Advances in the therapy of Alzheimer’s disease: targeting amyloid beta and tau and perspectives for the future

Abstract

Worldwide multidisciplinary translational research has led to a growing knowledge of the genetics and molecular pathogenesis of Alzheimer’s disease (AD) indicating that pathophysiological brain alterations occur decades before clinical signs and symptoms of cognitive decline can be diagnosed. Consequently, therapeutic concepts and targets have been increasingly focused on early-stage illness before the onset of dementia; and distinct classes of compounds are now being tested in clinical trials. At present, there is a growing consensus that therapeutic progress in AD delaying disease progression would significantly decrease the expanding global burden. The evolving hypothesis- and evidence-based generation of new diagnostic research criteria for early-stage AD has positively impacted the development of clinical trial designs and the characterization of earlier and more specific target populations for trials in prodromal as well as in pre- and asymptomatic at-risk stages of AD.

Keywords:

• Alzheimer’s disease
• amyloid beta immunotherapy
• bapineuzumab
• biological markers
• clinical trials
• prevention
• randomized controlled trials • systems biology
• solanezumab
• tau immunotherapy

Financial & competing interests disclosure

H Hampel and S Lista are supported by the AXA Research Fund, the Fondation Université Pierre et Marie Curie and the ‘Fondation pour la Recherche sur Alzheimer’, Paris, France. The research leading to these results has received funding from the program ‘Investissements d’avenir’ ANR-10-IAIHU-06. H Hampel declares no competing financial interests related to the present article. During the last 36 months, he has received lecture honoraria and/or research grants and/or travel funding and/or participated in scientific advisory boards and/or as a consultant to diagnostic, biotechnology and pharmaceutical companies involved in the manufacture and marketing of biomarkers and/or diagnostics and/or drugs or medicinal products for cognitive impairment and Alzheimer’s disease including Boehringer-Ingelheim, Bristol-Myers Squibb, Elan Corporation, Novartis, Eisai Inc., Pfizer Inc., Sanofi-Aventis, Roche Pharmaceuticals and Diagnostics, GE Healthcare, Avid, Eli Lilly and Company, GlaxoSmithKline-Biologicals, Jung-Diagnostics, Cytox, Takeda, Isis Pharmaceutical Inc. He is co-inventor in pending patent submissions relating to biological markers and/or diagnostics and has not received any royalties. S Lista declares no conflict of interest.

LS Schneider is partially supported by NIH P50 AG05142 and California Department of Health Services.

M Kivipelto receives research support from the Academy of Finland, the Swedish Research Council, Alzheimer Association, AXA Research Fund and EU 7th framework large collaborative project grant (HATICE). She has served on scientific advisory boards for Pfizer Inc., Elan Corporation, Alzheon and Nutricia and received speaker honoraria from Janssen, Novartis, Pfizer Inc. and Merz.

S Sindi receives postdoctoral funding from the ‘Fonds de la recherche en santé du Québec (FRSQ)’.

B Dubois acts as a consultant for AFFiRiS, Boehringer-Ingelheim and Eli Lilly and Company; he receives support for his institution (Institut de la Mémoire et de la Maladie d’Alzheimer [IM2A]) by Pfizer Inc. and Roche; he receives support for clinical trials by Eli Lilly and Company, EnVivo Pharmaceuticals Inc., Roche and Cytox.

PS Aisen serves on a scientific advisory board for NeuroPhage; he has served as a consultant to Elan, Wyeth, Eisai, Bristol-Myers Squibb, Eli Lilly and Company, NeuroPhage, Merck, Roche, Amgen, Genentech, Abbott, Pfizer, Novartis, Bayer, Astellas, Otsuka, Daiichi, AstraZeneca, Janssen, Medivation, Ichor, Toyama, Lundbeck, Biogen Idec, iPerian, Probiodrug, Somaxon, Biotie, Cardeus, Anavex, Kyowa Hakko Kirin Pharma, Medtronic, Abbvie, Cohbar; and he receives research support from Eli Lilly, and the NIH (NIA U01-AG10483 [PI], NIA U01-AG024904 [Coordinating Center Director], NIA R01-AG030048 [PI] and R01-AG16381 [Co-I]).

E Giacobini, K Broich and R Nisticò declare no conflict of interest.

Key issues

• The pathogenesis of Alzheimer’s disease (AD) is extremely complex because it covers both genetic and environmental factors. A spectrum of genetic factors plays a central role in the expression of AD in late-onset or sporadic forms.

• Currently, accessible AD pharmacological interventions consist of cholinesterase inhibitors and an N-methyl-d-aspartate receptor uncompetitive antagonist, memantine. These drugs can alleviate some of the psychological/behavioral symptoms in AD patients. Effective pharmacological therapies for AD prevention and treatment – that is, disease-modifying therapies – are still missing.

• Progress in understanding the genetics and molecular pathogenesis of AD have been translated into experimental approaches aimed at slowing down the development of the disease. As a result, clinical trials assessing various potential AD treatments have been intensified. Among these, compounds targeting amyloid beta (Aβ) or tau protein likely represent the most promising therapeutic strategies.

• Approaches to immunization against Aβ require: active immunization utilizing full-length Aβ or Aβ analogues together with or without an adjuvant; passive immunization, based on the use of humanized anti-Aβ antibodies or intravenous immunoglobulins.

• Phase III clinical trials for intravenous bapineuzumab did not show clinical benefit on primary or secondary outcome. The meaning of its effect on lowering cerebrospinal fluid p-tau levels is uncertain but could represent an effect on further neurodegeneration. The bapineuzumab development program has been discontinued.

• Regarding solanezumab, while the primary end points were not met in EXPEDITION 1 and EXPEDITION 2 trials, data reported in the pooled mild AD patient subsets of the trials suggested a cognitive effect. Based on the analysis in the pooled mild AD patients, the development of solanezumab for managing AD-associated dementia continues with a third Phase III clinical trial in mild AD, called EXPEDITION 3.

• The current state of anti-tau therapy in humans parallels the early phases of the anti-Aβ treatment approach while it is not clear which type of Aβ or tau to target, for how long to treat or immunize and at which stage of the disease to intervene. It is also not clear which conformational state (oligomers or truncated tau or aggregated tau) is responsible for neuronal dysfunction and degeneration and how tau exerts its toxicity and, like for Aβ, it is not known at which disease stage tau aggregation blockers would be most effective.

• The debate on the new AD diagnostic criteria has encouraged the development of prevention trials in at-risk and preclinical stages of AD. Such prevention initiatives – namely, DIAN, API and A4 – are separate, but interconnected, long-lasting projects.

• Currently, in Europe, there are three ongoing randomized controlled trials to prevent cognitive impairment and dementia/AD: The Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability, the Multidomain Alzheimer Prevention Trial and the Prevention of Dementia by Intensive Vascular Care study. All RCTs use a multidomain interventional approach to target several dementia risk factors and reduce the risk of developing dementia.

• In the forthcoming years, future therapeutics development of AD pathology will be informed by advances in studies of whole genomes and by the introduction of more advanced systemic analyses resulting from combined transcriptomics, proteomics and metabolomics/lipidomics approaches that span from single molecules to pathway signatures in patients. Thus, a systems biology-based approach is expected to elucidate the pathogenesis of AD.

Notes