"Effect of TTP488 in patients with mild to moderate Alzheimer's disease"Burstein, Aaron H; Grimes, Imogene; Galasko, Douglas R; AISEN, PAUL S; Sabbagh, Marwan; Mjalli, Adnan Mm
GRANTS:AG10483/AG/NIA NIH HHS/United States
BACKGROUND: TTP488, an antagonist at the Receptor for Advanced Glycation End products, was evaluated as a potential treatment for patients with mild-to-moderate Alzheimer's disease (AD). A previous report describes decreased decline in ADAS-cog (delta = 3.1, p = 0.008 at 18 months, ANCOVA with multiple imputation), relative to placebo, following a 5 mg/day dose of TTP488. Acute, reversible cognitive worsening was seen with a 20 mg/day dose. The present study further evaluates the efficacy of TTP488 by subgroup analyses based on disease severity and concentration effect analysis. METHODS: 399 patients were randomized to one of two oral TTP488 doses (60 mg for 6 days followed by 20 mg/day; 15 mg for 6 days followed by 5 mg/day) or placebo for 18 months. Pre-specified primary analysis, using an ITT population, was on the ADAS-cog11. Secondary analyses included as a key secondary variable the Clinical Dementia Rating-Sum of Boxes (CDR-SB), and another secondary variable of the ADCS-ADL. RESULTS: On-treatment analysis demonstrated numerical differences favoring 5 mg/day over placebo, with nominal significance at Month 18 (delta = 2.7, p = 0.03). Patients with mild AD, whether defined by MMSE or ADAS-cog, demonstrated significant differences favoring 5 mg/day on ADAS-cog and trends on CDR-sb and ADCS-ADL at Month 18. TTP488 plasma concentrations of 7.6-16.8 ng/mL were associated with a decreased decline in ADAS-cog over time compared to placebo. Worsening on the ADAS-cog relative to placebo was evident at 46.8-167.0 ng/mL. CONCLUSIONS: Results of these analyses support further investigation of 5 mg/day in future Phase 3 trials in patients with mild AD..
"Estimating long-term multivariate progression from short-term data"Donohue, Michael C; Jacqmin-Gadda, Helene; Le Goff, Melanie; Thomas, Ronald G; Raman, Rema; Gamst, Anthony C; Beckett, Laurel A; Jack, Clifford R Jr; Weiner, Michael W; Dartigues, Jean-Francois; AISEN, PAUL S
GRANTS:KL2 RR031978/RR/NCRR NIH HHS/United States;KL2 TR000099/TR/NCATS NIH HHS/United States;U01 AG024904/AG/NIA NIH HHS/United States;U19 AG010483/AG/NIA NIH HHS/United States;UL1 RR031980/RR/NCRR NIH HHS/United States
MOTIVATION: Diseases that progress slowly are often studied by observing cohorts at different stages of disease for short periods of time. The Alzheimer's Disease Neuroimaging Initiative (ADNI) follows elders with various degrees of cognitive impairment, from normal to impaired. The study includes a rich panel of novel cognitive tests, biomarkers, and brain images collected every 6 months for as long as 6 years. The relative timing of the observations with respect to disease pathology is unknown. We propose a general semiparametric model and iterative estimation procedure to estimate simultaneously the pathological timing and long-term growth curves. The resulting estimates of long-term progression are fine-tuned using cognitive trajectories derived from the long-term "Personnes Agees Quid" study. RESULTS: We demonstrate with simulations that the method can recover long-term disease trends from short-term observations. The method also estimates temporal ordering of individuals with respect to disease pathology, providing subject-specific prognostic estimates of the time until onset of symptoms. When the method is applied to ADNI data, the estimated growth curves are in general agreement with prevailing theories of the Alzheimer's disease cascade. Other data sets with common outcome measures can be combined using the proposed algorithm. AVAILABILITY: Software to fit the model and reproduce results with the statistical software R is available as the grace package. ADNI data can be downloaded from the Laboratory of NeuroImaging..
"The Preclinical Alzheimer Cognitive Composite: Measuring Amyloid-Related Decline"Donohue, Michael C; Sperling, Reisa A; Salmon, David P; Rentz, Dorene M; Raman, Rema; Thomas, Ronald G; Weiner, Michael; AISEN, PAUL S
IMPORTANCE As Alzheimer disease (AD) research moves to intervene in presymptomatic phases of the disease, we must develop outcome measures sensitive to the earliest disease-related changes. OBJECTIVE To demonstrate the feasibility of a cognitive composite outcome for clinically normal elderly participants with evidence of AD pathology using the ADCS Preclinical Alzheimer Cognitive Composite (ADCS-PACC). The ADCS-PACC combines tests that assess episodic memory, timed executive function, and global cognition. The ADCS-PACC is the primary outcome measure for the first clinical trial in preclinical AD (ie, the Anti-Amyloid Treatment in Asymptomatic Alzheimer's study). DESIGN, SETTING, AND PARTICIPANTS With the ADCS-PACC, we derive pilot estimates of amyloid-related decline using data from 2 observational studies conducted in North America and another conducted in Australia. The participants analyzed had normal cognition and mean ages of 75.81, 71.37, and 79.42 years across the 3 studies. MAIN OUTCOMES AND MEASURES For the 2 studies that collected data on Abeta levels (ADNI and AIBL), we estimate decline in a preclinical AD "Abeta-positive" placebo group and compare them with an "Abeta-negative" group. For the study that did not include data on Abeta levels (the ADCS Prevention Instrument [ADCS-PI] study), we grouped participants by the presence of APOE-epsilon4 and by clinical progression. RESULTS In ADNI, Abeta-positive participants showed more decline than did Abeta-negative participants with regard to the ADCS-PACC score at 24 months (mean [SE] difference, -1.239 [0.522] [95% CI, -2.263 to -0.215]; P = .02). In AIBL, the mean (SE) difference is significant at both 18 months (-1.009 [0.406] [95% CI, -1.805 to -0.213]; P = .01) and 36 months (-1.404 [0.452] [95% CI, -2.290 to -0.519]; P = .002). In the ADCS-PI study, APOE-epsilon4 allele carriers performed significantly worse on the ADCS-PACC at 24 months (mean [SE] score, -0.742 [0.294] [95% CI, -1.318 to -0.165]; P = .01) and 36 months (-1.531 [0.469] [95% CI, -2.450 to -0.612]; P = .001). In the ADCS-PI study, cognitively normal participants who progress from a global Clinical Dementia Rating score of 0 are significantly worse on the ADCS-PACC than cognitively normal participants who are stable with a global Clinical Dementia Rating score of 0 at months 12, 24, and 36 (mean [SE] ADCS-PACC score, -4.471 [0.702] [95% CI, -5.848 to -3.094]; P < .001). Using pilot estimates of variance and assuming 500 participants per group with 30% attrition and a 5% alpha level, we project 80% power to detect effects in the range of Delta = 0.467 to 0.733 on the ADCS-PACC. CONCLUSIONS AND RELEVANCE Analyses of at-risk cognitively normal populations suggest that we can reliably measure the first signs of cognitive decline with the ADCS-PACC. These analyses also suggest the feasibility of secondary prevention trials..
"Phase 3 trials of solanezumab for mild-to-moderate Alzheimer's disease"Doody, Rachelle S; Thomas, Ronald G; Farlow, Martin; Iwatsubo, Takeshi; Vellas, Bruno; Joffe, Steven; Kieburtz, Karl; Raman, Rema; Sun, Xiaoying; AISEN, PAUL S; Siemers, Eric; Liu-Seifert, Hong; Mohs, Richard
BACKGROUND: Alzheimer's disease is characterized by amyloid-beta plaques, neurofibrillary tangles, gliosis, and neuronal loss. Solanezumab, a humanized monoclonal antibody, preferentially binds soluble forms of amyloid and in preclinical studies promoted its clearance from the brain. METHODS: In two phase 3, double-blind trials (EXPEDITION 1 and EXPEDITION 2), we randomly assigned 1012 and 1040 patients, respectively, with mild-to-moderate Alzheimer's disease to receive placebo or solanezumab (administered intravenously at a dose of 400 mg) every 4 weeks for 18 months. The primary outcomes were the changes from baseline to week 80 in scores on the 11-item cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-cog11; range, 0 to 70, with higher scores indicating greater cognitive impairment) and the Alzheimer's Disease Cooperative Study-Activities of Daily Living scale (ADCS-ADL; range, 0 to 78, with lower scores indicating worse functioning). After analysis of data from EXPEDITION 1, the primary outcome for EXPEDITION 2 was revised to the change in scores on the 14-item cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-cog14; range, 0 to 90, with higher scores indicating greater impairment), in patients with mild Alzheimer's disease. RESULTS: Neither study showed significant improvement in the primary outcomes. The modeled difference between groups (solanezumab group minus placebo group) in the change from baseline was -0.8 points for the ADAS-cog11 score (95% confidence interval [CI], -2.1 to 0.5; P=0.24) and -0.4 points for the ADCS-ADL score (95% CI, -2.3 to 1.4; P=0.64) in EXPEDITION 1 and -1.3 points (95% CI, -2.5 to 0.3; P=0.06) and 1.6 points (95% CI, -0.2 to 3.3; P=0.08), respectively, in EXPEDITION 2. Between-group differences in the changes in the ADAS-cog14 score were -1.7 points in patients with mild Alzheimer's disease (95% CI, -3.5 to 0.1; P=0.06) and -1.5 in patients with moderate Alzheimer's disease (95% CI, -4.1 to 1.1; P=0.26). In the combined safety data set, the incidence of amyloid-related imaging abnormalities with edema or hemorrhage was 0.9% with solanezumab and 0.4% with placebo for edema (P=0.27) and 4.9% and 5.6%, respectively, for hemorrhage (P=0.49). CONCLUSIONS: Solanezumab, a humanized monoclonal antibody that binds amyloid, failed to improve cognition or functional ability. (Funded by Eli Lilly; EXPEDITION 1 and 2 ClinicalTrials.gov numbers, NCT00905372 and NCT00904683.)..
"Clinical trial of an inhibitor of RAGE-Abeta interactions in Alzheimer disease"Galasko, Douglas; Bell, Joanne; Mancuso, Jessica Y; Kupiec, James W; Sabbagh, Marwan N; van Dyck, Christopher; Thomas, Ronald G; AISEN, PAUL S
GRANTS:AG10483/AG/NIA NIH HHS/United States
OBJECTIVE: To examine safety, tolerability, and efficacy of PF-04494700, an inhibitor of the receptor for advanced glycation end products (RAGE), in mild to moderate Alzheimer disease (AD). METHODS: Double-blind, placebo-controlled trial at 40 academic centers (United States). Subjects with AD and Mini-Mental State Examination score 14-26 were randomized to PF-04494700 60 mg/day x 6 days, then 20 mg daily (high dose); 15 mg/day x 6 days, then 5 mg daily (low dose); or placebo, for 18 months. Clinical and laboratory measures were used to evaluate safety and tolerability. The primary efficacy measure was the Alzheimer's Disease Assessment Scale-cognitive (ADAS-cog). Secondary measures assessed clinical stage, function, behavior, MRI, and CSF biomarkers. RESULTS: A total of 399 subjects were randomized. In a prespecified interim analysis, when 50% of subjects had completed the 6-month visit, the high dose was associated with confusion, falls, and greater ADAS-cog decline and was discontinued. A second prespecified analysis compared low-dose and placebo groups for futility and safety approximately 12 months after all subjects were randomized. This analysis met criteria for futility, and treatment was discontinued. There were no safety concerns in the low-dose group. Analyses including post-futility data showed decreased decline on the ADAS-cog in the low-dose group at month 18. Other clinical and biomarker measures showed no differences between low-dose treatment and placebo. CONCLUSIONS: PF-04494700 at 20 mg/d was associated with increased adverse events and cognitive decline. At 5 mg/d, PF-04494700 had a good safety profile. A potential benefit for this low dose on the ADAS-cog is not conclusive, because of high dropout and discontinuation rates subsequent to the interim analyses. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that in patients with AD high-dose PF-04494700 increased cognitive decline at 6 months and Class IV evidence that low-dose PF-04494700 slowed cognitive decline at 18 months..
"Symptom onset in autosomal dominant Alzheimer disease: A systematic review and meta-analysis"Ryman, Davis C; Acosta-Baena, Natalia; AISEN, PAUL S; Bird, Thomas; Danek, Adrian; Fox, Nick C; Goate, Alison; Frommelt, Peter; Ghetti, Bernardino; Langbaum, Jessica B S; Lopera, Francisco; Martins, Ralph; Masters, Colin L; Mayeux, Richard P; McDade, Eric; Moreno, Sonia; Reiman, Eric M; Ringman, John M; Salloway, Steve; Schofield, Peter R; Sperling, Reisa; Tariot, Pierre N; Xiong, Chengjie; Morris, John C; Bateman, Randall J
OBJECTIVE: To identify factors influencing age at symptom onset and disease course in autosomal dominant Alzheimer disease (ADAD), and develop evidence-based criteria for predicting symptom onset in ADAD.METHODS: We have collected individual-level data on ages at symptom onset and death from 387 ADAD pedigrees, compiled from 137 peer-reviewed publications, the Dominantly Inherited Alzheimer Network (DIAN) database, and 2 large kindreds of Colombian (PSEN1 E280A) and Volga German (PSEN2 N141I) ancestry. Our combined dataset includes 3,275 individuals, of whom 1,307 were affected by ADAD with known age at symptom onset. We assessed the relative contributions of several factors in influencing age at onset, including parental age at onset, age at onset by mutation type and family, and APOE genotype and sex. We additionally performed survival analysis using data on symptom onset collected from 183 ADAD mutation carriers followed longitudinally in the DIAN Study.RESULTS: We report summary statistics on age at onset and disease course for 174 ADAD mutations, and discover strong and highly significant (p < 10-16, r2 > 0.38) correlations between individual age at symptom onset and predicted values based on parental age at onset and mean ages at onset by mutation type and family, which persist after controlling for APOE genotype and sex.CONCLUSIONS: Significant proportions of the observed variance in age at symptom onset in ADAD can be explained by family history and mutation type, providing empirical support for use of these data to estimate onset in clinical research..
"Effects of traumatic brain injury and posttraumatic stress disorder on Alzheimer's disease in veterans, using the Alzheimer's Disease Neuroimaging Initiative"Weiner, Michael W; Veitch, Dallas P; Hayes, Jacqueline; Neylan, Thomas; Grafman, Jordan; AISEN, PAUL S; Petersen, Ronald C; Jack, Clifford; Jagust, William; Trojanowski, John Q; Shaw, Leslie M; Saykin, Andrew J; Green, Robert C; Harvey, Danielle; Toga, Arthur W; Friedl, Karl E; Pacifico, Anthony; Sheline, Yvette; Yaffe, Kristine; Mohlenoff, Brian
GRANTS:Canadian Institutes of Health Research/Canada
Both traumatic brain injury (TBI) and posttraumatic stress disorder (PTSD) are common problems resulting from military service, and both have been associated with increased risk of cognitive decline and dementia resulting from Alzheimer's disease (AD) or other causes. This study aims to use imaging techniques and biomarker analysis to determine whether traumatic brain injury (TBI) and/or PTSD resulting from combat or other traumas increase the risk for AD and decrease cognitive reserve in Veteran subjects, after accounting for age. Using military and Department of Veterans Affairs records, 65 Vietnam War veterans with a history of moderate or severe TBI with or without PTSD, 65 with ongoing PTSD without TBI, and 65 control subjects are being enrolled in this study at 19 sites. The study aims to select subject groups that are comparable in age, gender, ethnicity, and education. Subjects with mild cognitive impairment (MCI) or dementia are being excluded. However, a new study just beginning, and similar in size, will study subjects with TBI, subjects with PTSD, and control subjects with MCI. Baseline measurements of cognition, function, blood, and cerebrospinal fluid biomarkers; magnetic resonance images (structural, diffusion tensor, and resting state blood-level oxygen dependent (BOLD) functional magnetic resonance imaging); and amyloid positron emission tomographic (PET) images with florbetapir are being obtained. One-year follow-up measurements will be collected for most of the baseline procedures, with the exception of the lumbar puncture, the PET imaging, and apolipoprotein E genotyping. To date, 19 subjects with TBI only, 46 with PTSD only, and 15 with TBI and PTSD have been recruited and referred to 13 clinics to undergo the study protocol. It is expected that cohorts will be fully recruited by October 2014. This study is a first step toward the design and statistical powering of an AD prevention trial using at-risk veterans as subjects, and provides the basis for a larger, more comprehensive study of dementia risk factors in veterans..
"Alzheimer's disease cooperative study prevention instrument project assessing resource use and volunteer and paid work in healthy elders: a longitudinal study" [Letter]Zhu, Carolyn W; Sano, Mary; Ferris, Steven H; Whitehouse, Peter J; Patterson, Marian B; Galasko, Douglas; Schneider, Lon S; AISEN, PAUL S
GRANTS:P50 AG005138/AG/NIA NIH HHS/United States;U01 AG010483/AG/NIA NIH HHS/United States
"Ventricular enlargement and its clinical correlates in the imaging cohort from the ADCS MCI donepezil/vitamin E study"Apostolova, Liana G; Babakchanian, Sona; Hwang, Kristy S; Green, Amity E; Zlatev, Dimitar; Chou, Yi-Yu; DeCarli, Charlie; Jack, Clifford R Jr; Petersen, Ronald C; AISEN, PAUL S; Cummings, Jeffrey L; Toga, Arthur W; Thompson, Paul M
GRANTS:AG16570/AG/NIA NIH HHS/United States;EB01651/EB/NIBIB NIH HHS/United States;LM05639/LM/NLM NIH HHS/United States;P30 AG010129/AG/NIA NIH HHS/United States;P41 RR013642/RR/NCRR NIH HHS/United States;R01 MH071940/MH/NIMH NIH HHS/United States;RR019771/RR/NCRR NIH HHS/United States;U54 RR021813/RR/NCRR NIH HHS/United States
We analyzed the baseline and 3-year T1-weighted magnetic resonance imaging data of 110 amnestic mild cognitive impairment (MCI) participants with minimal hippocampal atrophy at baseline from the Alzheimer's Disease Cooperative Study group MCI Donepezil/Vitamin E trial. Forty-six subjects converted to Alzheimer disease (AD) (MCIc), whereas 64 remained stable (MCInc). We used the radial distance technique to examine the differences in lateral ventricle shape and size between MCIc and MCInc and the associations between ventricular enlargement and cognitive decline. MCIc group had significantly larger frontal and right body/occipital horns relative to MCInc at baseline and significantly larger bilateral frontal, body/occipital, and left temporal horns at follow-up. Global cognitive decline measured with AD Assessment scale cognitive subscale and Mini-Mental State Examination and decline in activities of daily living (ADL) were associated with posterior lateral ventricle enlargement. Decline in AD Assessment scale cognitive subscale and ADL were associated with left temporal and decline in Mini-Mental State Examination with right temporal horn enlargement. After correction for baseline hippocampal volume, decline in ADL showed a significant association with right frontal horn enlargement. Executive decline was associated with right frontal and left temporal horn enlargement..
"Regional variability of imaging biomarkers in autosomal dominant Alzheimer's disease"Benzinger, Tammie L S; Blazey, Tyler; Jack, Clifford R Jr; Koeppe, Robert A; Su, Yi; Xiong, Chengjie; Raichle, Marcus E; Snyder, Abraham Z; Ances, Beau M; Bateman, Randall J; Cairns, Nigel J; Fagan, Anne M; Goate, Alison; Marcus, Daniel S; AISEN, PAUL S; Christensen, Jon J; Ercole, Lindsay; Hornbeck, Russ C; Farrar, Angela M; Aldea, Patricia; Jasielec, Mateusz S; Owen, Christopher J; Xie, Xianyun; Mayeux, Richard; Brickman, Adam; McDade, Eric; Klunk, William; Mathis, Chester A; Ringman, John; Thompson, Paul M; Ghetti, Bernardino; Saykin, Andrew J; Sperling, Reisa A; Johnson, Keith A; Salloway, Stephen; Correia, Stephen; Schofield, Peter R; Masters, Colin L; Rowe, Christopher; Villemagne, Victor L; Martins, Ralph; Ourselin, Sebastien; Rossor, Martin N; Fox, Nick C; Cash, David M; Weiner, Michael W; Holtzman, David M; Buckles, Virginia D; Moulder, Krista; Morris, John C
GRANTS:1S10RR022984-01A1/RR/NCRR NIH HHS/United States;U19AG032438/AG/NIA NIH HHS/United States;UL1 TR000448/TR/NCATS NIH HHS/United States;UL1 TR000448/TR/NCATS NIH HHS/United States
Major imaging biomarkers of Alzheimer's disease include amyloid deposition [imaged with [(11)C]Pittsburgh compound B (PiB) PET], altered glucose metabolism (imaged with [(18)F]fluro-deoxyglucose PET), and structural atrophy (imaged by MRI). Recently we published the initial subset of imaging findings for specific regions in a cohort of individuals with autosomal dominant Alzheimer's disease. We now extend this work to include a larger cohort, whole-brain analyses integrating all three imaging modalities, and longitudinal data to examine regional differences in imaging biomarker dynamics. The anatomical distribution of imaging biomarkers is described in relation to estimated years from symptom onset. Autosomal dominant Alzheimer's disease mutation carrier individuals have elevated PiB levels in nearly every cortical region 15 y before the estimated age of onset. Reduced cortical glucose metabolism and cortical thinning in the medial and lateral parietal lobe appeared 10 and 5 y, respectively, before estimated age of onset. Importantly, however, a divergent pattern was observed subcortically. All subcortical gray-matter regions exhibited elevated PiB uptake, but despite this, only the hippocampus showed reduced glucose metabolism. Similarly, atrophy was not observed in the caudate and pallidum despite marked amyloid accumulation. Finally, before hypometabolism, a hypermetabolic phase was identified for some cortical regions, including the precuneus and posterior cingulate. Additional analyses of individuals in which longitudinal data were available suggested that an accelerated appearance of volumetric declines approximately coincides with the onset of the symptomatic phase of the disease..
"A phase 3 trial of semagacestat for treatment of Alzheimer's disease"Doody, Rachelle S; Raman, Rema; Farlow, Martin; Iwatsubo, Takeshi; Vellas, Bruno; Joffe, Steven; Kieburtz, Karl; He, Feng; Sun, Xiaoying; Thomas, Ronald G; AISEN, PAUL S; Siemers, Eric; Sethuraman, Gopalan; Mohs, Richard
GRANTS:U01 AG010483/AG/NIA NIH HHS/United States;U19 AG010483/AG/NIA NIH HHS/United States
BACKGROUND: Alzheimer's disease is characterized by the presence of cortical amyloid-beta (Abeta) protein plaques, which result from the sequential action of beta-secretase and gamma-secretase on amyloid precursor protein. Semagacestat is a small-molecule gamma-secretase inhibitor that was developed as a potential treatment for Alzheimer's disease. METHODS: We conducted a double-blind, placebo-controlled trial in which 1537 patients with probable Alzheimer's disease underwent randomization to receive 100 mg of semagacestat, 140 mg of semagacestat, or placebo daily. Changes in cognition from baseline to week 76 were assessed with the use of the cognitive subscale of the Alzheimer's Disease Assessment Scale for cognition (ADAS-cog), on which scores range from 0 to 70 and higher scores indicate greater cognitive impairment, and changes in functioning were assessed with the Alzheimer's Disease Cooperative Study-Activities of Daily Living (ADCS-ADL) scale, on which scores range from 0 to 78 and higher scores indicate better functioning. A mixed-model repeated-measures analysis was used. RESULTS: The trial was terminated before completion on the basis of a recommendation by the data and safety monitoring board. At termination, there were 189 patients in the group receiving placebo, 153 patients in the group receiving 100 mg of semagacestat, and 121 patients in the group receiving 140 mg of semagacestat. The ADAS-cog scores worsened in all three groups (mean change, 6.4 points in the placebo group, 7.5 points in the group receiving 100 mg of the study drug, and 7.8 points in the group receiving 140 mg; P=0.15 and P=0.07, respectively, for the comparison with placebo). The ADCS-ADL scores also worsened in all groups (mean change at week 76, -9.0 points in the placebo group, -10.5 points in the 100-mg group, and -12.6 points in the 140-mg group; P=0.14 and P<0.001, respectively, for the comparison with placebo). Patients treated with semagacestat lost more weight and had more skin cancers and infections, treatment discontinuations due to adverse events, and serious adverse events (P<0.001 for all comparisons with placebo). Laboratory abnormalities included reduced levels of lymphocytes, T cells, immunoglobulins, albumin, total protein, and uric acid and elevated levels of eosinophils, monocytes, and cholesterol; the urine pH was also elevated. CONCLUSIONS: As compared with placebo, semagacestat did not improve cognitive status, and patients receiving the higher dose had significant worsening of functional ability. Semagacestat was associated with more adverse events, including skin cancers and infections. (Funded by Eli Lilly; ClinicalTrials.gov number, NCT00594568.).
"Perspective on future role of biological markers in clinical therapy trials of Alzheimer's disease: A long-range point of view beyond 2020"Hampel, Harald; Lista, Simone; Teipel, Stefan J; Garaci, Francesco; Nistico, Robert; Blennow, Kaj; Zetterberg, Henrik; Bertram, Lars; Duyckaerts, Charles; Bakardjian, Hovagim; Drzezga, Alexander; Colliot, Olivier; Epelbaum, Stephane; Broich, Karl; Lehericy, Stephane; Brice, Alexis; Khachaturian, Zaven S; AISEN, PAUL S; Dubois, Bruno
GRANTS:R01-AG030048/AG/NIA NIH HHS/United States;R01-AG16381/AG/NIA NIH HHS/United States;U01-AG024904/AG/NIA NIH HHS/United States;U01-AG10483/AG/NIA NIH HHS/United States
Recent advances in understanding the molecular mechanisms underlying various paths toward the pathogenesis of Alzheimer's disease (AD) has begun to provide new insight for interventions to modify disease progression. The evolving knowledge gained from multidisciplinary basic research has begun to identify new concepts for treatments and distinct classes of therapeutic targets; as well as putative disease-modifying compounds that are now being tested in clinical trials. There is a mounting consensus that such disease modifying compounds and/or interventions are more likely to be effectively administered as early as possible in the cascade of pathogenic processes preceding and underlying the clinical expression of AD. The budding sentiment is that "treatments" need to be applied before various molecular mechanisms converge into an irreversible pathway leading to morphological, metabolic and functional alterations that characterize the pathophysiology of AD. In light of this, biological indicators of pathophysiological mechanisms are desired to chart and detect AD throughout the asymptomatic early molecular stages into the prodromal and early dementia phase. A major conceptual development in the clinical AD research field was the recent proposal of new diagnostic criteria, which specifically incorporate the use of biomarkers as defining criteria for preclinical stages of AD. This paradigm shift in AD definition, conceptualization, operationalization, detection and diagnosis represents novel fundamental opportunities for the modification of interventional trial designs. This perspective summarizes not only present knowledge regarding biological markers but also unresolved questions on the status of surrogate indicators for detection of the disease in asymptomatic people and diagnosis of AD..
"Tracking pathophysiological processes in Alzheimer's disease: an updated hypothetical model of dynamic biomarkers"Jack, Clifford R Jr; Knopman, David S; Jagust, William J; Petersen, Ronald C; Weiner, Michael W; AISEN, PAUL S; Shaw, Leslie M; Vemuri, Prashanthi; Wiste, Heather J; Weigand, Stephen D; Lesnick, Timothy G; Pankratz, Vernon S; Donohue, Michael C; Trojanowski, John Q
GRANTS:AG11378/AG/NIA NIH HHS/United States;R01 AG011378/AG/NIA NIH HHS/United States
In 2010, we put forward a hypothetical model of the major biomarkers of Alzheimer's disease (AD). The model was received with interest because we described the temporal evolution of AD biomarkers in relation to each other and to the onset and progression of clinical symptoms. Since then, evidence has accumulated that supports the major assumptions of this model. Evidence has also appeared that challenges some of our assumptions, which has allowed us to modify our original model. Refinements to our model include indexing of individuals by time rather than clinical symptom severity; incorporation of interindividual variability in cognitive impairment associated with progression of AD pathophysiology; modifications of the specific temporal ordering of some biomarkers; and recognition that the two major proteinopathies underlying AD biomarker changes, amyloid beta (Abeta) and tau, might be initiated independently in sporadic AD, in which we hypothesise that an incident Abeta pathophysiology can accelerate antecedent limbic and brainstem tauopathy..
"Focal hemosiderin deposits and beta-amyloid load in the ADNI cohort"Kantarci, Kejal; Gunter, Jeffrey L; Tosakulwong, Nirubol; Weigand, Stephen D; Senjem, Matthew S; Petersen, Ronald C; AISEN, PAUL S; Jagust, William J; Weiner, Michael W; Jack, Clifford R Jr
GRANTS:K01 AG030514/AG/NIA NIH HHS/United States;P30 AG010129/AG/NIA NIH HHS/United States;P50 AG016574/AG/NIA NIH HHS/United States;R01 AG011378/AG/NIA NIH HHS/United States;R01 AG040042/AG/NIA NIH HHS/United States;R01 AG11378/AG/NIA NIH HHS/United States;R01 AG40042/AG/NIA NIH HHS/United States;U01 AG024904/AG/NIA NIH HHS/United States;U01 AG024904/AG/NIA NIH HHS/United States;Canadian Institutes of Health Research/Canada
BACKGROUND: Prevalence and risk factors for focal hemosiderin deposits are important considerations when planning amyloid-modifying trials for treatment and prevention of Alzheimer's disease (AD). METHODS: Subjects were cognitively normal (n = 171), early-mild cognitive impairment (MCI) (n = 240), late-MCI (n = 111), and AD (n = 40) from the Alzheimer's Disease Neuroimaging Initiative (ADNI). Microhemorrhages and superficial siderosis were assessed at baseline and on all available MRIs at 3, 6, and 12 months. beta-amyloid load was assessed with (18)F-florbetapir positron emission tomography. RESULTS: Prevalence of superficial siderosis was 1% and prevalence of microhemorrhages was 25% increasing with age (P < .001) and beta-amyloid load (P < .001). Topographic densities of microhemorrhages were highest in the occipital lobes and lowest in the deep/infratentorial regions. A greater number of microhemorrhages at baseline was associated with a greater annualized rate of additional microhemorrhages by last follow-up (rank correlation = 0.49; P < .001). CONCLUSIONS: Focal hemosiderin deposits are relatively common in the ADNI cohort and are associated with beta-amyloid load..
"Influence of genetic variation on plasma protein levels in older adults using a multi-analyte panel"Kim, Sungeun; Swaminathan, Shanker; Inlow, Mark; Risacher, Shannon L; Nho, Kwangsik; Shen, Li; Foroud, Tatiana M; Petersen, Ronald C; AISEN, PAUL S; Soares, Holly; Toledo, Jon B; Shaw, Leslie M; Trojanowski, John Q; Weiner, Michael W; McDonald, Brenna C; Farlow, Martin R; Ghetti, Bernardino; Saykin, Andrew J
GRANTS:IIS-1117335/PHS HHS/United States;K01 AG030514/AG/NIA NIH HHS/United States;K99 LM011384/LM/NLM NIH HHS/United States;P30 AG010129/AG/NIA NIH HHS/United States;P30 AG010133/AG/NIA NIH HHS/United States;P30AG010133/AG/NIA NIH HHS/United States;P30AG10133-18S1/AG/NIA NIH HHS/United States;R01 AG019771/AG/NIA NIH HHS/United States;R01 AG19771/AG/NIA NIH HHS/United States;R01 LM011360/LM/NLM NIH HHS/United States;R01AG19771/AG/NIA NIH HHS/United States;TL1 RR025759/RR/NCRR NIH HHS/United States;U01 AG024904/AG/NIA NIH HHS/United States;U01AG032984/AG/NIA NIH HHS/United States;U24AG021886/AG/NIA NIH HHS/United States;Canadian Institutes of Health Research/Canada
Proteins, widely studied as potential biomarkers, play important roles in numerous physiological functions and diseases. Genetic variation may modulate corresponding protein levels and point to the role of these variants in disease pathophysiology. Effects of individual single nucleotide polymorphisms (SNPs) within a gene were analyzed for corresponding plasma protein levels using genome-wide association study (GWAS) genotype data and proteomic panel data with 132 quality-controlled analytes from 521 Caucasian participants in the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort. Linear regression analysis detected 112 significant (Bonferroni threshold p=2.44x10(-5)) associations between 27 analytes and 112 SNPs. 107 out of these 112 associations were tested in the Indiana Memory and Aging Study (IMAS) cohort for replication and 50 associations were replicated at uncorrected p<0.05 in the same direction of effect as those in the ADNI. We identified multiple novel associations including the association of rs7517126 with plasma complement factor H-related protein 1 (CFHR1) level at p<1.46x10(-60), accounting for 40 percent of total variation of the protein level. We serendipitously found the association of rs6677604 with the same protein at p<9.29x10(-112). Although these two SNPs were not in the strong linkage disequilibrium, 61 percent of total variation of CFHR1 was accounted for by rs6677604 without additional variation by rs7517126 when both SNPs were tested together. 78 other SNP-protein associations in the ADNI sample exceeded genome-wide significance (5x10(-8)). Our results confirmed previously identified gene-protein associations for interleukin-6 receptor, chemokine CC-4, angiotensin-converting enzyme, and angiotensinogen, although the direction of effect was reversed in some cases. This study is among the first analyses of gene-protein product relationships integrating multiplex-panel proteomics and targeted genes extracted from a GWAS array. With intensive searches taking place for proteomic biomarkers for many diseases, the role of genetic variation takes on new importance and should be considered in interpretation of proteomic results..
"Development and implementation of the national Alzheimer's prevention registry" [Meeting Abstract]Langbaum, J; High, N; AISEN, P; Albert, M; Brown, K; Comer, M; Cummings, J; Manly, J; Petersen, R; Sperling, R; Strobel, G; Weiner, M; Tariot, P; Reiman, E
Background: To help advance the evaluation of promising Alzheimer's disease (AD) prevention therapies, we have launched the national, web-based Alzheimer's Prevention Registry ("Registry"). This Registry is intended to provide a shared resource to facilitate enrollment in prevention studies and to complement and enhance local efforts. The Registry will inform enrollees about the latest news in AD prevention research and about opportunities to participate in research in their community. The Registry aims to enroll 100,000 people by mid-2013; 250,000 by mid-2015. Methods: Interested adults of all ages, with and without memory and thinking problems, are eligible to join at www.endALZnow.org. Modeled after other disease registries, this Registry was purposefully designed to have a low threshold of commitment at entry. Individuals are asked to provide basic contact and demographic information and answer two questions related to their experience with AD. Additional information can be completed after joining through surveys at their convenience and discretion. Eblasts will be used to notify registrants about online surveys, prevention-focused studies and trials, and whom to contact to explore the possibility of their participation. Results: Prior to launching the Registry, a national message testing survey was conducted, revealing that 60% of adults would likely join the Registry and 63% would encourage others to enroll. The Registry had a pilot launch in May 2012, with official launch in October 2012. To date 9,157 have joined. Registrants are predominantly women (79%), report a family history of dementia (67%), have no diagnosis of cognitive impairment (97%), and a mean age of 55.8 (SD 13.7; median age 57). The most successful outreach mechanisms include news articles, TVand radio interviews, and paid online advertising. Conclusions: The Registry, which intends to create an interactive community of individuals who are passionate about fighting the disease and accelerate enrollment in prevention stud!.