Research update on Alzheimer’s disease and introduction to the Expert Review of Neurotherapeutics special issue

1. Context

There have been an increasing number of publications on new medications for Alzheimer’s disease (AD). Results from the first study in mild-to-moderate stages of AD using LMTM which inhibits the tau protein aggregation were recently published [1], and results from the second study in mild AD have been presented at the CTAD congress in San Diego on 8 December: although the analysis comparing low versus high doses in all participants showed no difference on cognitive and functional outcomes, there is the possibility that concurrent AD drugs interfered with the LMTM therapeutic activity. Similarly, the 5-HT6 receptor inhibitor antagonist idalopirdine which had shown encouraging results in donepezil-treated patients [2] did not show efficacy in high doses, but there is still hope for the lower doses still under testing. Thus, it appears that current trial designs where drugs are simply added on to each other do not allow to adequately measure positive (synergistic) and negative interactions. This is an important lesson as the field is planning combination therapies against various components of AD [3,4].

Results from a large-scale phase 3 study using the anti-amyloid drug solanezumab in mild AD were reported on 22 November as negative for the cognitive primary outcome. This antibody against the beta42-amyloid protein had shown encouraging results in mild AD using pooled analysis from two previous phase 3 studies [5]. Results from a phase 1b study using the monoclonal antibody aducanumab demonstrated a reduction in the amount of beta-amyloid in the brain and a stabilization of clinical decline that was dose-related [6]; this has led to a large phase 3 study, still enrolling. Drugs acting by inhibition of the enzyme ß-secretase (BACE1 inhibitor) such as verubecestat are showing encouraging results [7], and there is even consideration of combining acting on the amyloid protein in different ways (antibodies and BACE1 inhibitors).

This looks like a lot of medication to be used potentially in a lot of persons, and none has been demonstrated to achieve disease modification. Prevention of AD is thus clearly the current preferred alternative [8], and national plans in many countries are encouraging higher education and healthier lifestyles. The decrease in prevalence of dementia in the United States between 2000 and 2012 is attributed primarily to an increase in educational attainment [9], and other countries are reporting reductions attributed to stricter control of vascular risk factors in mid-life. An excellent overall perspective on how to defeat dementia has been written by science writer Elie Dolgin, in his feature news [10].

2. Introduction to this special issue

The articles selected for this special issue of Expert Review of Neurotherapeutics look back at lessons learned and look forward at alternatives to the current quasi-monopoly of anti-amyloid therapies. These articles look at the disease across its full spectrum.

From a diagnostic perspective, readers will find evidence that cerebrospinal fluid (CSF) and plasma biomarkers may play a role in the specific diagnosis of AD and as biological outcome variables (particularly neurogranin in CSF).

From a clinical trial design perspective, lessons learned from predominantly anti-amyloid drug trials include treat early, treat biologically and phenotypically homogeneous populations, use lower doses, possibly using shorter intervals when given by infusion, and take into account the rapidity of cognitive decline prior to randomization.

The evidence for and against the potential value of older drugs such as nonsteroidal anti-inflammatory drugs is described in detail and illustrates the current interest in neuroinflammation as a key pathophysiological component of AD, but at specific stages of the disease.

New therapeutic targets such as insulin resistance, mitochondrial dysfunction, and mTOR hyperactivity will be of great interest to readers.

3. Conclusions

The international authorship of this special issue, from Australia to South and North America, as well as Europe, illustrates global approach to dementia in general and to AD in particular. Even the World Health Organization is recognizing dementia as a global health priority.

Declaration of interest

S. Gauthier discloses clinical trial support from Lilly, Roche, TauRx and Lundbeck; he is a DSMB member for ADCS, ATRI, API and Eisai; he is a scientific advisor for AbbVie, Advantage, Alzheon, Axovant, Boehringer-Ingelheim, Firalis, Heptares, IntelGen, Kalgene, Lilly, Lundbeck, Novartis, Otsuka, Servier, Sanofi, Schwabe, Takeda, TauRx, TVM Capital and Roche. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Additional information

Funding

This paper was not funded.