk factors and disease mechanisms simultaneously Enroll individuals with substantial cognitive impairment Enroll at-risk individuals who do not yet have symptoms of dementia Trials last 6–12 months Trials last 18–24 months Focus on cognitive and functional outcome measures Look at multiple outcome measures, including surrogate measures like biomarkers Source: R. Stephen et al/Frontiers in Neurology 2021 Preemptive guidelines Two major reports came out in recent years addressing dementia prevention. The first, from the World Health Organization in 2019, recommends a healthy, balanced diet for all adults, and notes that the Mediterranean diet may help people who have normal to mildly impaired cognition. The 2020 Lancet Commission report, however, does not include diet in its list of modifiable risk factors, at least not yet. “Nutrition and dietary components are challenging to research with controversies still raging around the role of many micronutrients and health outcomes in dementia,” the report notes. The authors point out that a Mediterranean or the similar Scandinavian diet might help prevent cognitive decline in people with intact cognition, but “how long the exposure has to be or during which ages is unclear.” Neither report recommends any supplements. Plenty of people are waiting for some kind of advice to follow. Improving how these studies are done might enable scientists to finally sort out what kinds of diets can help hold back the heartbreaking damage that comes with Alzheimer’s disease. For some people, that knowledge might be enough to create change. “One of the reasons why things are so slow in our field is we’re trying to address a heterogeneous disease with one intervention at a time. And that’s just not going to work.” Nathaniel Chin “Inevitably, if you’ve had Alzheimer’s in your family, you want to know, ‘What can I do today to potentially reduce my risk?’ ” says molecular biologist Heather Snyder, vice president of medical and scientific relations at the Alzheimer’s Association. But changing long-term dietary habits can be hard. The foods we eat aren’t just fuel; our diets represent culture and comfort and more. “Food means so much to us,” Chin says. “Even if you found the perfect diet,” he adds, “how do you get people to agree to and actually change their habits to follow that diet?” The MIND diet, for example, suggests people eat less than one serving of cheese a week. In Wisconsin, where Chin is based, that’s a nonstarter, he says. But it’s not just about changing individual behaviors. Radd-Vagenas and other researchers hope that if they can show the brain benefits of some of these diets in rigorous studies, policy changes might follow. For example, research shows that lifestyle changes can have a big impact on type 2 diabetes. As a result, many insurance providers now pay for coaching programs that help participants maintain healthy diet and exercise habits. “You need to establish policies. You need to change cities, change urban design. You need to do a lot of things to enable healthier choices to become easier choices,” Radd-Vagenas says. But that takes meatier data than exist now. Questions or comments on this article? E-mail us at feedback@sciencenews.org A version of this article appears in the July 2, 2022 issue of Science News. Citations S. Charisis et al. Diet inflammatory index and dementia incidence: A population-based study. Neurology. Vol. 97. December 2021. doi: 10.1212/WNL.0000000000012973. T. Ngandu et al. A 2 year multidomain intervention of diet, exercise, cognitive training, and vascular risk monitoring versus control to prevent cognitive decline in at-risk elderly people (FINGER): a randomised controlled trial. Lancet. Vol 385. June 2015. doi: 10.1016/S0140-6736(15)60461-5. S. Radd-Vagenas et al. Effect of the Mediterranean diet on cognition and brain morphology and function: a systematic review of randomized controlled trials. The American Journal of Clinical Nutrition, Vol. 107. March 2018. doi: 10.1093/ajcn/nqx070.
  2. All, Like we've seen for cardiovascular disease, eating fish can be a mixed blessing. The omega-3 fatty acids (DHA/EPA) are thought to be beneficial, particularly for brain function. But the mercury, PCBs and other contaminants that bioaccumulate in the fat of fish may also have harmful effects. This new study[1] (thanks to Al Pater!) looks at the association between consumption of fish, plant omega-3s, brain mercury levels and Alzheimer's disease and brain mini-strokes. What they found is a bit nuanced, but worth thinking about. They gave 550 quite elderly but initially dementia-free people in several US nursing homes a yearly dietary questionnaire to measure their weekly intake of fish, DHA/EPA and the plant-derived omega-3 Alpha Linolenic Acid (ALA) until they died. Over an average follow-up of 4.5 years, 286 of the participates died (average age 89!). These folks' brains were autopsied to measure mercury levels and to look for physical signs of Alzheimer's disease (plaques and tangles) as well as brain injuries associated with other forms of dementia, in particular macroinfarctions and microinfarctions (i.e. strokes of various sizes). Here are the highlights of what they found: The more fish meals per week a subject consumed, the higher their brain mercury level (P < 0.02). There was no correlation between intake of ALA or DHA/EPA supplements and brain mercury level. For the majority of people (77%) who weren't carriers of the APOE4 allele that increases one's susceptibility to Alzheimer's disease, neither eating fish, dietary DHA/EPA nor consuming ALA had a significant effect (one way or the other) on the risk of Alzheimer's disease. For the minority (23%) of subjects who were APOE4 carriers, eating more fish and more dietary DHA/EPA was associated with a decreased risk of Alzheimer's disease markers (P < 0.04). Neither DHA/EPA supplements nor dietary ALA impacted Alzheimer's risk in these folks. Dietary ALA, but not fish or DHA/EPA, was associated with reduced prevalence of macroinfarctions (P < 0.03) and microinfarctions (P < 0.04) associated with non-Alzheimer's cognitive impairment, independent of APOE4 status. Those were the major, statistically significant findings. There is one more thing I noticed looking at the table below that appears interesting/suggestive for the majority of us who are lucky enough not have the APOE4 gene. The cells I've highlighted below represent the level of various markers of Alzheimer's disease for APOE4-negative folks. The red cells represent the level of Alzheimer's markers for people who ate the most fish (top red row), or the most dietary DHA/EPA (bottom red row). From the confidence intervals, you can see that none of them are individually significant. But also notice that all of them are positive, meaning there was a trend towards increased markers of Alzheimer's disease in APOE4-negative people who ate the most fish, especially fatty fish. In contrast, now look at the green cells, representing markers for Alzheimer's disease in APOE4-negative people who consumed the most plant-derived ALA. Notice these too are not individually significant, but all of them are negative, pointing towards a reduced risk of Alzheimer's disease with increasing ALA intake. From all this, my summary takeaway message from this study would be the following: For people with the APOE4 gene and therefore increased risk of Alzheimer's disease, eating fish is likely to reduce one's risk of Alzheimer's disease, despite increasing brain mercury levels For people without the APOE4 gene, fish consumption doesn't seem to reduce, and may even increase, one's risk of Alzheimer's disease For people without the APOE4 gene, plant-derived omega-3 ALA (e.g. from walnuts, olive oil, flax, chia) consumption may reduce one's risk of Alzheimer's disease For everyone, dietary ALA appears to reduce one's risk of brain markers for non-Alzheimer's cognitive impairment. Or more succinctly, ALA is likely to be good for everyone's brain health, and fish is likely to be good for the brain health of only the minority of people who carry the APOE4 allele. This seems like an illustration of a benefit of getting one's DNA sequenced with a company like 23andMe to determine whether one is a carrier of the APOE4 allele. --Dean ------------ [1] JAMA. 2016 Feb 2;315(5):489-97. doi: 10.1001/jama.2015.19451. Association of Seafood Consumption, Brain Mercury Level, and APOE e4 Status With Brain Neuropathology in Older Adults. Morris MC, Brockman J, Schneider JA, Wang Y, Bennett DA, Tangney CC, van de Rest O. Full text: http://jama.jamanetwork.com.sci-hub.io/article.aspx?articleID=2484683 Abstract IMPORTANCE: Seafood consumption is promoted for its many health benefits even though its contamination by mercury, a known neurotoxin, is a growing concern. OBJECTIVE: To determine whether seafood consumption is correlated with increased brain mercury levels and also whether seafood consumption or brain mercury levels are correlated with brain neuropathologies. DESIGN, SETTING, AND PARTICIPANTS: Cross-sectional analyses of deceased participants in the Memory and Aging Project clinical neuropathological cohort study, 2004-2013. Participants resided in Chicago retirement communities and subsidized housing. The study included 286 autopsied brains of 554 deceased participants (51.6%). The mean (SD) age at death was 89.9 (6.1) years, 67% (193) were women, and the mean (SD) educational attainment was 14.6 (2.7) years. EXPOSURES: Seafood intake was first measured by a food frequency questionnaire at a mean of 4.5 years before death. MAIN OUTCOMES AND MEASURES: Dementia-related pathologies assessed were Alzheimer disease, Lewy bodies, and the number of macroinfarcts and microinfarcts. Dietary consumption of seafood and n-3 fatty acids was annually assessed by a food frequency questionnaire in the years before death. Tissue concentrations of mercury and selenium were measured using instrumental neutron activation analyses. RESULTS: Among the 286 autopsied brains of 544 participants, brain mercury levels were positively correlated with the number of seafood meals consumed per week (??=?0.16; P?=?.02). In models adjusted for age, sex, education, and total energy intake, seafood consumption (=?1 meal/week) was significantly correlated with less Alzheimer disease pathology including lower density of neuritic plaques (ß?=?-0.69 score units [95% CI, -1.34 to -0.04]), less severe and widespread neurofibrillary tangles (ß?=?-0.77 score units [95% CI, -1.52 to -0.02]), and lower neuropathologically defined Alzheimer disease (ß?=?-0.53 score units [95% CI, -0.96 to -0.10]) but only among apolipoprotein E (APOE e4) carriers. Higher intake levels of a-linolenic acid (18:3 n-3) were correlated with lower odds of cerebral macroinfarctions (odds ratio for tertiles 3 vs 1, 0.51 [95% CI, 0.27 to 0.94]). Fish oil supplementation had no statistically significant correlation with any neuropathologic marker. Higher brain concentrations of mercury were not significantly correlated with increased levels of brain neuropathology. CONCLUSIONS AND RELEVANCE: In cross-sectional analyses, moderate seafood consumption was correlated with lesser Alzheimer disease neuropathology. Although seafood consumption was also correlated with higher brain levels of mercury, these levels were not correlated with brain neuropathology. PMID: 26836731
  3. Interesting post from Dr Greger : https://nutritionfacts.org/2022/04/26/oxidized-cholesterol-and-alzheimers-disease/?utm_source=NutritionFacts.org&amp;utm_campaign=979887baf1-RSS_BLOG_DAILY&amp;utm_medium=email&amp;utm_term=0_40f9e497d1-979887baf1-28418550&amp;mc_cid=979887baf1&amp;mc_eid=35e390afc1 "Oxidized cholesterol can be a hundred times more toxic than regular cholesterol, raising additional concerns about foods such as ghee, canned tuna, processed meat, and parmesan cheese. Too much cholesterol in the blood “has long been considered to act as a primary risk factor for developing Alzheimer’s disease and, possibly, Parkinson’s disease.” Striking images on autopsy show that the brain arteries of Alzheimer’s victims are clogged with fat and cholesterol, compared to non-demented elderly controls, as you can see at 0:16 in my video Oxidized Cholesterol as a Cause of Alzheimer’s Disease. But “cholesterol cannot be directly exported across the blood-brain barrier,” so it can’t get directly into—or out of—the brain. What if the brain has too much cholesterol and needs to get rid of some? As a safety valve, an enzyme in the brain can oxidize cholesterol. So, in that form, it can exit the brain and eventually the body. There’s a catch, though. “Although this fact means that the brain can eliminate excess amounts of these oxidation products,” it could be a two-way street. “t could conversely allow toxic amounts of oxysterols [oxidized cholesterol], present in the blood stream, to accumulate in the brain”—that is, to go the other way. "
  4. All, This new study [1] (science press coverage) appears like it might be a significant breakthrough in the treatment of Alzheimer's disease. Researchers appear to have discovered a small molecule that at least in rodents is safe, crosses the blood-brain barrier, and is effective at breaking up beta amyloid plaques, thought to play an important role in the neuronal death associated with Alzheimer's disease. From the article linked above: The Korean scientists, led by YoungSoo Kim of the Brain Science Institute at the Korea Institute of Science and Technology (KIST) in Seoul, investigated the ability of EPPS [4-(2-hydroxyethyl)-1-piperazinepropanesulphonic acid] to attach to amyloid-beta clumps and convert them into simpler, smaller molecules. Through a series of experiments, they found that EPPS could break apart plaque in a living mammal. They also found the molecule could be added to drinking water yet still travel in the blood to the brain and cross the blood-brain barrier, which otherwise prevents foreign material from entering the brain. EPPS could penetrate the barrier because it is a relatively small molecule, Kim said. The scientists found that doses between 30 and 100 milligrams per kilogram of body weight per day were effective in breaking up the amyloid beta. Further tests demonstrated that EPPS appears to have no toxic effects in mice up to 2,000 mg/kg per day. From the full text, not only did mice treated with EPPS show a reduction in beta amyloid plaques in their hippocampus and other brain areas in a dose dependent manner, they also showed less cognitive impairment relative to control mice using several measures of cognitive performance. The lead author is quite optimistic about this compound's potential: "I strongly believe these drug candidates [based on EPPS] will halt the neurodegeneration and rescue patients from death," Kim said. Here's hoping human trials prove that he's right! --Dean ------ [1] Nat Commun. 2015 Dec 8;6:8997. doi: 10.1038/ncomms9997. EPPS rescues hippocampus-dependent cognitive deficits in APP/PS1 mice by disaggregation of amyloid-β oligomers and plaques. Kim HY(1,)(2,)(3), Kim HV(1,)(2), Jo S(4), Lee CJ(4), Choi SY(1), Kim DJ(1), Kim Y(1,)(2). Full text: http://www.nature.com.sci-hub.io/ncomms/2015/151208/ncomms9997/abs/ncomms9997.html Alzheimer's disease (AD) is characterized by the transition of amyloid-β (Aβ) monomers into toxic oligomers and plaques. Given that Aβ abnormality typically precedes the development of clinical symptoms, an agent capable of disaggregating existing Aβ aggregates may be advantageous. Here we report that a small molecule, 4-(2-hydroxyethyl)-1-piperazinepropanesulphonic acid (EPPS), binds to Aβ aggregates and converts them into monomers. The oral administration of EPPS substantially reduces hippocampus-dependent behavioural deficits, brain Aβ oligomer and plaque deposits, glial γ-aminobutyric acid (GABA) release and brain inflammation in an Aβ-overexpressing, APP/PS1 transgenic mouse model when initiated after the development of severe AD-like phenotypes. The ability of EPPS to rescue Aβ aggregation and behavioural deficits provides strong support for the view that the accumulation of Aβ is an important mechanism underlying AD. PMCID: PMC4686862 PMID: 26646366
  5. All, Here is an interesting new study [1] (popular press story) that I appreciated as much for its data as its conclusions. In it, researchers identified a group of ~1400 "Wellderly" individuals - which they defined as: ndividuals who are >80 years old with no chronic diseases and who are not taking chronic medications. As you might imagine, these folks are pretty rare, and so they wanted to compare their genomes with those of an average population of elderly people. But first, they did an interesting thing - they compared the longevity of the siblings of the Wellderly cohort (who share a lot of genetics, and probably some lifestyle factors too, with the Wellderly folks) to see how their lifespan compares with the average US population. Here are the "survival curves" for the Wellderly siblings (red) vs. average folks (blue): As you can see, the Wellderly siblings had a more square mortality curve, but their survival curve wasn't shifted right - i.e. their "maximum lifespan" wasn't any longer than the average folks. Instead, both curves hit (near) zero around 100 years. Like the Wellderly themselves, their siblings appear to avoid / postpone the diseases of aging, and so do better in the "middle years" of elderliness (65-85), but beyond that have a mortality rate similar to the population as a whole. They then looked at the Wellderly folks' genetics. Interestingly, they didn't find their genomes to be particularly enriched with so-called "longevity genes" - those that have been identified as more common in centenarians or other very long-lived people. In other words, these folks are healthy agers, but don't seem to be blessed with genes for extreme longevity, which I thought was interesting. It suggests that at least to some degree healthy aging and extreme longevity are distinct, based both on the (sibling) survival curve data and their own genetics. Here is how the authors summarized this part of their findings: [O]ur results suggest that healthy aging is a genetically overlapping but divergent phenotype from exceptional longevity and that the healthy aging phenotype is potentially enriched for heritable components of both reduced risk of age-associated disease and resistance to age-associated disease. I'm curious what Michael would say, but it seems like this apparent distinction between disease avoidance and extreme longevity might undermine to some degree the SENS hypothesis - that aging simple is the accumulation of damage from the diseases of aging. Note: that is my potentially inaccurate summary of the SENS hypothesis... But what I found personally most interesting and helpful from this paper were two of their tables, listing the various genetic markers they tested for both longevity and Alzheimer's disease (AD). They quite explicitly listed the SNPs and which alleles of those SNPs are associated with longevity or AD. I've reproduced the two tables below, and added my own data, a friend's 23andMe data I have access to, and links to 23andMe so that any other 23andMe customers can check their own status for the corresponding SNPs. I've even added a tally at the bottom of each table with a genetic "score" - basically the number of "good" alleles one carries minus (in the case of the AD table) the number of "bad" alleles one carries. Although in the case of AD, it was the evil APOE4 allele that dominated - i.e. the biggest difference between the genes of the "Wellderly" folks and the average population was that the Wellderly were a lot less likely to carry APOE4 alleles. Anyway, here are the tables. First, the table with the SNPs and alleles previously identified (via other studies) to be associated with increased longevity. The "Longevity Allele" column shows that variant of the SNP that has been shown to be associated with increased longevity. The second column shows the gene the SNP is part of - as you can see many familiar names, including FOXO3, SIRT1, IL-6, IGF1, AKT (all of which I note have been associated with both CR and Cold Exposure in one way or another). The green letters show when I or "Person X" are carriers for the "good" longevity allele: Here are "live" links to the 23andMe page for each SNP so 23andMe customers can check their own results on these SNPs: https://www.23andme.com/you/explorer/snp/?snp_name=rs2802292 https://www.23andme.com/you/explorer/snp/?snp_name=rs1935949 https://www.23andme.com/you/explorer/snp/?snp_name=rs3758391 https://www.23andme.com/you/explorer/snp/?snp_name=rs5882 https://www.23andme.com/you/explorer/snp/?snp_name=rs1042522 https://www.23andme.com/you/explorer/snp/?snp_name=rs1800795 https://www.23andme.com/you/explorer/snp/?snp_name=rs2811712 https://www.23andme.com/you/explorer/snp/?snp_name=rs34516635 https://www.23andme.com/you/explorer/snp/?snp_name=rs2542052 https://www.23andme.com/you/explorer/snp/?snp_name=rs3803304 Here is the same sort of table, but this time for SNPs and Alleles associated with Alzheimer's disease and/or cognitive decline. Note, the last SNP in the table is the dreaded APOE4. As you can see from the p-value column, the APOE4 allele was far and away the most significant predictor of AD/cognitive decline, and the Wellderly had it less frequently that the general population (the column labelled "ITMI A2 Freq"). Also not that unlike the longevity SNPs, 23andMe didn't have data for many of the AD-related SNPs. Once again, the green letters show when I or "Person X" are carriers for the "good" allele (for avoiding AD) or and red letters show where one of us is a carrier for the "bad" allele (increasing risk of AD): Here are the direct links to 23andMe for the subset of SNPs from the table that were available (at least for me): https://www.23andme.com/you/explorer/snp/?snp_name=rs190982 https://www.23andme.com/you/explorer/snp/?snp_name=rs2718058 https://www.23andme.com/you/explorer/snp/?snp_name=rs1476679 https://www.23andme.com/you/explorer/snp/?snp_name=rs11771145 https://www.23andme.com/you/explorer/snp/?snp_name=rs11218343 https://www.23andme.com/you/explorer/snp/?snp_name=rs17125944 https://www.23andme.com/you/explorer/snp/?snp_name=rs10498633 https://www.23andme.com/you/explorer/snp/?snp_name=rs2075650 As you can see, for both the longevity SNPs and the AD SNPs, my score is a bit better than the score for my friend, "Person X" - so I got that goin' for me. And they are an unfortunate carrier of one APOE4 allele. ☹ To wrap up, the researchers also also found that a few of the Wellderly folks were enriched with an ultra-rare variants of a gene that seems to be especially protective against AD, called COL25A1 but I couldn't figure out what SNPs or alleles they were talking about. As always, these genetic marker studies need to be taken with a grain of salt. But it was fun to see where I and "Person X" stand regarding all these variants. I'd be curious if anyone else would be willing to share their data, or at least their "scores". --Dean ------- [1] Cell (2016), http://dx.doi.org/10.1016/j.cell.2016.03.022 Whole-Genome Sequencing of a Healthy Aging Cohort Galina A. Erikson5, Dale L. Bodian5, Manuel Rueda, Bhuvan Molparia, Erick R. Scott, Ashley A. Scott-Van Zeeland, Sarah E. Topol, Nathan E. Wineinger, John E. Niederhuber, Eric J. Topol6, Ali Torkamani6 Free full text: http://www.cell.com/cell/pdf/S0092-8674(16)30278-1.pdf Summary Studies of long-lived individuals have revealed few genetic mechanisms for protection against age-associated disease. Therefore, we pursued genome sequencing of a related phenotype—healthy aging—to understand the genetics of disease-free aging without medical intervention. In contrast with studies of exceptional longevity, usually focused on centenarians, healthy aging is not associated with known longevity variants, but is associated with reduced genetic susceptibility to Alzheimer and coronary artery disease. Additionally, healthy aging is not associated with a decreased rate of rare pathogenic variants, potentially indicating the presence of disease-resistance factors. In keeping with this possibility, we identify suggestive common and rare variant genetic associations implying that protection against cognitive decline is a genetic component of healthy aging. These findings, based on a relatively small cohort, require independent replication. Overall, our results suggest healthy aging is an overlapping but distinct phenotype from exceptional longevity that may be enriched with disease-protective genetic factors. PMID: Unavailable
  6. All, It's pretty much unimaginable that anyone reading this would not by now have heard about the cardiovascular benefits of dark chocolate, both in terms of preventing cardiovascular disease and even improving cardiovascular (athletic) performance. And you've probably heard the news that chocolate is good for brain health & cognition as well. Nevertheless, this new study [1], posted by Al, is noteworthy for several reasons. In it, researchers followed 530 elderly people over four years to see how their dietary habits, particularly wrt chocolate consumption, correlated with cognitive decline. The first surprising thing was the magnitude of the benefits of chocolate on cognitive health. Even after controlling for a host of potentially confounding risk factors, they found that chocolate consumption was associated with a whopping 40% reduction in likelihood of cognitive decline over the four year period. That's the good news. The not-so-good news is that this benefit was only seen in participants who eschewed caffeine. In fact, if limited to folks who consumed less than 75mg of caffeine a day (~1 cup of coffee), the cognitive protection associated with chocolate was even greater - a 50% lower risk of cognitive decline. They don't report it explicitly in the abstract (full text not available), but presumably caffeine drinkers did not see a significant cognitive benefit (nor harm!) from also consuming chocolate. This suggests the cognitive benefits of chocolate overlap and are hence redundant with (and not additive with) the beneficial effects of coffee/tea polyphenols and/or the caffeine they contain. Nevertheless, I'm going to continue consuming both cacao and caffeine products, because this is only one study, and heck, I enjoy them both ☺. --Dean --------- [1] J Alzheimers Dis. 2016 May 6. [Epub ahead of print] Chocolate Consumption is Associated with a Lower Risk of Cognitive Decline. Moreira A, Di?genes MJ, de Mendon?a A, Lunet N, Barros H. Abstract Cocoa-related products like chocolate have taken an important place in our food habits and culture. In this work, we aim to examine the relationship between chocolate consumption and cognitive decline in an elderly cognitively healthy population. In the present longitudinal prospective study, a cohort of 531 participants aged 65 and over with normal Mini-Mental State Examination (MMSE; median 28) was selected. The median follow-up was 48 months. Dietary habits were evaluated at baseline. The MMSE was used to assess global cognitive function at baseline and at follow-up. Cognitive decline was defined by a decrease =/> 2 points in the MMSE score between evaluations. Relative risk (RR) and 95% confidence interval (95% CI) estimates were adjusted for age, education, smoking, alcohol drinking, body mass index, hypertension, and diabetes. Chocolate intake was associated with a lower risk of cognitive decline (RR = 0.59, 95% CI 0.38-0.92). This protective effect was observed only among subjects with an average daily consumption of caffeine lower than 75 mg (69% of the participants; RR = 0.50, 95% CI 0.31-0.82). To our knowledge, this is the first prospective cohort study to show an inverse association between regular long-term chocolate consumption and cognitive decline in humans. KEYWORDS: Adenosine A2A receptors; Alzheimer?s disease; chocolate; cognition; prevention; theobromine PMID: 27163823
  7. Nickola from Singularity Webblog has a new interview with Dr. Michael Fossel, an expert on telomeres and telomerase. Quite an interesting interview. He has a new book, called the Telomerase Revolution and new company, called Telocyte, focused on extending telomerase to lengthen telomeres, and he claims, slow & reverse aging. Pretty big claims, and honestly he came across in the interview as a bit of a salesman... Unfortunately I can't seem to embed the video to start up at specific times, so I'm going to list the times of a couple interesting sections in the video, so you can jump ahead manually in the video embedded below: At 16:25 Nickola reads a single sentence summary of Fossel's "Telomere Theory of Aging" from his book. - He's basically saying that aging is a programmed result of changes in gene expression as the organism gets older, orchestrated by telomeres. When the relative length (not absolute length, he's clear to point out), of telomeres shortens, it changes which genes and especially how quickly genes get expressed, i.e. get read and translated into proteins. Without the right protein mix, bad things happen in cells, or more specifically, bad things continue to be generated, but they are no longer broken down at a fast enough rate. So they accumulate, and that is the major cause of cellular aging. So things like beta amyloid, or advanced glycation end products (AGEs), which can be broken down effectively in young animals, accumulate when telomeres get short and proteins aren't created to break them down. At 24:20 Fossel talks about why (teleologically) he thinks we age. That is, if its possible to keep the protein mix in cells "young" (via telomerase or some other method), why doesn't the body do this all the time? I was thinking he was going to say it's a tradeoff with cancer. But no, he doesn't. He says (to paraphrase) we age because the quicker a population turns over, the quicker it can adapt to a changing environment. For example, viruses that reproduce quickly can adapt very quickly via mutation. So organisms are designed to die off so that their mutated progeny can inherit the earth (or at least their parent's niche). I'm pretty dubious of this model... It doesn't seem to jibe with the "selfish gene" theory which seems pretty well established. But what do I know... At 33:40 and again at 40:30 he talks about the effectiveness (or lackthereof) of existing telomerase activator compounds, particularly astragalus. He says there is some evidence it works, but the supplements are either really expensive (like $200/mo) from reputable companies, or likely contain little astragalus if they are a lot cheaper. Josh Mitteldorf talks about telomerase and astragalus in several posts, like this one about a guy who has been taking high doses of astragalus since 2007. At 36:00 Fossel talks about the data in animals that suggests resetting telomere length can reverse aging as measured by quite a number of biomarkers. At 42:40 he talks about the potential side effects of lengthening telomeres, and specifically cancer. He makes an argument that cancer is unlikely to be significantly increased, but acknowledges there is the possibility that it would. His argument that it won't cause cancer is that extra telomerase upregulates expression of genes that repair DNA, so that will reduce cancer rate, balancing out with the extra ability for cells to divide. At 46:00 he says that's one reason they are targeting Alzheimer's Disease in their first clinical trial, because AD is a death sentence and these people are old anyway, so cancer won't have that long to proliferate and spread even if it is slightly increased by telomerase therapy. At 48:15 he talks about Liz Parrish and her "N=1" experiment with gene therapy, including telomerase activation. He understands her frustration with the slow progress of anti-aging research, but he is pretty skeptical that we'll be able to learn anything from her, because she is so young and healthy. He says she'll basically have zero credibility because of the way she's gone about it, without oversight, FDA approval, etc. He says they are going to go through the right FDA clinical trial process with their own efforts, at Telocyte. At 58:00 he talks about Aubrey and "longevity escape velocity". He says people 100 years from now will look back and identify the coming decade as the time frame when we cured aging. He says at 1:01:15 that there will be an "inflection point" that dramatically slows aging, whether you want to take the therapy or not, and whether there may be side effects or not, and that breakthrough will occur in the "next few years". He also disses Aubrey as not quite understanding the genetics involved in aging, and therefore being too conservative"by mistake", both in the timeframe for curing aging, and in the value of telomere therapy... At 1:02:00 he talks about the biotech company he started last year, Telocyte. They are planning a clinical trial to show they can "prevent and cure" Alzheimer's disease. If things go really well, he hoping to start a phase 1 clinical trial with a handful of AD patients around the end of 2016, have results 6 months later, and hopefully phase 2 trials shortly after that, if the phase 1 goes well. At 1:06:30 he talks about the clinical trial timeline in detail. At 1:10:20 he fields a question about how telomerase therapy can (or can't) deal with the other types of damage that accumulate with age. Like lipofuscin. He says "no problem", longer telomeres should do the trick. Not an entirely satisfying answer... At 1:15:40 he disses Aubrey again, as misunderstanding the relationship between senescent cells and aging. Dubious... At 1:17:40 if you look carefully he does the "finger twirl around the ear" gesture in reference to Aubrey, a gesture that is typically associated with someone being crazy, although with his words he says "Aubrey isn't thinking about the pathology [of senescent cells] well." At 1:19:50, he makes an interesting statement. He says that most people (hint - Aubrey) say that damage causes aging. He says that's backwards. Instead, aging permits damage to occur, or "aging causes damage". As we grow older, our telomeres shorten, causing changes in gene expression that results in poorer cellular repair and increased damage. Overall, as I said at the top, he comes across more as a salesman, rather than a researcher. He's very optimistic, and it would be great if he's right, and gets a chance to prove it, or be disproven, pretty soon... It seems like targeting AD might be a pretty good strategy to start with. --Dean
  8. Dean Pomerleau

    Nootropics

    I was surprised to find that a search of these forums turned up very little discussion of nootropics, or so-called "smart drugs", at least as far as I could find. Obviously cognitive performance and long-term brain health is an important consideration for everyone, but especially obsessive optimizers like us ☺. So I figured I'd start a thread to inquire if anyone has experimented with nootropics, and if so, which ones (if any) did you find beneficial. To kick off the discussion, I've never experimented with any nootropics myself, except for caffeine, which honestly I don't find has much of an observable effect on me (cognitive or otherwise), but I take it anyway (as coffee/tea, and as a B12-fortified mint) for other health reasons. But today I came across a new multi-nootropic supplement from someone I trust, respect and believe to be quite intelligent - Lincoln Cannon. Lincoln is the co-founder of the Mormon Transhumanism Association, a pretty cool longevity-focused organization to which I and many other non-Mormons belong. Lincoln is also responsible for formulating the New God Argument, which I find pretty compelling (see here for related discussion and here for science/philosophy heavyweights on the topic). But I digress... Thrivous, his new company (to which I have no affiliation), has developed a nootropic supplement called Clarity. Here is the Clarity label: Has anyone any personal experience, or done any research on any of these ingredients? Here is Lincoln's research on them, plus a couple others not included in this version of Clarity. They look reasonably beneficial (and harmless) based on the controlled studies Lincoln has compiled. The price is pretty reasonable - $25 for a month's supply. I'm forever interested in self-experimentation and lifestyle optimization, so I was thinking of conducting a single-blind, crossover trial on myself to see if I notice any difference between taking Clarity vs. a placebo. But if others have had bad experiences with these nootropics, or know of research that says they may be harmful, I'll obviously steer clear. Thanks! --Dean
  9. All, There seems to be growing evidence that systemic inflammation is involved in many diseases of aging, including cardiovascular disease, diabetes and cognitive impairment / Alzheimer's disease. This new study [1] speaks to the latter. It found the rate of cognitive decline in people suffering from mild cognitive impairment or early-stage Alzheimer's disease was 6x higher in those people who also suffered from periodontal disease, likely as a result of the systemic inflammatory effects of the subjects' infected gums. So take care of those teeth and gums! --Dean ---------- [1] PLoS One. 2016 Mar 10;11(3):e0151081. doi: 10.1371/journal.pone.0151081. eCollection 2016. Periodontitis and Cognitive Decline in Alzheimer's Disease. Ide M(1), Harris M(2), Stevens A(3), Sussams R(2,)(3), Hopkins V(3), Culliford D(4), Fuller J(5), Ibbett P(5), Raybould R(6), Thomas R(6), Puenter U(5), Teeling J(5), Perry VH(5), Holmes C(2,)(3). Author information: (1)Dental Institute, Kings College London, Guy's Hospital, London, United Kingdom. (2)University of Southampton, Faculty of Medicine, Clinical Experimental Science, Southampton, United Kingdom. (3)Memory Assessment and Research Centre, Moorgreen Hospital, Southampton, United Kingdom. (4)University of Southampton, Faculty of Health Sciences, NIHR CLAHRC Wessex Methodological Hub, Southampton, United Kingdom. (5)University of Southampton, Faculty of Natural and Environmental Science, Centre for Biological Sciences, Southampton, United Kingdom. (6)Medical Research Council Centre for Neuropsychiatric Genetics and Genomics, Institute of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff, United Kingdom. Free full text: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4786266/ Periodontitis is common in the elderly and may become more common in Alzheimer's disease because of a reduced ability to take care of oral hygiene as the disease progresses. Elevated antibodies to periodontal bacteria are associated with an increased systemic pro-inflammatory state. Elsewhere raised serum pro-inflammatory cytokines have been associated with an increased rate of cognitive decline in Alzheimer's disease. We hypothesized that periodontitis would be associated with increased dementia severity and a more rapid cognitive decline in Alzheimer's disease. We aimed to determine if periodontitis in Alzheimer's disease is associated with both increased dementia severity and cognitive decline, and an increased systemic pro inflammatory state. In a six month observational cohort study 60 community dwelling participants with mild to moderate Alzheimer's Disease were cognitively assessed and a blood sample taken for systemic inflammatory markers. Dental health was assessed by a dental hygienist, blind to cognitive outcomes. All assessments were repeated at six months. The presence of periodontitis at baseline was not related to baseline cognitive state but was associated with a six fold increase in the rate of cognitive decline as assessed by the ADAS-cog over a six month follow up period. Periodontitis at baseline was associated with a relative increase in the pro-inflammatory state over the six month follow up period. Our data showed that periodontitis is associated with an increase in cognitive decline in Alzheimer's Disease, independent to baseline cognitive state, which may be mediated through effects on systemic inflammation. PMCID: PMC4786266 PMID: 26963387
  10. All, In another apparent micronutrient synergy involving DHA for improved brain health (see Curcumin Elevates DHA in the Brain thread for the other), this new randomized control trial [1] found that supplementing for two years with three B-vitamins (folic acid, B6 and B12) slowed the cognitive decline that often leads from mild cognitive impairment (MCI) to Alzheimer's Disease (AD), but only if the person had "high normal" levels of serum DHA at baseline: When omega-3 fatty acid concentrations are low, B vitamin treatment has no effect on cognitive decline in MCI, but when omega-3 levels are in the upper normal range, B vitamins interact to slow cognitive decline. A clinical trial of B vitamins combined with omega-3 fatty acids is needed to see whether it is possible to slow the conversion from MCI to AD. Michael warns against CRers supplementing with DHA, but for brain health it seems that adequate DHA may be important. Curcumin might help increase DHA in the brain by boosting ALA->DHA conversion, but he's also dissed curcumin, so I'm wondering what he thinks of all this... --Dean ---------- [1] J Alzheimers Dis. 2016 Jan 6. [Epub ahead of print] Omega-3 Fatty Acid Status Enhances the Prevention of Cognitive Decline by B Vitamins in Mild Cognitive Impairment. Oulhaj A(1), Jernerén F(2), Refsum H(2,)(3), David Smith A(2), de Jager CA(4). Free full text: http://content.iospress.com/articles/journal-of-alzheimers-disease/jad150777 A randomized trial (VITACOG) in people with mild cognitive impairment (MCI) found that B vitamin treatment to lower homocysteine slowed the rate of cognitive and clinical decline. We have used data from this trial to see whether baseline omega-3 fatty acid status interacts with the effects of B vitamin treatment. 266 participants with MCI aged ≥70 years were randomized to B vitamins (folic acid, vitamins B6 and B12) or placebo for 2 years. Baseline cognitive test performance, clinical dementia rating (CDR) scale, and plasma concentrations of total homocysteine, total docosahexaenoic and eicosapentaenoic acids (omega-3 fatty acids) were measured. Final scores for verbal delayed recall, global cognition, and CDR sum-of-boxes were better in the B vitamin-treated group according to increasing baseline concentrations of omega-3 fatty acids, whereas scores in the placebo group were similar across these concentrations. Among those with good omega-3 status, 33% of those on B vitamin treatment had global CDR scores >0 compared with 59% among those on placebo. For all three outcome measures, higher concentrations of docosahexaenoic acid alone significantly enhanced the cognitive effects of B vitamins, while eicosapentaenoic acid appeared less effective. When omega-3 fatty acid concentrations are low, B vitamin treatment has no effect on cognitive decline in MCI, but when omega-3 levels are in the upper normal range, B vitamins interact to slow cognitive decline. A clinical trial of B vitamins combined with omega-3 fatty acids is needed to see whether it is possible to slow the conversion from MCI to AD. PMID: 26757190
  11. All, As we've discussed elsewhere, the formation of amyloid-beta plaques are known to be an important step in the progression of Alzheimer's disease. Exercise is known to help reduce amyloid plaque buildup, as discussed here. I think the fermented food natto may be beneficial for amyloid clearance as well, but that is more controversial. Sleep is known to be a time when the brain "cleans house", psychologically in terms of memory consolidation and synapse decay, but also literally, through the glymphatic transport system, which flushes toxins from the brain, including beta-amyloid plaques [2]: Clearance [of toxic proteins including beta-amyloid] during sleep is as much as two-fold faster than during waking hours. This new study [1] (popular press article), found that at least in rats, sleep posture influences the rate of glymphatic transport and toxin clearance. In particular, rats that were made to sleep on their (right) side while sleeping had better flow of their glymphatic fluid than rats who were either sitting up or lying on the back although beta-amyloid clearance wasn't much different between the two prone positions. And of course, rat brain morphology and circulatory system is quite a bit different from people, but the authors nevertheless speculate that sleeping on your side may be advantageous for brain health relative to sleeping on your back (or stomach). They didn't compare sleeping on the left vs right side in these rats, but in people it looks like sleeping on one's left side appears to be better for digestion / acid reflux than sleeping on one's right side. --Dean ----- [1] J Neurosci. 2015 Aug 5;35(31):11034-44. doi: 10.1523/JNEUROSCI.1625-15.2015. The Effect of Body Posture on Brain Glymphatic Transport. Lee H(1), Xie L(2), Yu M(3), Kang H(2), Feng T(4), Deane R(2), Logan J(5), Nedergaard M(2), Benveniste H(6). full text: http://www.jneurosci.org.sci-hub.io/content/35/31/11034.long The glymphatic pathway expedites clearance of waste, including soluble amyloid β (Aβ) from the brain. Transport through this pathway is controlled by the brain's arousal level because, during sleep or anesthesia, the brain's interstitial space volume expands (compared with wakefulness), resulting in faster waste removal. Humans, as well as animals, exhibit different body postures during sleep, which may also affect waste removal. Therefore, not only the level of consciousness, but also body posture, might affect CSF-interstitial fluid (ISF) exchange efficiency. We used dynamic-contrast-enhanced MRI and kinetic modeling to quantify CSF-ISF exchange rates in anesthetized rodents' brains in supine, prone, or lateral positions. To validate the MRI data and to assess specifically the influence of body posture on clearance of Aβ, we used fluorescence microscopy and radioactive tracers, respectively. The analysis showed that glymphatic transport was most efficient in the lateral position compared with the supine or prone positions. In the prone position, in which the rat's head was in the most upright position (mimicking posture during the awake state), transport was characterized by "retention" of the tracer, slower clearance, and more CSF efflux along larger caliber cervical vessels. The optical imaging and radiotracer studies confirmed that glymphatic transport and Aβ clearance were superior in the lateral and supine positions. We propose that the most popular sleep posture (lateral) has evolved to optimize waste removal during sleep and that posture must be considered in diagnostic imaging procedures developed in the future to assess CSF-ISF transport in humans. SIGNIFICANCE STATEMENT: The rodent brain removes waste better during sleep or anesthesia compared with the awake state. Animals exhibit different body posture during the awake and sleep states, which might affect the brain's waste removal efficiency. We investigated the influence of body posture on brainwide transport of inert tracers of anesthetized rodents. The major finding of our study was that waste, including Aβ, removal was most efficient in the lateral position (compared with the prone position), which mimics the natural resting/sleeping position of rodents. Although our finding awaits testing in humans, we speculate that the lateral position during sleep has advantage with regard to the removal of waste products including Aβ, because clinical studies have shown that sleep drives Aβ clearance from the brain. Copyright © 2015 the authors 0270-6474/15/3511034-11$15.00/0. PMCID: PMC4524974 [Available on 2016-02-05] PMID: 26245965 ------- [2] Rejuvenation Res. 2013 Dec;16(6):518-23. doi: 10.1089/rej.2013.1530. Sleep facilitates clearance of metabolites from the brain: glymphatic function in aging and neurodegenerative diseases. Mendelsohn AR(1), Larrick JW. Author information: (1)Panorama Research Institute and Regenerative Sciences Institute , Sunnyvale, California. Decline of cognition and increasing risk of neurodegenerative diseases are major problems associated with aging in humans. Of particular importance is how the brain removes potentially toxic biomolecules that accumulate with normal neuronal function. Recently, a biomolecule clearance system using convective flow between the cerebrospinal fluid (CSF) and interstitial fluid (ISF) to remove toxic metabolites in the brain was described. Xie and colleagues now report that in mice the clearance activity of this so-called "glymphatic system" is strongly stimulated by sleep and is associated with an increase in interstitial volume, possibly by shrinkage of astroglial cells. Moreover, anesthesia and attenuation of adrenergic signaling can activate the glymphatic system to clear potentially toxic proteins known to contribute to the pathology of Alzheimer disease (AD) such as beta-amyloid (Abeta). Clearance during sleep is as much as two-fold faster than during waking hours. These results support a new hypothesis to answer the age-old question of why sleep is necessary. Glymphatic dysfunction may pay a hitherto unsuspected role in the pathogenesis of neurodegenerative diseases as well as maintenance of cognition. Furthermore, clinical studies suggest that quality and duration of sleep may be predictive of the onset of AD, and that quality sleep may significantly reduce the risk of AD for apolipoprotein E (ApoE) ɛ4 carriers, who have significantly greater chances of developing AD. Further characterization of the glymphatic system in humans may lead to new therapies and methods of prevention of neurodegenerative diseases. A public health initiative to ensure adequate sleep among middle-aged and older people may prove useful in preventing AD, especially in apolipoprotein E (ApoE) ɛ4 carriers. PMID: 24199995
  12. We've known for quite some time that exercise (and CR!) can help stave off the cognitive decline that is often associated with aging. Scientists are now beginning to understand the mechanism underlying this effect. Here is a popular press description: http://www.kurzweilai.net/long-term-aerobic-exercise-prevents-age-related-brain-deterioration of a new paper [1] that helps elucidate the physiological mechanism of brain health preservation via exercise. The authors experimented with mice. They found that with age the support cells in the brain (microglia, astrocytes, etc.) are lost or become dysfunctional, reducing blood flow to neurons, increasing inflammation, etc. This age-related decline and damage was prevented in the mice that exercised (~2 miles per day on a running wheel). But exercise didn't have any positive effect in mice that were completely APOE-deficient. It is interesting that the APOE gene is involved in the beneficial cognitive benefits of exercise, since variants in this gene (i.e. APOE4) are well known to be associated with increased risk of Alzheimer's disease. Exactly what this means for people with APOE gene variants like APOE4 isn't clear, at least to me. Would exercise be somewhat of a waste of time for these people, unable to preserve cognitive health, like in the APOE-deficient mice? Or would exercise be more important for APOE4 carriers, to get the most from their relatively-impaired APOE activity on the brain? --Dean ----------- [1] PLOS Biology, October 29, 2015; DOI: 10.1371/journal.pbio.1002279 (open access) APOE Stabilization by Exercise Prevents Aging Neurovascular Dysfunction and Complement Induction. Ileana Soto, Leah C. Graham, Hannah J. Richter, Stephen N. Simeone, Jake E. Radell, Weronika Grabowska, W. Keith Funkhouser, Megan C. Howell, Gareth R. Howell. Abstract Aging is the major risk factor for neurodegenerative diseases such as Alzheimer's disease, but little is known about the processes that lead to age-related decline of brain structures and function. Here we use RNA-seq in combination with high resolution histological analyses to show that aging leads to a significant deterioration of neurovascular structures including basement membrane reduction, pericyte loss, and astrocyte dysfunction. Neurovascular decline was sufficient to cause vascular leakage and correlated strongly with an increase in neuroinflammation including up-regulation of complement component C1QA in microglia/monocytes. Importantly, long-term aerobic exercise from midlife to old age prevented this age-related neurovascular decline, reduced C1QA+ microglia/monocytes, and increased synaptic plasticity and overall behavioral capabilities of aged mice. Concomitant with age-related neurovascular decline and complement activation, astrocytic Apoe dramatically decreased in aged mice, a decrease that was prevented by exercise. Given the role of APOE in maintaining the neurovascular unit and as an anti-inflammatory molecule, this suggests a possible link between astrocytic Apoe, age-related neurovascular dysfunction and microglia/monocyte activation. To test this, Apoe-deficient mice were exercised from midlife to old age and in contrast to wild-type (Apoe-sufficient) mice, exercise had little to no effect on age-related neurovascular decline or microglia/monocyte activation in the absence of APOE. Collectively, our data shows that neurovascular structures decline with age, a process that we propose to be intimately linked to complement activation in microglia/monocytes. Exercise prevents these changes, but not in the absence of APOE, opening up new avenues for understanding the complex interactions between neurovascular and neuroinflammatory responses in aging and neurodegenerative diseases such as Alzheimer’s disease. Author Summary Aging is frequently accompanied with frailty and cognitive decline. In recent years, increasing evidence has linked physical inactivity with the development of dementias such as Alzheimer’s disease. In fact, it is recognized that exercise combats frailty and cognitive decline in older adults, but the biological mechanisms involved are not completely known. Understanding the biological changes that trigger cognitive deterioration during aging and the mechanisms by which exercise improves health and brain function is key to ensuring the quality of life of the elderly population and to reducing risk of dementias such as Alzheimer’s disease. Here, we show that the cerebrovascular system in mice significantly deteriorates with age, and the structure and function of the blood brain barrier is progressively compromised. These age-related neurovascular changes are accompanied by neuroinflammation and deficits in common and spontaneous behaviors in mice. We found, however, that exercise from middle to older age preserves the cerebrovascular health, prevents behavioral deficits and reduces the age-related neuroinflammation in the cortex and hippocampus in aged mice. Mice deficient in Apoe, a gene associated with longevity and Alzheimer’s disease, are resistant to the beneficial effects of exercise, suggesting a possible mediating role for APOE in the maintenance and function of the neurovascular system during aging.
  13. Dean Pomerleau

    Sleep Disturbances & Alzheimer's Disease

    Disturbed sleep patterns are known to be associated with cognitive impairment and Alzheimer's disease. But it isn't entirely clear whether Alzheimer's disease is caused by sleep disturbances or the other way around. This popular press article: http://www.kurzweilai.net/sleep-disruptions-similar-to-jet-lag-linked-to-memory-and-learning-problems on a new study [1] in mice helps to shed some light on the issue. They disrupted the sleep of both normal mice and mice breed to exhibit a mice-model of Alzheimer's disease by altering the day/night pattern of light they were exposed to every three days to simulate jet lag. They found the cognition (Morris water maze performance) of both types of mice were impaired by the disturbed sleep schedule. The impairment to learning was more pronounced in the Alzheimer's mice, and that the degree of impairment was proportional to the reduction of the endogenous antioxidant glutathione (GSH) in the brains of the mice, with Alzheimer's mice showing a greater reduction in GSH than the normal mice. This would seem to emphasize the importance of maintaining good sleep patterns in order to avoid cognitive decline and Alzheimer's disease with aging. --Dean --------- [1] Journal of Alzheimer's Disease, vol. Preprint, no. Preprint, pp. 1-16, 2015; DOI: 10.3233/JAD-150026 Circadian Disruption Reveals a Correlation of an Oxidative GSH/GSSG Redox Shift with Learning and Impaired Memory in an Alzheimer’s Disease Mouse Model. LeVault, Kelsey, Tischkau, Shelley, Brewer, Gregory. It is unclear whether pre-symptomatic Alzheimer’s disease (AD) causes circadian disruption or whether circadian disruption accelerates AD pathogenesis. In order to examine the sensitivity of learning and memory to circadian disruption, we altered normal lighting phases by an 8 h shortening of the dark period every 3 days (jet lag) in the APPSwDI NOS2–/– model of AD (AD-Tg) at a young age (4-5 months), when memory is not yet affected compared to non-transgenic (non-Tg) mice. Analysis of activity in 12-12 h lighting or constant darkness showed only minor differences between AD-Tg and non-Tg mice. Jet lag greatly reduced activity in both genotypes during the normal dark time. Learning on the Morris water maze was significantly impaired only in the AD-Tg mice exposed to jet lag. However, memory 3 days after training was impaired in both genotypes. Jet lag caused a decrease of glutathione (GSH) levels that tended to be more pronounced in AD-Tg than in non-Tg brains and an associated increase in NADH levels in both genotypes. Lower brain GSH levels after jet lag correlated with poor performance on the maze. These data indicate that the combination of the environmental stress of circadian disruption together with latent stress of the mutant amyloid and NOS2 knockout contributes to cognitive deficits that correlate with lower GSH levels.
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