Norman Relkin, MD, PhD 

Medscape Neurology & Neurosurgery.  2006;8(2) ©2006 Medscape

　

Introduction

There were no unequivocal breakthroughs in the treatment of Alzheimer's disease (AD) announced at the 2006 International Conference on Alzheimer's Disease (ICAD) in Madrid, Spain, July 15-20. However, this meeting did highlight many exciting works in progress, ranging from methods for early and more accurate differential diagnosis of dementia to an impressive array of potential disease-modifying treatments in various stages of preclinical and clinical development.

Diagnostics

Amyloid Imaging

A full day's satellite conference and several scientific sessions at ICAD were devoted entirely to the topic of brain imaging of dementia and mild cognitive impairment (MCI). More than a dozen presentations involved the positron emission tomography (PET) radioligand, called the Pittsburgh Compound (PIB), which binds to fibrillar beta-amyloid in the brain to create images of plaque neuropathology in living patients. Several investigations examined PIB's utility in distinguishing among patients with clinically diagnosed MCI, AD, depression and other forms of dementia. Alexander Frizell Santillo and colleagues^[1] reported that PIB could distinguish most cases of AD from frontotemporal dementias (FTD), although at least 2 cases out of 10 with FTD showed some PIB retention. It is unclear whether the latter is due to age-related amyloid deposition in some patients with FTD, coincident AD in those patients, or binding of PIB to proteins other than beta-amyloid. Agneta Nordberg and colleagues^[2] made several interesting observations in a study that was the first to examine the performance of PIB in serial scans performed in the same patients over a 2-year period. They reported that PIB showed a 3% to 7% test-retest reliability, suggesting that the technique may be sufficiently reproducible to permit monitoring response to antiamyloid treatments over time. Among MCI patients in the study who progressed to frank AD, all were found to have PIB retention. However, there was no significant change in PIB retention in individual AD patients after 2 years despite decreasing cerebral metabolism over the same time.

These and other studies collectively suggest that PIB may be an early marker of cerebral amyloid deposition, but that it may not be sensitive to progression of disease once dementia becomes manifest. Further studies are needed to establish whether PIB has suitable characteristics for clinical use and if so, how it can be used.

Cerebrospinal Fluid Biomarkers

Several presentations at ICAD focused on the use of small panels of cerebrospinal fluid (CSF) biomarkers to improve the diagnosis and prediction of AD. Sebastiaan Engelborghs and colleagues^[3] presented data indicating that the cerebrospinal fluid markers beta-amyloid-42, total tau, and phospho-tau-181 have diagnostic sensitivity and specificity equal to that of a full clinical battery of tests for AD. Kaj Blennow^[4] reported that these particular markers in combination are useful for identifying MCI patients at highest risk of progressing to AD. In a 4-year study of 134 patients with MCI in which CSF samples were taken at baseline, the combination of CSF total-tau and beta-amyloid 42/phospho-tau181 ratio was 95% sensitive and 87% specific in distinguishing patients progressing to AD from those with MCI who did not progress or who developed other dementias. Further prospective studies will be required to establish the value of this battery of CSF markers in predicting conversion from MCI to AD in actual clinical practice.

Therapeutics

Existing Therapies

One of the few studies presented at ICAD that could have an impact on AD clinical practice in the relatively near future was a clinical trial of a new patch for transdermal administration of rivastigmine. Oral rivastigmine is currently approved for treating symptoms of mild-to-moderate Alzheimer's disease and recently became the first cholinesterase inhibitor approved in the United States to treat dementia in Parkinson's disease. Bengt Winblad and colleagues^[5] presented results of the IDEAL trial, a 1195-patient study sponsored by Novartis that compared 2 doses of a transdermal-delivery rivastigmine patch (equivalent to 9.4 mg/24 h and 17.4 mg/24 h, respectively) and 6 mg oral capsules twice daily vs placebo. The lower-dose patch was as effective as the oral therapy, but it was associated with only about one third as many gastrointestinal side effects. No difference in side effects was observed between the higher-dose patch and oral treatment. Because gastrointestinal side effects are the type most frequently reported in association with this agent, the low-dose transdermal delivery system appears to offer advantages in terms of tolerability.

Malin Degerman Gunnarsson and colleagues^[6] presented results of a small study that investigated CSF obtained from 9 AD patients treated with memantine. Her group found a statistically significant effect on phospho-tau, a biomarker associated with AD neurofibrillary pathology. Two other biomarkers related to neuronal death (total tau) and plaques (beta-amyloid) were unchanged. No clinically significant effect on disease progression was observed in the patients in this study. It was concluded that follow-up studies will be needed to determine whether memantine does exert a disease-modifying effect in AD.

The AD Therapeutic Pipeline

There has been phenomenal growth in the number and types of treatments for AD under development. The largest number of presentations at ICAD were about altering processing of the beta-amyloid peptide, followed by strategies relating to the tau protein, inflammation, oxidative stress, and other mechanisms. A considerable amount of attention at this meeting was afforded to medications used to treat diabetes, based largely on epidemiologic studies showing decreased risk for dementia in patients receiving these agents.

Peroxisome Proliferator-Activated Receptor-Gamma (PPAR-gamma) Agonists

The potential use of antidiabetes medications for treating AD is supported by clinical evidence and by epidemiologic observations of reduced risk for AD among diabetics treated with certain oral hypoglycemic agents. PPAR-gamma agonists in particular are under study as potential treatments for AD owing to their reported effects on beta-amyloid levels and suppression of inflammation in animal models of AD. Pioglitazone is a PPAR-gamma agonist approved to treat type 2 diabetes mellitus and was studied by David Geldmacher and colleagues^[7] in an 18-month, double-blind, placebo-controlled, add-on pilot study in 29 subjects with mild-to-moderate AD. The study authors reported that there was no statistically significant group differences observed in measures of cognition, function, or behavior between the pioglitazone 45 mg daily (n = 14) and placebo (n = 15) groups, although a 3.5-point mean difference in the age-adjusted ADAS-Cog (Alzheimer's Disease Assessment Scale - Cognitive) was observed at 12 months.

Rosiglitazone is another PPAR-gamma agonist approved to treat type 2 diabetes. Studied previously in over 500 AD patients, it was reported to show no significant effects on cognition in the primary intention-to-treat analysis but a positive clinical response in apoliprotein E epsilon 4 allele (APOE ε4) noncarriers.^[8] David Hosford and colleagues^[9] further analyzed this dataset. As in the analysis of the ADS-Cog data, no significant treatment effects were observed at week 24 for measures of global clinical status (CIBIC-Plus), behavior (NPI), functional status (DAD), or cognition (MMSE). Exploratory analyses suggested that improvement in APOE ε 4 noncarriers found on the ADAS-Cog was also observed for the CIBIC-Plus, DAD, and NPI measures. Further studies will be needed to establish whether PPAR-gamma agonists are of value in treating AD.

Immunotherapy

While most of the presentations at ICAD concerning immunotherapy were preclinical in nature, a few clinical trial results were discussed.

Tyler Kokjohn and colleagues^[10] examined brains from 2 patients immunized in the Elan-sponsored AN-1792 active vaccination study. One of the 2 patients died after developing meningoencephalitis that ultimately led to premature termination of that study. Kokjohn and coworkers found that active immunotherapy with AN-1792 successfully disrupted amyloid in senile plaques and diffuse deposits, but that impaired clearance of soluble amyloid from the brain raised levels of these potentially toxic intermediates in gray and white matter. These provocative results suggest that clearing plaques may not be sufficient to exert a therapeutic effect in AD unless this is coupled with a mechanism fostering clearance of soluble forms of amyloid. Second-generation active vaccination trials are now under way in AD patients.

Passive immunotherapy involves administration of antibodies from exogenous sources. Humanized monoclonal antibodies and natural human polyclonal antibody preparations are currently being tested in clinical trials. Eric Siemers and colleagues^[11] reported on the effects of a humanized mouse monoclonal antibody directed against the central domain of the amyloid molecule which is currently being tested as an agent for passive immunotherapy against beta-amyloid in mild-to-moderate AD. The study was not powered to show clinical efficacy, and no consistent changes in ADAS-Cog scores were observed. The focus of this study was to assess the safety profile and effects of this antibody on amyloid-related biomarkers. Two out of 4 subjects who received the 10-mg/kg dose experienced mild shaking and dizziness that lasted less than 2 hours after the infusions. Robust and highly significant increases in plasma beta-amyloid 40 concentrations were observed with all doses, and an increase in CSF beta-amyloid 40 was observed at all but the lowest antibody concentration. These findings indicate that this monoclonal antibody is well tolerated at all but the highest dose tested, and that it exerts measurable effects on amyloid dynamics in plasma and CSF.

Basia Adamiak and colleagues^[12] presented 18-month results from an open-label clinical study of intravenous immunoglobulin (IVIg) in 8 patients with mild-to-moderate AD. A previous report found improvements in cognition and lower CSF amyloid levels after 6 months of IVIg treatment.^[13] When IVIg treatment was stopped for 3 months, these subjects declined. Resumption of IVIg arrested the decline in 6 of 8 subjects and maintained MMSE scores at or above pretreatment levels at 18 months. IVIg is now being studied in a placebo-controlled, double-blind phase 2 study.

A minority of medications currently under development target the tau protein, which is the central component of neurofibrillary tangles. In a novel approach to anti-tau therapy, Ayodeji Asuni and colleagues^[14] examined the effects of active immunization with tau peptide in transgenic (P301L) mice that develop neurofibrillary tangles. They found that the vaccine led to a tau-specific antibody response that significantly reduced aggregated tau in the brain but not soluble tau levels. In addition, the immunized animals performed better than the controls on behavioral tasks. While this study represents an early stage of preclinical development, it suggests that immunotherapy may be a viable approach to treating tau-related pathology in AD and other disorders.

R-flurbiprofen

Gordon Wilcock and colleagues^[15] reported results from a phase 2, double-blind, placebo-controlled 1-year trial of R-flurbiprofen (MPC-7869) in 207 patients with mild-to-moderate AD. R-flurbiprofen is described as a selective amyloid-beta 42-lowering agent on the basis of its properties in animal studies. Analysis of the phase 2 trial results stratified by stage of disease showed a benefit in measures of activities of daily living and global function at 12 months in mild AD patients who received an 800-mg twice-daily dose of flurbiprofen. These benefits appeared to persist 1-2 years later per results from a follow-up study. No benefit was observed in moderate AD patients. The agent was generally well tolerated and the authors considered the results sufficiently encouraging to warrant further clinical trials, which are ongoing.

Leuprolide

Scientists at Voyager Pharmaceutical hypothesize that AD is related to the dysregulation of luteinizing hormone (LH), which in turn may foster beta-amyloid accumulation and tau phosphorylation. Leuprolide acetate is an LH-releasing hormone agonist approved for treatment of prostate cancer, endometriosis, and a number of other conditions and is being tested as a potential treatment for AD. Barbra LaPlante and colleagues^[16] presented results from a subgroup analysis of 50 participants in a 109-patient phase 2, double-blind, placebo-controlled, dose-ranging clinical study of leuprolide for mild-to-moderate AD. Leuprolide was well tolerated in women with AD and fostered slower decline over 48 weeks on measures of cognition and global function as compared with placebo. Phase 3 pivotal studies of a proprietary formulation of leuprolide acetate are now under way.

Conclusion

There were far more approaches to AD diagnosis and treatment presented at ICAD than could be discussed in this brief review. Many of these agents are the subjects of studies in progress, and only limited clinical trial data were available for presentation at the 2006 ICAD meeting. This includes various secretase inhibitors, amyloid fibrillogenesis inhibitors, anti-inflammatories, antioxidants, statins, and homocysteine-lowering agents as well as other approaches. Despite their exclusion from this review, these and other treatments are under study as candidates for AD pharmacotherapy.

The overall impression conveyed at the 2006 ICAD meeting is that the field is maturing and advancing at a prodigious rate. New imaging methods are providing unprecedented glimpses of AD neuropathology in living patients. Proteomic and genomic based-approaches promise even more objective means of diagnosing AD and predicting progression from MCI to AD. Clinical trials now under way represent real-world tests of the amyloid hypothesis as well as competing theories of AD pathogenesis. It will still take several years for suitable studies to be completed to validate developments. While these advances may not come in time for those already affected by this illness, the direction and momentum of ongoing research provides considerable ground for encouragement about the future.

Santillo AF, Engler H, Kilander L, et al. PIB deposition in frontotemporal dementia in comparison with Alzheimer's disease and healthy volunteers: a PET study. Program and abstracts of the 10th International Conference on Alzheimer's Disease and Related Disorders; July 15-20, 2006; Madrid, Spain. Abstract P2-344. Nordberg AK, Forsberg A, Engler H, et al. PIB amyloid imaging in brain of AD and MCI patients — relation to CSF markers and cognition. Program and abstracts of the 10th International Conference on Alzheimer's Disease and Related Disorders; July 15-20, 2006; Madrid, Spain. Abstract IC-103-01. Engelborghs S, Marien P, Vloeberghs E, Somers N, Nagels G, De Deyn PP. Diagnostic performance of a CSF-biomarker panel compared to clinical diagnosis in 100 autopsy-confirmed dementia cases. Program and abstracts of the 10th International Conference on Alzheimer's Disease and Related Disorders; July 15-20, 2006; Madrid, Spain. Abstract O3-01-06. Blennow K. State and perpectives of biomarkers research using innovative methods, novel study design, and bio-banking. Program and abstracts of the 10th International Conference on Alzheimer's Disease and Related Disorders; July 15-20, 2006; Madrid, Spain. Abstract S4-01-06. Winblad B, Cummings J, Zechner S, et al. IDEAL: A 24-week placebo-controlled study of the first transdermal patch in Alzheimer's disease — rivastigmine patch versus capsule. Program and abstracts of the 10th International Conference on Alzheimer's Disease and Related Disorders; July 15-20, 2006; Madrid, Spain. Abstract HT-006. Degerman Gunnarsson M, Kilander L, Sudelof J, Basun H, Lannfelt L. Reduction of hyperphosphorylated-tau during memantine treatment of Alzheimer's disease. Program and abstracts of the 10th International Conference on Alzheimer's Disease and Related Disorders; July 15-20, 2006; Madrid, Spain. Abstract O3-05-07. Geldmacher DS, Fritsch T, McClendon MJ, Lerner AJ, Landreth GE. A double-blind, placebo-controlled, 18-month pilot study of the PPAR-gamma agonist pioglitazone in Alzheimer's disease. Program and abstracts of the 10th International Conference on Alzheimer's Disease and Related Disorders; July 15-20, 2006; Madrid, Spain. Abstract P2-408. Risner ME, Saunders AM, Altman JF, et al; Rosiglitazone in Alzheimer's Disease Study Group. Efficacy of rosiglitazone in a genetically defined population with mild-to-moderate Alzheimer's disease. Pharmacogenomics J. 2006;6:246-254. Epub 2006 Jan 31. Hosford DA, Altman JFB, Saunders AM, et al. Efficacy of rosiglitazone (RSG) in patients with mild to moderate Alzheimer's disease (AD). Program and abstracts of the 10th International Conference on Alzheimer's Disease and Related Disorders; July 15-20, 2006; Madrid, Spain. Abstract O4-03-07. Kokjohn TA, Beach TG, Esh CL, et al. Amyloid-beta peptide remnants in AN-1792-immunized Alzheimer's disease patients. Program and abstracts of the 10th International Conference on Alzheimer's Disease and Related Disorders; July 15-20, 2006; Madrid, Spain. Abstract P4-296. Siemers ER, Benson C, Gonzales C, et al. Safety assessments and biomarker changes following a monoclonal A beta antibody given to subjects with Alzheimer's disease. Program and abstracts of the 10th International Conference on Alzheimer's Disease and Related Disorders; July 15-20, 2006; Madrid, Spain. Abstract O4-03-04. Adamiak B, Monthe C, Bender H, et al. Intravenous immunoglobulin (IVIG) maintains cognition over 18 months in patients with Alzheimer's disease (AD). Program and abstracts of the 10th International Conference on Alzheimer's Disease and Related Disorders; July 15-20, 2006; Madrid, Spain. Abstract O3-05-04. Relkin N, Szabo P, Adamiak B, et al. Intravenous immunoglobulin (IVIg) treatment causes dose-dependent alterations in plasma beta-amyloid levels and anti-A beta antibody titers in plasma and cerebrospinal fluid of Alzheimer's disease patients. Neurology. 2005;64(suppl 1):A144. Asuni AA, Quartermain D, Sigurdsson EM. TAU-based immunotherapy for dementia. Program and abstracts of the 10th International Conference on Alzheimer's Disease and Related Disorders; July 15-20, 2006; Madrid, Spain. Abstract O2-05-04. Wilcock GK, Black SE, Hawort J, et al, MPC-7869 Phase 2 Study Investigators. Efficacy and safety of MPC-7869 (R-flurbiprofen), a selective A beta 42-lowering agent, in Alzheimer's disease (AD): results of a 12-month phase 2 trial and 1-year follow-on study. Program and abstracts of the 10th International Conference on Alzheimer's Disease and Related Disorders; July 15-20, 2006; Madrid, Spain. Abstract O4-03-08. LaPlante BJ, Powers CF, Gault JL, Reynolds BD, Gregory CW. Stabilization of cognitive decline in Alzheimer's disease following treatment with leuprolide acetate. Program and abstracts of the 10th International Conference on Alzheimer's Disease and Related Disorders; July 15-20, 2006; Madrid, Spain. Abstract P4-353.