After Disappointments, Alzheimer’s Researchers Seek Out New Paths Biomarkers and Combination Therapies May Lead To Disease-Modifying Treatments, Experts Say Susan Worley

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o date, all efforts to develop a disease-modifying treatment amyloid therapies at earlier stages of the disease,” Dr. Sperling for Alzheimer’s disease (AD) have been unsuccessful. says. “The solanezumab trials, in particular, showed a benefit in patients with mild dementia, but none of the studies shows Consequently, the treatments available to address the statistically significant effects clinically or on biomarkers in disease treat only the symptoms (Table 1). However, the the moderate dementia groups. Another lesson we learned is many clinical trials that have ended in disappointment may that we need to be able to give enough of these antibodies to yet prove to have a silver lining, as a critical and collaborative increase binding enough to remove amyloid. In the bapineure-examination of premises that guided earlier research is zumab studies, dosing was limited by side effects; that wasn’t taking place in their aftermath. Experts have long agreed on two primary neuropathological true in the solanezumab studies, which may be why they were hallmarks of AD: beta-amyloid (Aβ) plaques and hyperphosable to see some evidence of a clinical effect in a subgroup.” phorylated tau in the form of neurofibrillary tangles, both of Rethinking AD pathophysiology which are present in the brains of individuals with AD. Most efforts to develop a disease-modifying treatment have focused Puzzling to many inside and outside of the field of AD research on Aβ-related interventions. Reports on phase 3 trials of two is the fact that some individuals with significant beta-amyloid such interventions, anti-Aβ antibodies bapineuzumab (Janssen/ accumulation can remain cognitively normal.5,6 Moreover, 1 2 Pfizer) and solanezumab (Eli Lilly), which involved more studies have shown that AD-like neurodegenerative patterns can occur in patients without any beta-amyloid than 4,000 patients, appeared in a January 2014 accumulation.7 issue of the New England Journal of Medicine. Both agents were tested in patients with mild“We don’t have all the answers about amyloid to-moderate AD, and although both successfully yet and we don’t yet have enough data,” says reached their targets and showed evidence of Dr. Sperling, “But the preponderance of data so clearing or modifying Aβ deposits in the brain, far suggests that people who have evidence of amyloid accumulation over time show a faster neither agent significantly improved clinical rate of decline than people who do not. outcomes in AD patients. Among the lessons learned from these and “That does not mean that everyone with other failed clinical trials, including those of amyloid accumulation will develop Alzheimer’s an active anti-Aβ vaccine,3 John Trojanowski, disease,” she adds. “Most likely there are MD, PhD, Director of the Institute on Aging factors that confer resistance to amyloid, and and the Alzheimer’s Disease Core Center at as with high cholesterol and heart disease, the University of Pennsylvania, says three are John Trojanowski, MD, PhD amyloid most likely is only one part of the AD most important. puzzle. We know, for example, that the vast “First, we know that we must intervene at an earlier stage majority who have high cholesterol will never have a heart of the disease,” Dr. Trojanowski says, “so it is now essential to attack or stroke, so cholesterol is only one contributing factor to heart disease. design prevention trials or clinical trials that address prodromal AD. Second, we must use biomarkers in all patient populations “Even if amyloid is only a contributing factor to Alzheimer’s to increase confidence in diagnosis and also to monitor target disease, intervening at the right stage may prove to be benefiengagement, as well as response to therapy. And third, we must cial,” Dr. Sperling says. “I do think there are many other factors develop drugs that address other AD targets, such as tau tangles.” to consider, some of which may prove to be synergistic among Reisa Sperling, MD, Director of the Center for Alzheimer’s individuals who are amyloid positive. For example, for a given amount of amyloid, we know that APOE4 [the gene apolipoResearch and Treatment at Brigham and Women’s Hospital and Massachusetts General Hospital and Professor of Neurology protein Ε4] can further influence the rate of cognitive decline.” at Harvard Medical School, cites these same lessons, with Although it is well established that amyloid accumulation occurs early in the AD process,8 most experts agree that it is an emphasis on the need to treat the right target at the right stage of disease.4 only part of the puzzle, in part because its correlation with “Phase 3 trials with both bapineuzumab and solanezumab cognitive decline and disease progression so far remains weak. suggest that it’s more likely that we will have success with anti“The cascade hypothesis posits that Aβ in some way trigSusan Worley is a freelance medical writer who resides in Pennsylvania.

Disclosure: The author reports that she has no commercial or financial relationships in regard to this article.

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After Disappointments, Alzheimer’s Researchers Seek Out New Paths Table 1 Current Treatments for Symptoms The FDA has approved five treatments for symptoms of Alzheimer’s disease, but one of them, tacrine (Cognex, Sciele Pharma) has been discontinued in the U.S. Use of these interventions can result in moderate but temporary improvement in cognitive function in individuals with mild-tomoderate dementia. Generic Name (Brand)

Manufacturer

Postulated Mechanism of Action

Approximate Cost for 30 Days24

Galantamine (Razadyne)

Janssen Pharmaceuticals

Enhances cholinergic function by increasing the concentration of acetylcholine through reversible inhibition of its hydrolysis by cholinesterase. The effect of galantamine may diminish with disease progression, as fewer cholinergic neurons remain functionally intact.25

$265 to $550 depending on dosage and formulation

Rivastigmine (Exelon)

Novartis Pharmaceuticals

Enhances cholinergic function by increasing the concentration of acetylcholine through reversible inhibition of its hydrolysis by cholinesterase. The effect of rivastigmine may diminish with disease progression, as fewer cholinergic neurons remain functionally intact.26

$310

Donepezil (Aricept)

Eisai

Enhances cholinergic function by increasing the concentration of acetylcholine through reversible inhibition of its hydrolysis by acetylcholinesterase.27

$340 to $380 depending on dosage and formulation

Memantine (Namenda)

Forest Pharmaceuticals

N-methyl-D-aspartate (NMDA) receptor antagonism; memantine preferentially binds to the NMDA receptoroperated cation channels.28

$290

gers tau pathology,” says Dr. Trojanowski, “but solid evidence study will seek to quantify amyloid-related cognitive decline for this has been lacking since the earliest articulation of this and obtain data on nonamyloid factors that contribute to AD. hypothesis. We still do not have any studies to support the idea Imaging Techniques and that shutting down Aβ might affect tau pathology. Perhaps there Nonimaging Biomarkers will be a benefit in the earliest stages of the disease; shutting down Aβ may attenuate or block the progression of some of Because a successful treatment for AD may require interventhe other pathologies in Alzheimer’s disease, including tangles, tion prior to the emergence of symptoms, early identification of Lewy bodies, and [protein] TDP-43—we don’t know for sure. pathology that indicates an increased likelihood of developing Suppressing the plaques at an early stage also could result in a AD dementia is critical. Imaging and nonimaging biomarkers, transient effect; it’s possible there could be a plateau for a year as well as genetic information, are necessary to improve the or more, and then the disease could come back sensitivity and specificity of all assessments, with a vengeance because of the spread of the from those undergone at presymptomatic other pathologies. stages of the disease to those associated with “It’s important to continue to pursue other the monitoring of treatment. The field has seen targets,” Dr. Trojanowski adds. “I think comremarkable growth in all of these areas. bination therapy is the way of the future, and “We now have three FDA-approved amyloid tend to agree with colleagues who say that we imaging agents, including florbetapir (Amyvid, are now witnessing the last of the era of the Avid Radiopharmaceuticals, approved in monotherapy clinical trials. An initial resistance 2012)10 followed by flutemetamol (Vizamyl, to the idea of combination therapy existed in GE Healthcare) and florbetaben (Neuraceq, other therapeutic areas, in cancer and AIDS, Piramal Imaging), that build on the foundation of for example, and yet, particularly for AIDs, it the research tracer [11C] Pittsburgh Compound has turned out to be the winning strategy.” B (PiB)11 for the detection of cerebral amyloid burden in individuals with cognitive changes,” Indeed, Dr. Sperling, who is co-lead investigaReisa Sperling, MD says Andrew Saykin, PsyD, ABCN, Director of tor of the A4 trial (see “Current Clinical Trials” later in this article) intends to pursue non­amyloid as well as the Indiana Alzheimer Disease Center at Indiana University amyloid targets, expecting that the A4 trial design will serve School of Medicine and Genetics Core Leader at the Alzheimer’s as a platform for future secondary prevention trials with other Disease Neuroimaging Initiative (ADNI). “These F18-labeled agents, and ultimately for combinations of agents.9 In addition, PET [positron-emission tomography] tracers are an important individuals screened for the trial who do not show evidence of improvement over the first generation of experimental amyloid elevated amyloid accumulation may be eligible to participate tracers labeled with C11, which has a very short half-life. in LEARN, a companion observational study. The LEARN “Another major development has been the standardiza-

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After Disappointments, Alzheimer’s Researchers Seek Out New Paths tion of quantitative MRI [magnetic resonance neuro­degenerative changes leading to other imaging] markers, particularly for morphoforms of dementia. Unlike CSF, where multimetric analysis of the integrity of structures plex assays can search for a range of abnormal proteins, in most cases PET scans are limited such as the entorhinal cortex and hippocampus [Figure 1], which are affected early, as well as to a single molec­ular target, such as amyloid for assessing cortical thickness,” Dr. Saykin plaque. Usually only one or two PET scans are administered to minimize radiation exposure.” says. “These atrophy measures previously required very time-consuming manual meas­ Imaging can provide information that is sigurements and now can be estimated using nificantly more detailed when used in conjuncsophisticated software packages. Also importion with genetic information and nonimaging biomarkers. tant are advanced MRI techniques12 such as diffusion tensor imaging, resting state, and “Different biomarkers are likely to be more task-based functional MRI, arterial spin labeluseful at particular stages of disease or in ing perfusion, and MR spectroscopy, all of screening different at-risk groups,” Dr. Saykin Andrew Saykin, which provide complementary mechanistic says. “Once AD is detected during the early prePsyD, ABCN data. While all of these noninvasive MRI techclinical or prodromal phases, prior to extensive niques have proven to be sensitive to early stages of disease, neurodegenerative changes, imaging can serve as a longituit is not yet clear which ensemble of techniques will be most dinal biomarker to monitor response to therapy. Imaging and reliable, informative, and predictive as a biomarker for AD.” other approaches such as CSF analysis and genetics provide complementary information when used in combination. Our New developments in the realm of tau imaging,13,14 although group and others have reported, for example, that PET, MRI, still in the early stages, also have been very encouraging. Many CSF, and plasma biomarker results are all significantly influ­ outside of the field, including patients and their families, hope enced by variation in APOE and other genes.” that sophisticated imaging techniques may eventually replace the more invasive collection of cerebrospinal fluid (CSF) via Progress in the development of blood-based biomarkers,15 lumbar puncture, but for now researchers still depend on which is occurring at a very rapid pace,16 is tempered somewhat CSF assays. by the need for validation. “Advances in imaging already provide noninvasive means for “There is a critical need for inexpensive and noninvasive detecting AD-related changes or heightened risk for progresbiological markers to improve early detection and diagnosis of AD,” says Maria Carrillo, PhD, Vice President of Medical and sive cognitive decline,” says Dr. Saykin. “However, as with all methods, imaging has limitations. For example, despite Scientific Relations at the Alzheimer’s Association. “Blood-based the great progress in PET tracers for amyloid and tau, PET biomarkers with the potential for widespread clinical use will cannot yet detect several other important proteins that cause need to be validated in large groups of subjects who are represen-

Healthy Brain

Cerebral cortex

Ventricles

Severe Alzheimer’s Disease

Ventricles

Hippocampus Entorhinal cortex Figure 1 A Healthy Brain Compared to One With Advanced Alzheimer’s Disease This illustration shows the effects of advanced Alzheimer’s disease on the brain. The cerebral cortex, entorhinal cortex, and hippocampus shrink dramatically, damaging areas responsible for cognition and memory. Fluid-filled ventricles become larger. Source: National Institute on Aging

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After Disappointments, Alzheimer’s Researchers Seek Out New Paths (APP) mutations have been assigned to receive solanezumab or gantenerumab in a phase 2 trial that may last up to two years. If biomarker endpoints are successfully met in the phase 2 trial, participants will make a seamless transition to a phase 3 trial (the DIAN-TU Adaptive Prevention Trial) with a cognitive endpoint and an expected total enrollment of 400 participants. Presenilin 1, presenilin 2, and APP mutations are rare, and individuals with these mutations together account for less than 1 percent of all individuals who develop AD. The goal of the DIAN-TU trials is to use biomarkers of target engagement, such as amyloid PET and CSF amyloidbeta measures, in addition to downstream biomarkers, including CSF tau, phospho-tau, MRI structural atrophy, functional MRI, PET with [18F]-fluorodeoxyglucose, and tau PET imaging, to track changes in the brains of individuals with these gene mutations who have not yet developed AD. The trial will also seek to test drugs that may slow or halt disease-related changes and possibly prevent the emergence of Maria Carrillo, PhD Current Clinical Trials symptoms such as memory loss. The DIAN-TU Current clinical trials, characterized by a new focus on trial platform is evaluating additional drugs to test in registration trials with built-in seamless transitions from biomarker secondary prevention, involve the testing of populations to cognitive endpoints. comprising asymptomatic individuals at risk of developing AD, presymptomatic individuals with AD-related mutations, and/or individuals with prodromal AD. The Collaboration The API ADAD Study for Alzheimer’s Prevention (CAP) consortium facilitates colThe Alzheimer’s Prevention Initiative (API) Autosomal laborative interactions among the first four of the following Dominant Alzheimer’s Disease (ADAD) trial is one of the first trials to maximize translatable findings. The Food and Drug prevention trials conducted in cognitively healthy individuAdministration and European Medicines Agency, with input als who are certain to develop AD because of their genetic from CAP, issued guidance to assist these trials in pursuing background. This study will include approximately 300 people an innovative regulatory pathway.17 from a large extended family in Colombia who share risk for a rare genetic mutation that typically triggers AD symptoms around age 45.20,21 The A4 Study The Anti-Amyloid Treatment in Asymptomatic Alzheimer’s Participants in the double-blind, placebo-controlled trial Disease (A4) study9 is a three-year, placebo-controlled, randomwill receive an injection of either crenezumab (Genentech/ ized clinical trial that will screen 5,000 clinically normal older AC Immune) or a placebo at set intervals for up to five years. individuals to identify and enroll 1,000 with increased amyloid The study will test whether crenezumab can protect paraccumulation on PET imaging, who are thus at increased risk ticipants in the short or long term from developing signs of for cognitive decline. Individuals enrolled in the first trial will AD. Using targeted biomarkers, state-of-the-art imaging, and be randomized to receive solanezumab or placebo; screened sophisticated cognitive measures—which allow researchers individuals who do not show evidence of elevated amyloid to detect and track the disease presymptomatically—researchaccumulation may be eligible to participate in the LEARN ers will be able to see whether the amount of amyloid in the brain decreases, whether brain size is maintained, and, most study, a companion observational arm that will run parallel to importantly, whether cognitive function is preserved. the A4 treatment arm with identical cognitive assessments. A4 and LEARN study participants will be followed for 168-week In addition, to better understand the natural process of treatment and observation periods. Investigators anticipate early-onset autosomal-dominant AD, researchers will compare that the A4 trial design will serve as a platform for secondary changes in clinical symptoms and signs over time in people prevention trials with other anti-amyloid agents, such as betawith and without the mutation who are treated with a placebo. secretase inhibitors, and for combinations of agents. Following the completion of the trial, efficacy and biomarker data and findings will be shared with the entire research community. tative of a diverse aging population, and the gathering, storage, and processing of such biomarkers must be standardized for dependability of use and consistent interpretation of results.” An International Society to Advance Alzheimer’s Research and Treatment (ISTAART) professional interest area (PIA) is creating standards and guidelines for the development of novel blood biomarkers and intends to validate them for use in research settings, clinical trials, diagnostics, and clinical practice. This ISTAART PIA also is developing a central data repository and sample bank network. “A blood test for determining cholesterol levels is now available almost anywhere in the world,” Dr. Carrillo says, “and there are recognized standards for how and when to take the blood, how to process it, and how to interpret the results. The ISTAART PIA will help develop similar standards for AD biomarkers, so that eventually simple predictive and diagnostic tests can be effectively implemented.”

The DIAN-TU Study

In 2012, the Dominantly Inherited Alzheimer’s Network Trials Unit (DIAN-TU)18,19 launched a phase 2/3, randomized, double-blind, placebo-controlled, multicenter study of solanezumab or gantenerumab (Hoffman-LaRoche) in individuals at risk for dominantly inherited AD. A total of 210 participants with presenilin 1, presenilin 2, or amyloid precursor protein

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The TOMMORROW Trial

The TOMMORROW trial is designed to test the effectiveness of pioglitazone (AD-4833; Takeda), a drug already FDAapproved to treat type-2 diabetes, in the prevention of AD in individuals at risk for the disease. It also will examine the degree to which the TOMM40 risk allele confers a greater

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After Disappointments, Alzheimer’s Researchers Seek Out New Paths placebo, based on comparisons of cognitive decline, functional decline, and changes in activities of daily living. Approximately 5,800 asymptomatic individuals between the ages of 65 and 83 years will be screened with the goal of enrolling about 120 participants at each of approximately 50 sites. All participants will undergo a blood test to establish APOE and TOMM40 genotypes. Cognitively normal individuals determined to be at high risk for developing AD will be randomized to receive either AD-4833 or placebo, and those in the treatment group will receive AD-4833 orally once per day.

The SNIFF Study

The Study of Nasal Insulin in the Fight Against Forgetfulness (SNIFF) is a multicenter, double-blind, placebo-controlled phase 2/3 trial sponsored by the Alzheimer’s Disease Cooperative Study to evaluate the impact of inhaled insulin in participants with mild memory impairment and early AD.23 In this 18-month study, approximately 240 people ages 55 to 85 years will be given either intranasal insulin (INI) or placebo for 12 months, followed by an open-label six-month period during which all participants will receive INI. Some evidence indicates that insulin performs multiple functions in the brain and that insulin dysregulation may contribute to AD pathogenesis. INI has shown promise in short-term clinical trials. Conducted at 29 locations, SNIFF will examine INI’s effects on cognition, entorhinal cortex and hippocampal atrophy, and CSF biomarkers. The study aims to examine whether baseline AD biomarker profile, gender, or the presence of the APOE4 allele predict treatment response.

Conclusion

Figure 2 A Healthy Neuron Versus a Diseased Neuron Illustrations of a healthy neuron (above) and a diseased neuron (below). In Alzheimer’s disease, many neurons stop functioning, lose connections with other neurons, and die. Alzheimer’s disrupts processes vital to neurons and their networks, including communication, metabolism, and repair. Source: National Institute on Aging chance of developing AD.22 In this five-year, phase 3, double-blind, placebo-controlled study, researchers will examine whether pioglitazone’s ability to regulate glucose metabolism and insulin sensitivity and reduce inflammation will have a protective effect that is sufficient to prevent high-risk patients from developing mild cognitive impairment and AD. Pioglitazone’s efficacy in delaying the onset of AD in cognitively normal individuals will be compared with

During the past decade, clinical trials that have focused on strategies for reducing the production and accumulation of Aβ in the brains of individuals with AD have offered valuable information. They have launched a new era of AD prevention trials, in which the pursuit of methods for modulating Aβ levels will be accompanied by the use of novel biomarkers that should offer greater insights into the role that Aβ plays in the disease process. Knowledge gleaned from these trials also has begun to inform the development of drugs that address nonamyloid targets, including at least one that involves a creative method for crossing the blood–brain barrier,23 and most likely will continue to inform research that ultimately moves in the direction of combination therapy.

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Salloway S, Sperling R, Fox NC, et al. Two phase 3 trials of bapineuzumab in mild-to-moderate Alzheimer’s disease. N Engl J Med 2014;370(4):322–333. Doody RS, Thomas RG, Farlow M, et al. Phase 3 trials of solanezumab for mild-to-moderate Alzheimer’s disease. N Engl J Med 2014;370(4):311–321. Vellas B, Black R, AN1792 (QS-21)-251 Study Team, et al. Longterm follow-up of patients immunized with AN1792: reduced functional decline in antibody responders. Curr Alzheimer Res 2009;6(2):144–151. Sperling RA , Jack CR, Aisen PS. Testing the right target and right drug at the right stage. Sci Transl Med 2011;3(111):111cm33. Arnold SE, Louneva N, Cao K, et al. Cellular, synaptic, and biochemical features of resilient cognition in Alzheimer’s disease. Neurobiol Aging 2013;34(1):157–168. continued on page 374

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Alzheimer’s Researchers Seek New Paths continued from page 369 6. Negash S, Wilson RS, Leurgans SE, et al. Resilient brain aging: characterization of discordance between Alzheimer’s disease pathology and cognition. Curr Alzheimer Res 2013;10(8):844–851. 7. Wirth M, Villeneuve S, Haase CM, et al. Associations between Alz­ heimer disease biomarkers, neurodegeneration, and cognition in cognitively normal older people. JAMA Neurol 2013;70(12):1512–1519. 8. Villemagne VL, Burnham S, Bourgeat P, et al. Amyloid β deposition, neurodegeneration, and cognitive decline in sporadic Alzheimer’s disease: a prospective cohort study. Lancet Neurol 2013;12(4):357–367. 9. Sperling RA, Rentz DM, Johnson KA, et al . Stopping AD before symptoms begin? Sci Transl Med 2014;6(228):228fs13. 10. Doraiswamy PM, Sperling RA, Johnson K, et al. Florbetapir F 18 amyloid PET and 36-month cognitive decline: a prospective multicenter study. Molecular Psychiatry [published online ahead of print March 11, 2014] doi:10.1038/mp.2014.9. 11. Klunk WE, Engler H, Nordberg A, et al. Imaging brain amyloid in Alzheimer’s disease with Pittsburgh Compound-B. Ann Neurol 2004;55(3):306–319. 12. Risacher SL, Saykin AJ. Neuroimaging and other biomarkers for Alzheimer’s disease: the changing landscape of early detection. Annu Rev Clin Psychol 2013;9:621–648. 13. Maruyama M, Shimada H, Suhara T, et al. Imaging of tau pathology in a tauopathy mouse model and in Alzheimer patients compared to normal controls. Neuron 2013;79(6):1094–1108. 14. Xia CF, Arteaga J, Chen G, et al. [(18)F]T807, a novel tau positron emission tomography imaging agent for Alzheimer’s disease. Alzheimers Dement 2013:9(6):666–676. 15. Snyder HM, Carrillo MC, Grodstein F, et al. Developing novel blood-based biomarkers for Alzheimer’s disease. Alzheimers Dement 2014;10(1):109–114. 16. Mapstone M, et al Plasma phospholipids identify antecedent memory impairment in older adults. Nat Med 2014; doi:10.1038/ nm.3466. 17. Kozauer N, Katz R. Regulatory innovation and drug devel­ opment for early-stage Alzheimer’s disease. N Engl J Med 2013;368(13):1169–1171. 18. Bateman RJ, Xiong C, Benzinger TL, et al. Clinical and biomarker changes in dominantly inherited Alzheimer’s disease. N Engl J Med 2012;367(9):795–804. 19. Moulder KL , Snider BJ, Mills SL, et al. Dominantly Inherited Alzheimer Network: facilitating research and clinical trials. Alzheimer’s Res Therapy 2013;5(5):48. 20. National Institutes of Health. A study of crenezumab versus pla­ cebo in preclinical PSEN1 E280A mutation carriers to evaluate efficacy and safety in the treatment of autosomal-dominant Alzheimer disease, including a placebo-treated noncarrier cohort. Available at: http://www.clinicaltrials.gov/ct2/show/ NCT01998841. Accessed April 14, 2014. 21. Reiman EM, Quiroz YT, Fleisher AS, et al. Brain imaging and fluid biomarker analysis in young adults at genetic risk for autosomal dominant Alzheimer’s disease in the presenilin 1 E280A kindred: A case-control study. Lancet Neurol 2012;11(12):1048–1056. 22. National Institutes of Health. Biomarker qualification for risk of mild cognitive impairment (MCI) due to Alzheimer’s disease (AD) and safety and efficacy evaluation of pioglitazone in delaying its onset. Available at: http://clinicaltrials.gov/show/NCT01931566. Accessed April 14, 2014. 23. National Institutes of Health. The study of nasal insulin in the fight against forgetfulness (SNIFF). Available at: http://clinicaltrials. gov/show/NCT01767909. Accessed April 14, 2014. 24. Red Book Online. Ann Arbor, Michigan; Truven Health Analytics. Accessed April 2, 2014. 25. Razadyne, prescribing information. Titusville, New Jersey; Janssen Pharmaceuticals; 2013. 26. Exelon, prescribing information. East Hanover, New Jersey; No­ vartis Pharmaceuticals; 2013. 27. Aricept, prescribing information. Woodcliff Lake, New Jersey; Eisia Inc.; 2013. 28. Namenda, prescribing information. St. Louis, Missouri; Forest Laboratories; 2013. n

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After disappointments, Alzheimer's researchers seek out new paths: biomarkers and combination therapies may lead to disease-modifying treatments, experts say.

Developing a disease-modifying treatment for Alzheimer's disease has stymied researchers. A collaborative re-examination of premises that guided disap...
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