{"602586":{"#nid":"602586","#data":{"type":"news","title":"Data Detectives Shift Suspicions in Alzheimer\u0027s from Usual Suspect to Inside Villain","body":[{"value":"\u003Cp\u003EThe mass pursuit of a conspicuous suspect in Alzheimer\u0026rsquo;s disease may have held back research success for decades. Now, a \u003Ca href=\u0022https:\/\/content.iospress.com\/articles\/journal-of-alzheimers-disease\/jad170490?resultNumber=0\u0026amp;totalResults=315\u0026amp;start=0\u0026amp;q=mitchell%2C+cassie+s.\u0026amp;dc_issued_year=2017\u0026amp;resultsPageSize=10\u0026amp;rows=10\u0022 target=\u0022_blank\u0022\u003Enew data analysis\u003C\/a\u003E that has untangled evidence amassed in years of Alzheimer\u0026rsquo;s studies encourages researchers to refocus their investigations.\u003C\/p\u003E\r\n\r\n\u003Cp\u003EHeaps of plaque formed from amyloid-beta that accumulate in afflicted brains are what stick out under the microscope in tissue samples from \u003Ca href=\u0022https:\/\/www.nia.nih.gov\/health\/alzheimers-disease-fact-sheet\u0022 target=\u0022_blank\u0022\u003EAlzheimer\u0026rsquo;s\u003C\/a\u003E sufferers, and that eye-catching junk has long seemed an obvious culprit in the disease. But\u0026nbsp;data analysis of the cumulative evidence doesn\u0026rsquo;t support giving so much attention to that usual suspect, according to a \u003Ca href=\u0022https:\/\/content.iospress.com\/articles\/journal-of-alzheimers-disease\/jad170490?resultNumber=0\u0026amp;totalResults=315\u0026amp;start=0\u0026amp;q=mitchell%2C+cassie+s.\u0026amp;dc_issued_year=2017\u0026amp;resultsPageSize=10\u0026amp;rows=10\u0022 target=\u0022_blank\u0022\u003Enew study from the Georgia Institute of Technology\u003C\/a\u003E.\u003C\/p\u003E\r\n\r\n\u003Cp\u003EThough the bad amyloid-beta protein does appear to be an accomplice in the disease, the study has pointed to a seemingly more likely red-handed offender, another protein-gone-bad called phosphorylated \u003Ca href=\u0022https:\/\/en.wikipedia.org\/wiki\/Tau_protein\u0022 target=\u0022_blank\u0022\u003Etau\u003C\/a\u003E (p-tau). What\u0026rsquo;s more, the Georgia Tech data analysis of multiple studies done on mice also turned up signs that multiple biochemical actors work together in Alzheimer\u0026rsquo;s to tear down neurons, the cells that the brain uses to do its work.\u003C\/p\u003E\r\n\r\n\u003Ch4\u003E\u003Cstrong\u003ESuspect line-up: P-tau implicated, plaque not so much\u003C\/strong\u003E\u003C\/h4\u003E\r\n\r\n\u003Cp\u003EAnd the corrupted amyloid-beta that appeared more directly in cahoots with p-tau in the sabotage of brain function was not tied up in that plaque. In the line-up of the biochemical suspects examined, principal investigator \u003Ca href=\u0022https:\/\/bme.gatech.edu\/bme\/faculty\/Cassie-S.-Mitchell\u0022 target=\u0022_blank\u0022\u003ECassie Mitchell, an assistant professor in the Wallace H. Coulter Department of Biomedical Engineering\u003C\/a\u003E at Georgia Tech and Emory University, said the data pointed to a pecking order of culpability.\u003C\/p\u003E\r\n\r\n\u003Cp\u003E\u0026ldquo;The most important one would be the level of phosphorylated tau present. It had the strongest connection with cognitive decline,\u0026rdquo; Mitchell said. \u0026ldquo;The correlation with \u003Ca href=\u0022https:\/\/www.alz.org\/braintour\/plaques.asp\u0022 target=\u0022_blank\u0022\u003Eamyloid\u003C\/a\u003E\u003Ca href=\u0022https:\/\/www.alz.org\/braintour\/plaques.asp\u0022 target=\u0022_blank\u0022\u003E plaque\u003C\/a\u003E was there but very weak; not nearly as strong as the correlation between p-tau and cognitive decline.\u0026rdquo;\u003C\/p\u003E\r\n\r\n\u003Cp\u003EMitchell, a biomedical informaticist, and first author Colin Huber statistically analyzed data gleaned from 51 existing lab studies in mice genetically augmented with a human form of Alzheimer\u0026rsquo;s. They published their analysis \u003Ca href=\u0022https:\/\/content.iospress.com\/articles\/journal-of-alzheimers-disease\/jad170490?resultNumber=0\u0026amp;totalResults=315\u0026amp;start=0\u0026amp;q=mitchell%2C+cassie+s.\u0026amp;dc_issued_year=2017\u0026amp;resultsPageSize=10\u0026amp;rows=10\u0022 target=\u0022_blank\u0022\u003Ein the current edition of the \u003Cem\u003EJournal of Alzheimer\u0026rsquo;s Disease\u003C\/em\u003E\u003C\/a\u003E. The research was funded by the National Institutes of Health.\u003C\/p\u003E\r\n\r\n\u003Ch4\u003E\u003Cstrong\u003EThe crime: Eviscerating the brain\u003C\/strong\u003E\u003C\/h4\u003E\r\n\r\n\u003Cp\u003EOne look at an image of an Alzheimer\u0026rsquo;s afflicted brain is unflinching testimony to the disease\u0026rsquo;s cruelty: It \u003Ca href=\u0022https:\/\/www.nia.nih.gov\/health\/alzheimers-disease-fact-sheet#changes\u0022 target=\u0022_blank\u0022\u003Edestroys of up to 30 percent of a brain\u0026rsquo;s mass\u003C\/a\u003E, carving out ravines and depositing piles of molecular junk, most visibly amyloid plaque.\u003C\/p\u003E\r\n\r\n\u003Cp\u003EThe plaque builds up outside of neurons, while inside neurons, p-tau forms similar junk known as \u003Ca href=\u0022https:\/\/en.wikipedia.org\/wiki\/Neurofibrillary_tangle\u0022 target=\u0022_blank\u0022\u003Eneurofibrillary tangles\u003C\/a\u003E that many researchers believe push the cells to their demise. But many biochemical machinations behind Alzheimer\u0026rsquo;s are still unknown, and the fight to uncover them has vexed researchers for decades.\u003C\/p\u003E\r\n\r\n\u003Cp\u003ESince the \u003Ca href=\u0022http:\/\/www.bbc.com\/news\/av\/magazine-35279750\/the-world-s-forgotten-first-alzheimer-s-patient\u0022 target=\u0022_blank\u0022\u003Efirst patient was diagnosed by Dr. Aloysius Alzheimer between 1901 and 1906\u003C\/a\u003E, little medical progress has been made. Though some available medications may mitigate symptoms somewhat, none significantly slow disease progression, let alone stop it.\u003C\/p\u003E\r\n\r\n\u003Cp\u003EAlzheimer\u0026rsquo;s mostly strikes late in life. Longer lifespans in industrialized countries have ballooned the caseload, advancing the disease to a major cause of death.\u003C\/p\u003E\r\n\r\n\u003Ch4\u003E\u003Cstrong\u003EMeet the syndicate: Assassin, accomplices, stooges\u003C\/strong\u003E\u003C\/h4\u003E\r\n\r\n\u003Cp\u003EEven though p-tau showed the strongest correlation with cognitive decline, and amyloid-beta only a slight correlation, that doesn\u0026rsquo;t mean that p-tau is committing the crime inside cells all by itself while amyloid loiters in spaces outside of cells in large gangs, creating a distraction. Mitchell\u0026rsquo;s data analysis has pointed to dynamics more enmeshed than that.\u003C\/p\u003E\r\n\r\n\u003Cp\u003E\u0026ldquo;Though the study had clear trends, it also had a good bit of variance that would indicate multiple factors influencing outcomes,\u0026rdquo; Mitchell said. And a particular manifestation of amyloid-beta has piqued the researchers\u0026rsquo; ire.\u003C\/p\u003E\r\n\r\n\u003Cp\u003ELittle pieces are water soluble, that is, not tied up in clumps of plaque. The data has shown that these tiny amyloids may be up to no good. After p-tau levels, the study revealed that those of soluble amyloid-beta had the second-strongest correlation with cognitive decline.\u003C\/p\u003E\r\n\r\n\u003Cp\u003E\u0026ldquo;Lumpy amyloid-beta, the stuff we see, ironically doesn\u0026rsquo;t correlate as well\u0026nbsp;with cognitive decline as the soluble amyloid,\u0026rdquo; Mitchell said. \u0026ldquo;The amyloid you don\u0026rsquo;t see is like the sugar in your tea that dissolves and hits your taste buds versus the insoluble amyloid, which is more like the sugar that doesn\u0026rsquo;t dissolve and stays at the bottom of the cup.\u0026rdquo;\u003C\/p\u003E\r\n\r\n\u003Cp\u003ESome Alzheimer\u0026rsquo;s researchers have cited evidence indicating that free-floating amyloid helps produce the corrupted p-tau via a chain of reactions that centers around \u003Ca href=\u0022https:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC4340754\/\u0022 target=\u0022_blank\u0022\u003EGSK3 \u003C\/a\u003E(Glycogen synthase kinase 3), an enzyme that arms tau with phosphorous, turning it into a potential biochemical assassin.\u003C\/p\u003E\r\n\r\n\u003Cp\u003EIncidentally, Mitchell\u0026rsquo;s study also looked at un-phosphorylated tau and found its levels do not correlate with cognitive decline. \u0026ldquo;That makes sense,\u0026rdquo; Mitchell said. \u0026ldquo;Regular tau is the backbone of our neurons, so it has to be there.\u0026rdquo;\u003C\/p\u003E\r\n\r\n\u003Cp\u003EAlso, p-tau is a normal part of healthy cells, but in Alzheimer\u0026rsquo;s it is wildly overproduced.\u003C\/p\u003E\r\n\r\n\u003Ch4\u003E\u003Cstrong\u003EMassive dataset: 528 mice rat out p-tau\u003C\/strong\u003E\u003C\/h4\u003E\r\n\r\n\u003Cp\u003EOne advantage of \u003Ca href=\u0022http:\/\/searchsqlserver.techtarget.com\/definition\/data-mining\u0022 target=\u0022_blank\u0022\u003Edata mining\u003C\/a\u003E 51 existing studies versus doing one new lab experiment, is that the cumulative analysis adds the sample sizes of so many studies together for a whopping grand total. Mitchell\u0026rsquo;s analysis encompassed results from past experiments carried out on, all totaled, 528 Alzheimer\u0026rsquo;s mice.\u003C\/p\u003E\r\n\r\n\u003Cp\u003EA previous study Mitchell led had already indicated that amyloid-beta plaque levels may not be the most productive target for drug development. Separate reports by other researchers on failed human trials of drugs that fought plaque would seem to corroborate this.\u003C\/p\u003E\r\n\r\n\u003Cp\u003EMitchell\u0026rsquo;s prior analysis examined lab studies that used an Alzheimer\u0026rsquo;s lab mouse model that did not allow for the study of p-tau. Mitchell\u0026rsquo;s current analysis covered studies involving a different mouse model that did allow for the observation of p-tau.\u003C\/p\u003E\r\n\r\n\u003Cp\u003EMitchell\u0026rsquo;s latest findings have corroborated the prior study\u0026rsquo;s findings on amyloid, and also added p-tau as a key suspect in cognitive decline.\u003C\/p\u003E\r\n\r\n\u003Ch4\u003E\u003Cstrong\u003EPrincipal investigator: My take on possible treatments\u003C\/strong\u003E\u003C\/h4\u003E\r\n\r\n\u003Cp\u003ETo arrive at the 51 studies with data suitable for inclusion in their analysis, Mitchell\u0026rsquo;s research team sifted through hundreds of Alzheimer\u0026rsquo;s research papers, and over time, Mitchell has examined a few thousand herself. She has gained some impressions of how biomedical research may need to tackle the disease\u0026rsquo;s slippery biochemical labyrinth.\u003C\/p\u003E\r\n\r\n\u003Cp\u003E\u0026ldquo;When we see multifactorial diseases, we tend to think we\u0026rsquo;ll need multifactorial treatments,\u0026rdquo; Mitchell said. \u0026ldquo;That seems to be working well with cancer, where they combine chemotherapy with things like immunotherapy.\u0026rdquo;\u003C\/p\u003E\r\n\r\n\u003Cp\u003EAlso, Alzheimer\u0026rsquo;s diagnosticians might be wise to their adopt cancer colleagues\u0026rsquo; early detection stance, she said, as Alzheimer\u0026rsquo;s disease appears to start long before amyloid-beta plaque appears and cognitive decline sets in.\u003C\/p\u003E\r\n\r\n\u003Cp\u003EAbove all, basic research should cast a broader net.\u003C\/p\u003E\r\n\r\n\u003Cp\u003E\u0026ldquo;I think p-tau is going to have to be a big part,\u0026rdquo; she said. \u0026ldquo;And it may be time to not latch onto amyloid-beta plaque so much like the field has for a few decades.\u0026rdquo;\u003C\/p\u003E\r\n\r\n\u003Cp\u003E\u003Cstrong\u003EDid you know? Cassie Mitchell is also an Olympic medalist!\u003C\/strong\u003E \u003Ca href=\u0022https:\/\/www.youtube.com\/watch?v=oMgsyToEghg\u0022 target=\u0022_blank\u0022\u003EWatch her video here\u003C\/a\u003E.\u003C\/p\u003E\r\n\r\n\u003Cp\u003E\u003Ca href=\u0022http:\/\/www.rh.gatech.edu\/features\/alzheimers-killing-mind-first\u0022 target=\u0022_blank\u0022\u003EAlso READ: Our feature on Alzheimer\u0026rsquo;s research\u003C\/a\u003E \u0026ndash; \u003Ca href=\u0022http:\/\/www.rh.gatech.edu\/features\/alzheimers-killing-mind-first\u0022 target=\u0022_blank\u0022\u003EKilling the Mind First\u003C\/a\u003E\u003C\/p\u003E\r\n\r\n\u003Cp\u003ELike this article?\u0026nbsp;\u003Ca href=\u0022http:\/\/www.rh.gatech.edu\/subscribe\u0022 target=\u0022_blank\u0022\u003EGet our email newsletter here.\u003C\/a\u003E\u003C\/p\u003E\r\n\r\n\u003Cp\u003E\u003Cem\u003EGeorgia Tech\u0026rsquo;s Connor Yee, Taylor May, and Apoorva Dhanala coauthored the study. Funding was provided by the National Institute of Neurological Disorders and Stroke at the National Institutes of Health (grants NS069616, NS098228, and NS081426). Any findings or conclusions are those of the authors and not necessarily of the sponsor.\u003C\/em\u003E\u003C\/p\u003E\r\n","summary":null,"format":"limited_html"}],"field_subtitle":"","field_summary":[{"value":"\u003Cp\u003EThe pursuit of the usual suspect in Alzheimer\u0026#39;s research may be distracting from a more direct culprit in the disease, according to a study that analyzed data from 51 published experiments. P-tau looked a good bit more culpable than amyloid-beta plaque.\u003C\/p\u003E\r\n","format":"limited_html"}],"field_summary_sentence":[{"value":"It may be high time to refocus Alzheimer\u0027s research, as a new study strongly points to a biochemical culprit traditionally less pursued."}],"uid":"31759","created_gmt":"2018-02-19 16:34:18","changed_gmt":"2018-03-21 03:30:31","author":"Ben Brumfield","boilerplate_text":"","field_publication":"","field_article_url":"","dateline":{"date":"2018-02-19T00:00:00-05:00","iso_date":"2018-02-19T00:00:00-05:00","tz":"America\/New_York"},"extras":[],"hg_media":{"602578":{"id":"602578","type":"image","title":"Alzheimer\u0027s brain shrinkage illustration NIA NIH","body":null,"created":"1519056525","gmt_created":"2018-02-19 16:08:45","changed":"1519056574","gmt_changed":"2018-02-19 16:09:34","alt":"","file":{"fid":"229667","name":"brain shrink 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