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1.  Peripheral and central effects of γ-secretase inhibition by semagacestat in Alzheimer’s disease 
Introduction
The negative efficacy study examining the γ-secretase inhibitor semagacestat in mild to moderate Alzheimer’s disease (AD) included a number of biomarkers of the disease as well as safety outcomes. We analyzed these data to explore relationships between drug exposure and pharmacodynamic effects and to examine the correlations among outcome measures.
Methods
The study was a multicenter, randomized, placebo-controlled trial of two dose regimens of semagacestat and a placebo administered for 18 months to individuals with mild to moderate AD. Changes in measures of central and peripheral drug activity were compared between the three treatment groups using one-way analysis of variance. The relationship between changes in each of the outcome measures and measures of drug exposure and peripheral pharmacodynamic effect were assessed using Spearman’s correlation coefficient.
Results
Assignment to the active treatment arms was associated with reduction in plasma amyloid-β (Aβ) peptides, increase in ventricular volume, decrease in cerebrospinal fluid phosphorylated tau (p-tau) and several other laboratory measures and adverse event categories. Within the active arms, exposure to drug, as indicated by area under the concentration curve (AUC) of blood concentration, was associated with reduction in plasma Aβ peptides and a subset of laboratory changes and adverse event rates. Ventricular volume increase, right hippocampal volume loss and gastrointestinal symptoms were related to change in plasma Aβ peptide but not AUC, supporting a link to inhibition of γ-secretase cleavage of the amyloid precursor protein. Cognitive decline correlated with ventricular expansion and reduction in p-tau.
Conclusion
These findings may inform future studies of drugs targeting secretases involved in Aβ generation.
Trial registration
ClinicalTrials.gov Identifier: NCT00594568. Registered 11 January 2008.
Electronic supplementary material
The online version of this article (doi:10.1186/s13195-015-0121-6) contains supplementary material, which is available to authorized users.
doi:10.1186/s13195-015-0121-6
PMCID: PMC4461930  PMID: 26064192
2.  Autosomal-dominant Alzheimer's disease: a review and proposal for the prevention of Alzheimer's disease 
Autosomal-dominant Alzheimer's disease has provided significant understanding of the pathophysiology of Alzheimer's disease. The present review summarizes clinical, pathological, imaging, biochemical, and molecular studies of autosomal-dominant Alzheimer's disease, highlighting the similarities and differences between the dominantly inherited form of Alzheimer's disease and the more common sporadic form of Alzheimer's disease. Current developments in autosomal-dominant Alzheimer's disease are presented, including the international Dominantly Inherited Alzheimer Network and this network's initiative for clinical trials. Clinical trials in autosomal-dominant Alzheimer's disease may test the amyloid hypothesis, determine the timing of treatment, and lead the way to Alzheimer's disease prevention.
doi:10.1186/alzrt59
PMCID: PMC3109410  PMID: 21211070
3.  Alzheimer's disease therapeutic research: the path forward 
The field of Alzheimer's disease therapeutic research seems poised to bring to clinic the next generation of treatments, moving beyond symptomatic benefits to modification of the underlying neurobiology of the disease. But a series of recent trials has had disappointingly negative results that raise questions about our drug development strategies. Consideration of ongoing programs demonstrates difficult pitfalls. But a clear path forward is emerging. Successful strategies will utilize newly available tools to reconsider issues of diagnosis, assessment and analysis, facilitating the study of new treatments at early stages in the disease process at which they are most likely to yield major clinical benefits.
doi:10.1186/alzrt2
PMCID: PMC2719107  PMID: 19674435

Results 1-3 (3)