Introduction: Despite significant progress, a disease-modifying therapy for Alzheimer’s disease (AD) has not yet been developed. Recent findings implicate soluble oligomeric amyloid beta as the most relevant protein conformation in AD pathogenesis. We recently described a signaling cascade whereby oligomeric amyloid beta binds to cellular prion protein on the neuronal cell surface, activating intracellular Fyn kinase to mediate synaptotoxicity. Fyn kinase has been implicated in AD pathophysiology both in in vitro models and in human subjects, and is a promising new therapeutic target for AD. Herein, we present a Phase Ib trial of the repurposed investigational drug AZD0530, a Src family kinase inhibitor specific for Fyn and Src kinase, for the treatment of patients with mild-to-moderate AD. Methods: The study was a 4-week Phase Ib multiple ascending dose, randomized, double-blind, placebo-controlled trial of AZD0530 in AD patients with Mini-Mental State Examination (MMSE) scores ranging from 16 to 26. A total of 24 subjects were recruited in three sequential groups, with each randomized to receive oral AZD0530 at doses of 50 mg, 100 mg, 125 mg, or placebo daily for 4 weeks. The drug:placebo ratio was 3:1. Primary endpoints were safety, tolerability, and cerebrospinal fluid (CSF) penetration of AZD0530. Secondary endpoints included changes in clinical efficacy measures (Alzheimer’s Disease Assessment Scale – cognitive subscale, MMSE, Alzheimer’s Disease Cooperative Study – Activities of Daily Living Inventory, Neuropsychiatric Inventory, and Clinical Dementia Rating Scale – Sum of Boxes) and regional cerebral glucose metabolism measured by fluorodeoxyglucose positron emission tomography. Results: AZD0530 was generally safe and well tolerated across doses. One subject receiving 125 mg of AZD0530 was discontinued from the study due to the development of congestive heart failure and atypical pneumonia, which were considered possibly related to the study drug. Plasma/CSF ratio of AZD0530 was 0.4. The 100 mg and 125 mg doses achieved CSF drug levels corresponding to brain levels that rescued memory deficits in transgenic mouse models. One-month treatment with AZD0530 had no significant effect on clinical efficacy measures or regional cerebral glucose metabolism. Conclusions: AZD0530 is reasonably safe and well tolerated in patients with mild-to-moderate AD, achieving substantial central nervous system penetration with oral dosing at 100–125 mg. Targeting Fyn kinase may be a promising therapeutic approach in AD, and a larger Phase IIa clinical trial of AZD0530 for the treatment of patients with AD has recently launched. Trial registration: ClinicalTrials.gov: NCT01864655. Registered 12 June 2014.

Introduction: Recent studies have shown that several strains of transgenic Alzheimer’s disease (AD) mice overexpressing the amyloid precursor protein (APP) have cortical hyperexcitability, and their results have suggested that this aberrant network activity may be a mechanism by which amyloid-β (Aβ) causes more widespread neuronal dysfunction. Specific anticonvulsant therapy reverses memory impairments in various transgenic mouse strains, but it is not known whether reduction of epileptiform activity might serve as a surrogate marker of drug efficacy for memory improvement in AD mouse models. Methods: Transgenic AD mice (APP/PS1 and 3xTg-AD) were chronically implanted with dural electroencephalography electrodes, and epileptiform activity was correlated with spatial memory function and transgene-specific pathology. The antiepileptic drugs ethosuximide and brivaracetam were tested for their ability to suppress epileptiform activity and to reverse memory impairments and synapse loss in APP/PS1 mice. Results: We report that in two transgenic mouse models of AD (APP/PS1 and 3xTg-AD), the presence of spike-wave discharges (SWDs) correlated with impairments in spatial memory. Both ethosuximide and brivaracetam reduce mouse SWDs, but only brivaracetam reverses memory impairments in APP/PS1 mice. Conclusions: Our data confirm an intriguing therapeutic role of anticonvulsant drugs targeting synaptic vesicle protein 2A across AD mouse models. Chronic ethosuximide dosing did not reverse spatial memory impairments in APP/PS1 mice, despite reduction of SWDs. Our data indicate that SWDs are not a reliable surrogate marker of appropriate target engagement for reversal of memory dysfunction in APP/PS1 mice.

Background: Sleep disturbances have long been associated with Alzheimer’s disease (AD), and there is a growing interest in how these disturbances might impact AD pathophysiology. Despite this growing interest, surprisingly little is known about how sleep architecture and the broader neuronal network are affected in widely used transgenic mouse models of AD. Objective: We analyzed sleep and electroencephalography (EEG) power in three transgenic mouse models of AD, using identical and commercially available hardware and analytical software. The goal was to assess the suitability of these mouse lines to model sleep and the broader neuronal network dysfunction measured by EEG in AD. Methods: Tg2576, APP/PS1, and 3xTgAD transgenic AD mice were studied using in vivo EEG recordings for sleep/wake time and power spectral analysis. Results: Both the APP/PS1 model at 8– 10 months and the Tg2576 model at 12 months of age exhibited stage-dependent decreases in theta and delta power, and shifts in the power spectra toward higher frequencies. Stage-dependent power spectral analyses showed no changes in the 3xTgAD model at 18 months of age. The percentage of time spent awake, in non-rapid eye movement sleep (NREM), or in rapid-eye-movement sleep (REM) was not different between genotypes in any of the transgenic lines. Conclusion: Our findings are consistent with data from several other transgenic AD models as well as certain studies in patients with mild cognitive impairment. Further studies will be needed to better understand the correlation between EEG spectra and AD pathophysiology, both in AD models and the human condition.

Lecanemab and donanemab are monoclonal antibody therapies that remove amyloid-beta from the brain. They are the first therapies that alter a fundamental mechanism, amyloid-beta deposition, in Alzheimer disease (AD). To inform Canadian decisions on approval and use of these drugs, the Canadian Consortium on Neurodegeneration in Aging commissioned Work Groups to review evidence on the efficacy and safety of these new therapies, as well as their projected impacts on Canadian dementia systems of care. We included persons with lived experience with Alzheimer disease in the discussion about the benefits and harms. Our review of the trial publications found high quality evidence of statistically significant group differences, but also recognized that there are mixed views on the clinical relevance of the observed differences and the value of therapy for individual patients. The drugs are intended for persons with early AD, at a stage of mild cognitive impairment or mild dementia. If patients are treated, then confirmation of AD by positron emission tomography or cerebrospinal fluid analysis and monitoring for risk of amyloid-related imaging abnormalities was recommended, as done in the clinical trials, although it would strain Canadian resource capacity. More data are needed to determine the size of the potentially eligible treatment population in Canada.