Safety, pharmacokinetics and quantitative EEG modulation of TAK-071, a novel muscarinic M1 receptor positive allosteric modulator, in healthy subjects.

Aims: TAK-071 is a muscarinic M receptor positive allosteric modulator designed to have low cooperativity with acetylcholine. This was a first-in-human study to evaluate the safety, pharmacokinetics, and pharmacodynamics of TAK-071.

Methods: TAK-071 was administered as single and multiple doses in a randomized, double-blind, placebo-controlled, parallel-group design in healthy volunteers alone and in combination with donepezil.

Measuring cognition and function in the preclinical stage of Alzheimer's disease.

The Alzheimer's Association's Research Roundtable met in November 2016 to explore how best to measure changes in cognition and function in the preclinical stage of Alzheimer's disease. This review will cover the tools and instruments currently available to identify populations for prevention trials, and measure subtle disease progression in the earliest stages of Alzheimer's disease, and will include discussions of suitable cognitive, behavioral, functional, composite, and biological endpoints for prevention trials. Current prevention trials are reviewed including TOMMOROW, Alzheimer's Prevention Initiative Autosomal Dominant Alzheimer's Disease Trial, the Alzheimer's Prevention Initiative Generation Study, and the Anti-Amyloid Treatment in Asymptomatic Alzheimer's to compare current approaches and tools that are being developed.

Estimating Alzheimer's Disease Progression Rates from Normal Cognition Through Mild Cognitive Impairment and Stages of Dementia.

Background: Alzheimer's Disease (AD) can be conceptualized as a continuum: patients progress from normal cognition to mild cognitive impairment (MCI) due to AD, followed by increasing severity of AD dementia. Prior research has measured transition probabilities among later stages of AD, but not for the complete spectrum.

Objective: To estimate annual progression rates across the AD continuum and evaluate the impact of a delay in MCI due to AD on the trajectory of AD dementia and clinical outcomes.

The potent BACE1 inhibitor LY2886721 elicits robust central Aβ pharmacodynamic responses in mice, dogs, and humans.

BACE1 is a key protease controlling the formation of amyloid β, a peptide hypothesized to play a significant role in the pathogenesis of Alzheimer's disease (AD). Therefore, the development of potent and selective inhibitors of BACE1 has been a focus of many drug discovery efforts in academia and industry. Herein, we report the nonclinical and early clinical development of LY2886721, a BACE1 active site inhibitor that reached phase 2 clinical trials in AD.

Validation of a multiplex assay for simultaneous quantification of amyloid-β peptide species in human plasma with utility for measurements in studies of Alzheimer's disease therapeutics.

The aim of this study was to validate the INNO-BIA plasma amyloid-β (Aβ) forms assay for quantification of Aβ1-40 and Aβ1-42 according to regulatory guidance for bioanalysis and demonstrate its fitness for clinical trial applications. Validation parameters were evaluated by repeated testing of human EDTA-plasma pools. In 6 separate estimates, intra-assay coefficients of variation (CV) for repeated testing of 5 plasma pools were ≤9% and relative error (RE) varied between -35% and +22%.