Bruce Albala

Detecting cognitive changes in preclinical Alzheimer's disease: A review of its feasibility

Significant progress has been made in characterizing the biological changes occurring in preclinical Alzheimers disease (AD). Cognitive dysfunction has been viewed, however, as a late‐stage phenomenon, despite increasing evidence that changes may be detected in the decades preceding dementia. In the absence of comprehensive evidence‐based guidelines for preclinical cognitive assessment, longitudinal cohort and neuroimaging studies have been reviewed to determine the temporal order and brain biomarker correlates of specific cognitive functions. Episodic memory decline was observed to be the most salient cognitive function, correlating with high levels of amyloid deposition and hypoconnectivity across large‐scale brain networks. Prospective studies point to early decline in both episodic and semantic memory processing as well as executive functions in the predementia period. The cognitive tests have, however, been principally those used to diagnose dementia. New procedures are required which target more finely the medial temporal lobe subregions first affected by clinically silent AD pathology.

Recommended cognitive outcomes in preclinical Alzheimer's disease: Consensus statement from the European Prevention of Alzheimer's Dementia project

The Horizon 2020/IMI European Prevention of Alzheimers Dementia (EPAD) project will undertake large‐scale proof‐of‐concept trials in predementia Alzheimers disease (AD). Within EPAD, the monitoring of cognitive trajectories in the preclinical period will constitute a central outcome measure; however, there are currently no clear guidelines as to how this should be achieved as most measures have been developed for the period around dementia diagnosis. The EPAD Scientific Advisory Group for Clinical and Cognitive Outcomes identified appropriate cognitive measures based on a literature search covering both cognitive correlates of preclinical brain changes from imaging studies and cognitive changes observed over time in nondementia population cohorts developing incident dementia. These measures were evaluated according to the following criteria: validity, coherence with biomarker changes, psychometric properties, cross‐cultural suitability, availability of alternative forms, and normative data limited practice effects. The resulting consensus statement provides recommendations for both future drug trials and research into preclinical Alzheimers disease.

A single dose of the beta-secretase inhibitor, e2609, decreases CSF bace1 enzymatic activity in cynomolgus monkeys

Figure 2. Correlation Between CSF BACE1 Activity Levels and CSF Ab 1-x levels in All Monkey Samples Mark Matijevic, Hideki Watanabe, Yoshiaki Sato, Francois Bernier, Shannon McGrath, Lynne Burns, Noboru Yamamoto, Makoto Ogo, Zoltan Dezso, Jesse Chow, Yoshiya Oda, June Kaplow, Bruce Albala, Eisai, Andover, MA, USA; Eisai, Tsukuba, Japan; Formerly Eisai (when work was completed), Worcester, MA, USA; Eisai, Woodcliff Lake, NJ, USA; Eisai,Woodcliffe Lake, NJ, USA. Contact e-mail: mark_matijevic@eisai.com

ELENBECESTAT, A NOVEL BACE INHIBITOR, DEMONSTRATES SIMILAR PHARMACOKINETICS AND TOLERABILITY IN JAPANESE SUBJECTS WITH MULTIPLE DOSINGS

in the clinical outcomes. The decline in cognition and other clinical endpoints over 18 months in participants receiving verubecestat was similar across all exposure quartiles. The estimated slope of AUC effect on ADAS-cog disease progression was small (-4.4e-5) and the 90% CI contained zero. Conclusions:Overall, these results indicate that EPOCH tested drug exposures and target engagement consistent with 72% and 90% inhibition of Ab production at the 12 and 40 mg doses, respectively. Together with the lack of exposure-dependency in the cognition data, these results suggest that insufficient dose or target engagement was not the driver for the failure to meet the clinical endpoints as expected exposures were achieved. Ref 1. Clin Pharmacol Ther. 2015 Mar;97(3):210-4.

PRECLINICAL STUDIES WITH ELENBECESTAT, A NOVEL BACE1 INHIBITOR, SHOW NO EVIDENCE OF HYPOPIGMENTATION

inhibition of LTP in a dose-dependent manner. Finally, we examined if systemic passive immunization could prevent or reverse the persistent inhibition of LTP measured in vivo 7 days after a single i.c.v. injection of synthetic Aß42. A single systemic injection of MEDI1814, given either prior to i.c.v. treatement with Aß on day 1, or prior to recording synaptic plasticity on day 7, prevented the disruption of LTP. In contrast, neither prenor post-Aß treatment with the control antibody was effective. Conclusions: Intracerebral or systemic administration of a high affinity monoclonal antibody directed to the C-terminus of Aß42 rapidly prevents or reverses synaptic plasticity impairment in the rat hippocampus caused by synthetic or human AD brainderived Ab aggregates.