Investigating the potential of combination therapies targeting the cholinergic system in Alzheimer´s disease

The complexity of Alzheimer´s disease (AD) must be addressed targeting different mechanisms.

Since the cholinergic system is degenerating in the early days of AD, is the persisting target for the current treatment and was the target for our previous clinical trial on nerve growth factor (NGF) therapy in AD with positive results, we will in this proposal explore the potential of the cholinergic system further.

Our overall aim is to develop a combination therapy for AD using different mechanisms targeting the cholinergic system.We have based this project on our recent new findings on the cholinesterase inhibitors (ChEIs) being associated with reduced mortality and cardio- and cerebrovascular events and reduction of risk for severe dementia in particular with galantamine in addition to our positive data on safety, tolerability and efficacy in our previous clinical trial on cell therapy using encapsulated cells releasing NGF to the basal forebrain in AD-patients.We plan to in a novel AD mouse model explore a combination therapy consisting of the ChEI galantamine in combination with concomitant encapsulated delivery of NGF to the basal forebrain and BDNF to the hippocampus.

In parallel we will develop new biomarker tools to monitor treatment response evaluating cholinergic and inflammatory markers in CSF and plasma as well as neuroimaging with projection analyses of the cholinergic circuitry in the brain of patients with AD.