Las Vegas: New Partner, New Game Plan for Lou Ruvo Brain Institute
Relationships forged amidst the glitz and glamour of Las Vegas have a reputation for ending badly. The one between the University of Nevada, Reno (UNR), and the Lou Ruvo Brain Institute (LRBI) was apparently no exception. LRBI, the brainchild of Las Vegas businessman Larry Ruvo, was conceived as a state-of-the-art research center drawing the field’s leading experts for the study of Alzheimer’s, Parkinson’s, Huntington’s, and other neurologic disorders. The University was on board as a partner early on in the venture, and even received state funding to help defray the costs of running clinical operations at the institute, said Zaven Khachaturian, who was then president of LRBI. But as the building designed by star architect Frank Gehry was taking shape in downtown Las Vegas, UNR was taking steps in the other direction, and the deal eventually fell apart (see related Las Vegas Sun news). Enter the Cleveland Clinic. In February this year, Larry Ruvo and Toby Cosgrove, CEO of the Cleveland Clinic, struck a deal. It will see the Midwest health care provider gain a foothold in the southwest and also propel itself into the realm of Alzheimer’s and other neurodegenerative diseases, currently not one of the Clinic’s strong suits.
The Cleveland Clinic has been thinking about investing in the brain and cognition for the last 20 years, according to Randy Schiffer, Chief Medical Director of what is now called the Cleveland Clinic Lou Ruvo Center for Brain Health. “As Dr. Cosgrove has said, ‘in the twentieth century the Cleveland Clinic led cardiovascular disease developments. In the twenty-first century, the brain, and especially cognition, will be our arena,’” Schiffer said.
Schiffer was chairman of neurology and psychiatry at Texas Tech, Lubbock, for 10 years. He had been recruited by the Cleveland Clinic to establish a medical program for cognitive disorders in January 2009, just before the clinic’s deal with the Lou Ruvo Brain Institute came together. He found his stint in Ohio to be short-lived, noting that he didn’t really move to Cleveland but more through it, and on out to Nevada. “Though the Center for Brain Health is throughout the Cleveland Clinic Enterprise system, and long-term the science and infrastructure will be in Cleveland, over the next couple of years the growth and opportunities will be here in Las Vegas,” Schiffer told ARF.
So what does the Cleveland Clinic deal mean for the Lou Ruvo Brain Institute? “Originally, the plan was to create a different model for how care is provided and also try to make the center a new model for collaborative research,” said Khachaturian, president emeritus of LRBI and CEO of Keep Memory Alive, the foundation set up to support the institute. “Right now, and I’m assuming until the building is paid for, the focus will be on setting up clinical operations and running the clinic.” What does this mean for cutting-edge AD research? Though sources were unwilling to go on the record, the sense leading AD researchers expressed privately was that at least in the near future, it means that there won’t be any.
“We are building a center of excellence, both in Cleveland and here, that will be dedicated to cognition,” Schiffer claimed. He envisages treating all the cognitive disorders, including Alzheimer’s and mild cognitive impairment, which will account for about half of the center’s operations. “We are first going to make a high-volume, high-quality, patient-care system that will be branded with the same kind of procedures here as in Cleveland, and long term at other sites.” (The clinical has plans for a center in Reno, Nevada, and potentially in Weston, Florida.)
A clinic for routine care of neurodegenerative disorders is a pressing need in Nevada, particularly the southern part of the state. Four hundred forty miles north of Las Vegas, the University of Nevada, Reno, does have a program. “Patients were waiting anywhere from a few months to six months to see a neurologist,” said Khachaturian. That has changed. The Cleveland Clinic’s Las Vegas center has brought in some neurologists, including Charlie Bernick, who had been running the UNR program, and the number of patients that are going through has increased substantially since the clinic opened its doors July 13. The clinic is now receiving 25-30 new patients per week, Schiffer said.
Attendees of the Clinical Trials on Alzheimer’s Disease meeting, held 29-30 October 2009 in Las Vegas, were treated to a tour of the new facility. The building is almost complete. To the admittedly architecturally unskilled eye of a reporter, its front side evokes the notion of an uncoordinated giant having played with a stack of house-sized Legos. At the back is the large atrium, draped with a convoluted steel lattice, which has become the iconic face of the center; it is still under construction. That atrium will serve as a hub of sorts, a space for people to congregate by day and a venue for educational outreach and philanthropic activities by night. On the clinic side of the building, the center is equipped with a state-of-the art 3 Tesla MRI machine, which takes faster brain images and is less claustrophobic than smaller machines—advantages when imaging patients who are susceptible to agitation and disorientation. The images are handed off to a team of neurologists in Cleveland who interpret the results. Patients don’t wait when entering the center. They are greeted by chaperones, many of them volunteers, and led straight to the examination room. This is partly to spare early-stage or MCI patients the discomfort of being in a waiting room with end-stage patients, said Schiffer, adding “That’s because we don’t want them to get to that stage.” (To date, there is no cure for AD; all patients progress to an advanced stage or die of other causes before.)
Model of the completed Lou Ruvo Center. Image credit: Keep Memory Alive
Wes Ashford of Stanford University, California, who took the tour, thought the program, with its heavy reliance of support staff, was similar in scope to those at other clinics, including the Stanford/VA Alzheimer’s Center. “The big problem with such programs is that they really are not cost-effective unless supported in some unconventional way,” he said.
As for research, Schiffer said he does have plans to get involved. “I believe we need new ideas in Alzheimer’s disease, I think we need novel approaches, such as non-amyloid interventions,” he said. “I’m only doing this because of the hope that we can, in effect, set up something here that will materially contribute to changing the course of Alzheimer’s disease.” The center has two NIH grants, one to develop a biomarker and the other to conduct a clinical trial. Schiffer was coy about future research plans but said he was interested in ideas that are even too creative for the NIH. He would not elaborate further. It seems that in Vegas, not only poker players hold their cards close to the chest.—Tom Fagan.
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Las Vegas: AD, Risk, ApoE—Tomm40 No Tomfoolery
Though the ApoE4 variant is the strongest genetic risk factor for late-onset Alzheimer disease, it offers no definitive test. Some people who inherited ApoE4 alleles never get AD, while others without ApoE4 do. Partly for this reason, consensus recommendations have generally discouraged genetic testing for ApoE outside research settings. Could the diagnostic potential of this genetic marker be improved? Enter Tomm40, aka translocase of the outer mitochondrial membrane 40. This gene lies in close proximity to, and is in linkage disequilibrium (read co-inherited) with, ApoE. Allen Roses, who originally identified ApoE as a genetic risk factor for AD, made a case for this gene at the Leon Thal Symposium on 28 October, and again in a panel discussion on biomarker validation at a Clinical Trials on Alzheimer’s Disease (CTAD) meeting held 29-30 October 2009, both in Las Vegas, Nevada. Roses, who left GSK to return to Duke University, Durham, North Carolina, had initially presented the data at ICAD in Vienna (see ARF related news story).
Variation in the length of a poly T section within intron 6 of Tomm40 can improve the prediction of when a given person will likely develop AD, Roses claimed. “Basically you can take anyone who is ApoE3/3, 3/4, or 4/4, who make up 85 percent of AD cases, and we can assess their risk [of AD], based on genotype, for the next 5-7 years,” Roses told ARF.
Roses said that in consultation with the FDA, he has devised a clinical trial that will not only validate whether Tomm40 analysis can predict age of onset of AD, but based on that analysis also stratify subjects for therapeutic intervention to delay onset. Steve Ferris, New York University, was at the CTAD meeting and said that he liked the trial design. “It’s a tremendous shortcut to combine risk prediction with age of onset, and combine that with a clinical trial of treatment,” he said. The trial is planned to begin enrolling at Duke, a site in Russia, and two sites in Australia next year.
Roses’s Tomm40 analysis relies on phylogenetics, which is usually the study of evolutionary relationships between different species, genera, and even phyla (hence the name). Roses and colleagues used this analysis to construct a family tree of a 10 Kb sequence of DNA within the ApoE/Tomm40 region of chromosome 19. Over the course of human evolution, multiple mutations have occurred at this locus, some on DNA strands carrying ApoE4 and some linked to ApoE3. The analysis can determine which mutations in the region came first (the base of the tree) and which ones came later (the branches). It turns out that the tree’s branches, or clades in phylogenetic parlance, can be separated into several major groups based on the length of the poly T variation. Because these mutations are in linkage disequilibrium with the ApoE allele, some of the poly T variants are more often associated with ApoE3 and some with ApoE4. The evolutionary history of this region of DNA is, in fact, more complex, with some mutations occurring more than once, sometimes on strands carrying ApoE3 and sometimes linked to ApoE4.
Nevertheless, the phylogenetic analysis shows one branch point in the history of this region of DNA that results in two major clades, one carrying long forms of the Tomm40 poly T mutation (19-36 T) and one carrying short forms (14-16 T). While ApoE4 is predominantly (98 percent of the time) associated with the long forms, ApoE3 can be linked to either short or long poly Ts. Essentially, anyone who has an ApoE3/4 genotype has one long Tomm40 poly T (on the ApoE4 strand) and either a short or long poly T on the ApoE3 strand.
How, then, does this relate to Alzheimer disease? “We looked at the age of onset in patients, most of whom had autopsy-proven Alzheimer disease, who were ApoE3/4. All the long/long Tomm40 variants came out the same as ApoE4/ApoE4 data previously, with average age of onset of about 70. But when we looked at the short/longs—short attached to ApoE3 and long attached to ApoE4—age of onset came out to 78,” said Roses. In essence, the length of the Tomm40 poly T variants determines age of onset in ApoE3/4 individuals. If replicated, the eight-year difference would be dramatic, given the suggestion that the incidence of AD could be halved if the age of onset were pushed out by five years. The number of people with AD is slated to reach 115 million worldwide by 2050 if present trends continue (see World Alzheimer Report [.pdf]). Roses cautioned that the phylogenetic data applied only to Caucasians and that other ethnic groups may have a different Tomm40/ApoE evolutionary history.
The situation gets more complex when a person is ApoE3/3 because the Tomm40 poly T possibilities are threefold; short/short, short/long, or long/long. “When we look at [ApoE3/3s] we see age-of-onset curves that cover the whole spectrum from about age 55 through 90,” said Roses. Within that spectrum, Tomm40 creates a pattern, however. People who are ApoE3/3 and have two very long copies of the poly T repeat may have an earlier age of onset, before age 70. “And when we looked at a small group of patients who have Alzheimer disease that began in their fifties, several of those are not just ApoE4/4. There were also ApoE3/3 and ApoE3/4 patients, with a high frequency of ApoE3 with a very long Tomm40,” said Roses. The data help explain why some people with ApoE3/3 are at higher risk for AD. It may also explain why some people who are ApoE4/4 are spared. In their study sample of 255 people, Roses and colleagues found two rare cases who carried ApoE4/4 but were heterogeneous for the Tomm40 poly T, having one short and one long form. Both those individuals had a recorded age of onset of 78, said Roses, which equals that of people who possess an ApoE3/short;ApoE4/long genotype. The data are slated for publication in November in The Parmacogenomics Journal.
“It remains to be seen whether or not Tomm40 turns out to be a true association with age at onset or not, or just linked to ApoE4,” said Rachelle Doody, Baylor College of Medicine, Houston, Texas. “But meanwhile, it is an intriguing hypothesis that Alzheimer’s might somehow be related to the transport of proteins across the mitochondrial membrane,” she added. Doody has worked with Medivation Inc., a company that sponsors clinical and preclinical studies of Dimebon, which showed some benefit in AD patients and is purported to have a mitochondrial mechanism of action (see ARF related news story). “Medivation has been saying for some time that the mitochondrial permeability transition pore and flux of Aβ across the mitochondrial membrane might be part of the physiology of the disease,” said Doody. “So Tomm40 is another little convergent piece of data that hasn’t been replicated yet.”
The Tomm40 phylogenetic data address the fundamental question of which polymorphisms on the ApoE stretch of DNA are actually contributing to the risk for AD. Some studies, especially genomewide association studies (GWAS), do not sequence entire regions of DNA but instead rely on single nucleotide polymorphisms, or tag SNPs (see ARF related news story) that lie nearby. In the case of ApoE, the DNA chips that are used to simultaneously measure ~1,000,000 polymorphisms in GWAS studies are actually not measuring ApoE directly, but are measuring the nearby Tomm40 and ApoC1 genes, because that is where the tag SNPs lie. In fact, recent GWAS analysis turned up three new potential risk genes for Alzheimer disease, each with statistical p values of around 10-8 to 10-7 (see ARF related news story). People made a big deal about those, but not about several SNPs in the Tomm40 region with extraordinarily high p values, one of 10-157, said Roses. “They ignored it because they thought it was explained by ApoE, but ApoE wasn’t even on the chips they were measuring.” Roses and colleagues originally found the Tomm40 polymorphisms by deep-sequencing the locus on chromosome 19, rather than relying on detection by DNA chips. “We found that the p value really depended on the allele frequency differences. No matter how we analyzed it, ApoE could not account for the p values we had,” he told ARF. That’s when they dug deeper and found the poly T mutations.
Roses, who —would you guess?—is partial to red wine, has set up two virtual companies to commercialize research and development of this data. Shiraz Pharmaceuticals Inc. will manage intellectual property derived from the Tomm40 discovery, while Zinfandel Pharmaceuticals Inc. will carry out risk validation. That would be a five-year study, noted Roses. Because he does not want to wait for validation of the Tomm40 test before running a prevention trial, he worked with the FDA on a Voluntary Exploratory Data Submission to approve a simultaneous validation/prevention study. “On October 7 we got our answer and it was consistent with one of the scenarios we discussed” he said (see Opportunity for Prevention of Alzheimer’s study, or OPAL).
If it turns out that the length of the Tomm40 poly T does have a dramatic impact on age of onset, then that could call into question all previous studies that have stratified analysis based on ApoE4, suggested Lon Schneider of University of Southern California, Los Angeles. “From a pragmatic clinical level, this work suggests that the wrong Tomm40 polymorph raises the risk level of ApoE3s to the same level as 4s. This implies that all past research comparing E4s to E3s is muddied because it's like comparing E4s to a mixed group in which about half have the same risk as E4 carriers and half have a lower risk,” Schneider told ARF. He added that he hopes prior studies saved DNA samples.
When nudged at CTAD to say what treatment might be used for the intervention part of the OPAL study, Roses hinted that it may be a PPAR-γ agonist, such as rosiglitazone. There is evidence that PPAR-γ agonists can improve mitochondrial function (see Wu et al., 2009), increase neuronal spine density (see ARF related news story), protect neurons and synapses against amyloid-β (see ARF related news story), and improve learning and memory in mouse models of AD (see Escribano et al., 2009). The drug also has a good safety profile. “If you are going to give a drug to normal people to prevent something, the FDA would like it to be the safest possible drug,” said Roses.
However, several Phase 3 clinical trials of rosiglitazone in AD conducted by GlaxoSmithKline (see ARF related news story) showed no significant effects by E4 or E3 status. “Perhaps GSK should genotype the saved DNA for Tomm40 polymorphs and reanalyze the efficacy outcomes based on both ApoE and Tomm40 status,” Schneider suggested. Roses said the company had turned down a request to this effect. For her part, Doody questioned the value of such post-hoc analysis. “If Tomm40 does get replicated and proven, then it will be of interest as a potential modifier, but that would not automatically lead to subgroups in clinical trials because age at onset isn’t the factor of importance. It is whether you have the disease and whether you can be treated with the agent,” she said.—Tom Fagan.
- Vienna: In Genetics, Bigger Is Better—Data Sharing Nets Three New Hits
- Dimebon: Bright Star or Black Hole?
- Charting Genetic Diversity—First Haplotype Map Appears
- Insulin, Insulin-like Signaling and Neurodegeneration—Is Resistance Futile?
- Peptide Brace Against AD—Insulin, Neuropeptide Y Tame Aβ Toxicity
- Outlook for PPARγ Agonists Not So Rosi
- Wu JS, Lin TN, Wu KK. Rosiglitazone and PPAR-gamma overexpression protect mitochondrial membrane potential and prevent apoptosis by upregulating anti-apoptotic Bcl-2 family proteins. J Cell Physiol. 2009 Jul;220(1):58-71. PubMed.
- Escribano L, Simón AM, Pérez-Mediavilla A, Salazar-Colocho P, Del Río J, Frechilla D. Rosiglitazone reverses memory decline and hippocampal glucocorticoid receptor down-regulation in an Alzheimer's disease mouse model. Biochem Biophys Res Commun. 2009 Feb 6;379(2):406-10. PubMed.
- Vienna: In Genetics, Bigger Is Better—Data Sharing Nets Three New Hits
- Dimebon: Bright Star or Black Hole?
- Charting Genetic Diversity—First Haplotype Map Appears
- Insulin, Insulin-like Signaling and Neurodegeneration—Is Resistance Futile?
- Peptide Brace Against AD—Insulin, Neuropeptide Y Tame Aβ Toxicity
- Outlook for PPARγ Agonists Not So Rosi
- Las Vegas: New Partner, New Game Plan for Lou Ruvo Brain Institute
Las Vegas: Prevention Prominent at CTAD
At the second annual Clinical Trials on Alzheimer’s Disease meeting, 29-30 October 2009 in Las Vegas, prevention—how, when, with what interventions—dominated the discussions. Everyone seems for it in principle, but views diverged from there. Here are some of the main points.
Proving that prevention can work is going to require lengthy and large-scale clinical trials, and but one challenge for such trials will be figuring out whom to include. One option—to study only people who are highly susceptible to AD—raises the question of how to identify such high-risk groups. Speakers offered several suggestions for screening tools, ranging from bio- and genetic markers to memory testing to non-invasive techniques such as a risk index.
ApoE4 to date is the strongest genetic risk factors for late-onset Alzheimer disease, but it is not predictive. The recent discovery of polymorphisms in the Tomm40 gene that lies near ApoE on chromosome 19 might eventually fine-tune the predictive power of ApoE genotyping (see ARF related CTAD news). A different approach to genetic risk is to study adult children of affected individuals. Mark Sager, University of Wisconsin, Madison, described the Wisconsin Registry for Alzheimer’s Prevention. WRAP is following middle-aged people who have at least one parent with AD. Begun 8 years ago, WRAP has recruited participants from all over the country. They are highly motivated, Sager noted, adding that that WRAP has been overwhelmed with volunteers and experienced little attrition. WRAP tests individuals every four years for cognition and also collects serum, plasma, and DNA samples. In collaboration with Sager, Sterling Johnson, from the William S. Middleton Memorial Veterans Hospital, Madison, has included members of the WRAP cohort in brain imaging analyses. He recently reported that family history affects functional MRI signals in specific areas of the brain, including the medial temporal lobe, during memory tasks (see Xu et al., 2009). At CTAD, Johnson also reported that a variety of brain areas show differences in diffusion tensor imaging (DTI) signals between people with and without a family history of AD. Curiously, the scientists found that DTI showed greater atrophy in people with a maternal family history than with a paternal one (see also Mosconi et al., 2007; Mosconi et al., 2009).
Johnson is not sure why fMRI or DTI differences emerge in people with a family history of AD who are themselves cognitively healthy at present, but said he plans to image participants with PiB PET, as well, to look for the presence of amyloid as a possible link. The scientists also found that the additional presence of ApoE4 alleles lead to even greater DTI differences from controls with no family history. The work suggests that family history confers risk over and above that explained by ApoE4 genotype along. Sager said he plans to work with Roses to investigate the possible genetic connection, which could be influenced by genetic variation in the nearby Tomm40 gene (see ARF related CTAD news).
There is currently no robust blood test for AD. However, blood samples collected from cohorts such as WRAP might eventually prove useful for biomarker analysis. One novel idea presented by Rick Einstein from the biotech company ExonHit Therapeutics in Paris, France, is to use a transcript microarray approach to test biological fluids. Genotyping delivers a static assessment of risk, whereas transcription profiling informs about dynamic changes that may be useful for diagnosis or to monitor intervention, Einstein said. The company performed a proof of concept with blood samples from AD patients and controls. From 177 samples in a training set, Einstein and colleagues generated transcript signatures from 120 samples chosen at random. They then used the 57 remaining samples to re-iterate the test and improve the transcript signature. This was then applied to 110 AD patient and 101 control samples, yielding a sensitivity of 74 percent and specificity of 67 percent. When applied to people with Mini-Mental State Exam (MMSE) scores of 26-30 specificity rose to 80 percent. (CSF Aβ/tau tests exceed that percentage – they and combinations of CSF with brain imaging have set a high bar for sensitivity and specificity of AD detection.) Einstein did not describe the profile but noted that ranking transcripts in the array against disease severity highlighted the kinase JAK2 as strongly linked to disease. This kinase has been implicated in Aβ toxicity (Chiba et al., 2008; see also Ray et al., 2007).
Another area of urgency for prevention trials concerns cognitive instruments that pick up subtle memory effects not detected by the MMSE, a crude screen for memory impairment. Herman Buschke, Albert Einstein College of Medicine, New York, summarized his Memory Capacity Test (MCT). Even though the MCT is a simple cued recall test, it appears to detect subtle and early cognitive decline, Buschke claimed.
The test uses two 16-category word lists that people are asked to remember. The test analysis measures “associative binding” of words on the second list to words from the same category in the first list. In other words, it calculates to what extent a person remembers words on the second list when they remember words from the same category on the first. Buschke found that some people with normal recall on the first list have lower-than-normal binding scores. “The test identifies early presymptomatic memory impairment when memory is otherwise within normal limits,” said Buschke. People who are demented or have MCI also have lower-than-normal binding scores on the MCT, and people who score below normal on many common tests of cognition also score below normal on the MCI, giving it some face validity.
Poor MCT scores also correlate with the presence of amyloid in the brain as measured by PiB PET, said Buschke. Slated for publication in Neurology, this work, by Reisa Sperling, Brigham and Women’s Hospital, and Keith Johnson at Massachusetts General Hospital, both in Boston, may help address the significance of PiB retention in supposedly normal individuals (see ARF related news story). Since PiB imaging began, researchers have been surprised to find substantial binding in cognitively normal people. The MCT analysis suggests that these people may actually have underlying memory problems, making Buschke’s memory test potentially useful for identifying truly normal controls in prevention or treatment trial settings. In addition, the MCT is a pencil-and-paper test that only takes six minutes, making it suitable for rapid screening of normal subjects for prevention trials a primary care setting.
A related methodology for detecting early cognitive decline is the CogState test battery of working memory. This is a commercial computer-based set of tests that uses playing card images to query memory (has the person seen the card presented earlier) and reaction time (how quickly do they push a button to record whether they have seen the card or not). In the Melbourne Healthy Aging Study in Australia, researchers found that people with MCI perform poorly compared to controls on this test, and also show faster decline over a twelve month period (see Maruff et al., 2004). David Darby from CogState, Melbourne, and the Florey Neuroscience Institute in Parkville, Australia, plans to use the test in a novel trial design that seemed well-received by the audience at CTAD. As with the MCT, Darby used PiB binding correlation to show that this CogState test has some validity. In a community screening study, Darby found that people who decline fastest in quarterly tests also test positive for PiB. Darby now plans to enroll 10,000 normal elders in a screening program and to offer subsequent clinical trials to them. Part of the novelty is that because Darby will have CogState baseline and six months of trajectory data, the patients will serve as their own controls. After this initial run-in, Darby envisages a delayed-start or a withdrawal trial design to assess disease modification. Darby said that looking very early in the disease process enhances one’s chance of seeing a drug effect. Lon Schneider, University of Southern California, Los Angeles, expressed concern about the ethics of such a design, but Darby replied that volunteers enrolled in the screening program would sign consent forms before any baseline data would be taken.
Overall, a writer took away the impression that the field is moving toward studying people earlier in the disease process. One of the themes that repeated itself was the idea of distinguishing between early (eMCI ) and late (lMCI) phases. Attendees also grappled with whether MCI should be labeled preAD, or prodromal AD. Ron Petersen, Mayo Clinic, Rochester, Minnesota, cautioned that clinicians may be uncomfortable telling patients they have “pre-AD” because some patients who do not end up with AD would be labeled erroneously. On that note, Schneider tempered the audience’s collective prevention enthusiasm with a reminder that the underlying biology of AD is still not understood and that the etiology is likely highly heterogeneous. He noted that it is hard to prevent something when the etiology is unclear. “We should be very careful about the drug we use. We should have a really good reason to believe it will work because these trials are time-consuming exercises,” Schneider said, adding that he strongly advocated efforts to model and simulate prevention trials before embarking on real trials.—Tom Fagan.
- Las Vegas: AD, Risk, ApoE—Tomm40 No Tomfoolery
- St. Louis: Imaging Preclinical AD—Can You See it Coming in the Brain?
- Xu G, McLaren DG, Ries ML, Fitzgerald ME, Bendlin BB, Rowley HA, Sager MA, Atwood C, Asthana S, Johnson SC. The influence of parental history of Alzheimer's disease and apolipoprotein E epsilon4 on the BOLD signal during recognition memory. Brain. 2009 Feb;132(Pt 2):383-91. PubMed.
- Mosconi L, Brys M, Switalski R, Mistur R, Glodzik L, Pirraglia E, Tsui W, De Santi S, de Leon MJ. Maternal family history of Alzheimer's disease predisposes to reduced brain glucose metabolism. Proc Natl Acad Sci U S A. 2007 Nov 27;104(48):19067-72. PubMed.
- Mosconi L, Mistur R, Switalski R, Brys M, Glodzik L, Rich K, Pirraglia E, Tsui W, De Santi S, de Leon MJ. Declining brain glucose metabolism in normal individuals with a maternal history of Alzheimer disease. Neurology. 2009 Feb 10;72(6):513-20. PubMed.
- Chiba T, Yamada M, Sasabe J, Terashita K, Shimoda M, Matsuoka M, Aiso S. Amyloid-beta causes memory impairment by disturbing the JAK2/STAT3 axis in hippocampal neurons. Mol Psychiatry. 2009 Feb;14(2):206-22. PubMed.
- Ray S, Britschgi M, Herbert C, Takeda-Uchimura Y, Boxer A, Blennow K, Friedman LF, Galasko DR, Jutel M, Karydas A, Kaye JA, Leszek J, Miller BL, Minthon L, Quinn JF, Rabinovici GD, Robinson WH, Sabbagh MN, So YT, Sparks DL, Tabaton M, Tinklenberg J, Yesavage JA, Tibshirani R, Wyss-Coray T. Classification and prediction of clinical Alzheimer's diagnosis based on plasma signaling proteins. Nat Med. 2007 Nov;13(11):1359-62. PubMed.
- Maruff P, Collie A, Darby D, Weaver-Cargin J, Masters C, Currie J. Subtle memory decline over 12 months in mild cognitive impairment. Dement Geriatr Cogn Disord. 2004;18(3-4):342-8. PubMed.
Las Vegas: 2020 Vision—AD Prevention in 11 Years?
Could foresight be 2020 for Alzheimer disease? Zaven Khachaturian has proposed a national strategic plan of preventing the disease within 11 years. Prevention, or even just delay of onset, is a lofty goal that topped the agenda at the Clinical Trials on Alzheimer’s Disease (CTAD) meeting held 29-30 October 2009 in Las Vegas, Nevada, and at the Leon Thal symposium also held there the day before. Presentations dealt with the logistics of prevention trials and with ideas for identifying at-risk subjects (see ARF related news story). But is prevention of Alzheimer’s by 2020 feasible?
Khachaturian is president emeritus of the Lou Ruvo Brain Institute (now the Cleveland Clinic Lou Ruvo Center for Brain Health; see ARF related news story). He formed a not-for-profit called PAD2020 (prevent AD by 2020) to push forward the recommendations of the Alzheimer’s Study Group (ASG). This task force of political, medical, philanthropic, and industry leaders formulated a national strategic plan for tackling Alzheimer disease (see ARF related news story). It issued its report last April (see ARF related news story) and then disbanded. In an appendix to the report, 139 thought leaders in the field endorsed the goal of developing the capability to prevent AD by 2020 provided that the effort “is backed by sufficient funding and pursued with an appropriate, disciplined strategy.”
The ASG had no power to appropriate funds to put its strategy into action. “A lot of these reports tend to be received by Congress and the Administration but never lead to any specific program or legislation,” said Khachaturian. “The idea [of PAD2020] is to carry forward the ASG recommendation into an implementation plan that would have specific targets and a specific budget request that would be sent to Congress,” he said. The Alzheimer’s Breakthrough Act of 2009, which is stuck in committee stage in Congress, would authorize $1 billion in funding for Alzheimer’s research, caregiving, and prevention awareness, but would not actually appropriate funds. “That is basically a hunting license,” said Khachaturian. “You can have a license but no game.”
Khachaturian is hoping some of the top minds in neurodegenerative research will bring their best game to PAD2020. Currently, he has enlisted the help of Ron Petersen at the Mayo Clinic, Rochester, Minnesota; John Trojanowski and Virginia Lee at the University of Pennsylvania, Philadelphia; Stanley Prusiner at the University of California, San Francisco; and Peter Snyder from Brown University, Providence, Rhode Island. Khachaturian envisions workgroups of 10-15 people that will consider a variety of potential projects, including identification of new drug targets, creation of an international patient registry, establishment of a national Institutional Review Board, a tool box for primary care physicians to assess risk, and new models to finance clinical trials.
Robert Egge, who directed the ASG, is now Vice President, Public Policy and Advocacy for the Alzheimer’s Association, which partly funded the ASG report. “If the idea is to convene thought leaders to really figure out, from a scientific perspective, what it would take to do a prevention initiative that the ASG calls for, then I think that next step in thinking and planning is essential,” he said. Egge said that the Association supports Khachaturian’s approach, though it has not, as yet, struck a formal partnership with PAD2020. Doug Galasko, University of California, San Diego, told ARF, “There have been a fair amount of discussion and the occasional conference aimed at new approaches to prevention, but relatively few organized efforts to put infrastructure in place and to think through what all of the barriers might be to actually implementing appropriate prevention studies.”
Khachaturian believes that to realize the goal of AD prevention, funding mechanisms may have to change. He wants to consider programs that are difficult to fund through the NIH, and to pool resources from different government agencies, industry, private foundations into a common fund. (The existing Foundation for the NIH already develops public-private partnerships.) Khachaturian said that he considers the current model for federal appropriations for AD research inadequate. “The current model is that the NIH appropriates a set amount, and we are expected to solve a problem within those budget constraints,” he said. He wants PAD2020 to take a different approach. “PAD2020 would build the budget from the ground up. It would insist that to solve the problem of preventing the disease within 10 years, we are going to need the following infrastructure, the following kind of scientists, the following resources. We would present that to the government and say these are the things we need.” Whether that would sit well with Congress or the Administration is unclear, but Khachaturian envisions a bold mindset, the likes of which have led to the splitting of the atom, the Apollo space missions, or the building of the Panama Canal. These were large national projects that took 10 or fewer years to achieve. “We think that kind of approach will make us go faster and further with Alzheimer’s than the random walk model we use now, where very little planning takes place and not enough resources are placed in a systematic way to solve the problem,” he said.
For more on this initiative, see Khatchaturian and Khatchaturian, 2009 [.pdf].—Tom Fagan.