The cholinergic system and treatment response in subtypes of Alzheimer’s disease

Abstract

BACKGROUND The heterogeneity within Alzheimer’s disease (AD) seriously challenges the development of disease modifying treatments. We investigated volume of the basal forebrain, hippocampus, and precuneus in atrophy subtypes of AD, and explored the relevance of subtype stratification in a clinical trial on encapsulated cell biodelivery (ECB) of nerve growth factor (NGF) to the basal forebrain. METHODS Structural MRI data was collected for 90 amyloid-positive patients and 69 amyloid-negative healthy controls at baseline, 6-, 12-, and 24-month follow-up. The effect of the NGF treatment was investigated in 10 biopsy verified AD patients with structural MRI data at baseline and at 6- or 12-months follow-up. Patients were classified as typical, limbic-predominant, hippocampal-sparing, or minimal atrophy AD, using a validated visual assessment method. Volumetric analyses were performed using a region-of-interest approach. RESULTS All AD subtypes showed reduced basal forebrain volume as compared with controls. Limbic-predominant subtype showed fastest basal forebrain atrophy rate, whereas minimal atrophy subtype did not show significant volume decline over time. Atrophy rates of hippocampus and precuneus also differed across subtypes. The NGF treatment seemed to slow the rate of atrophy in precuneus and hippocampus, particularly in the hippocampal-sparing AD subtype. CONCLUSIONS The cholinergic system is differentially affected in distinct atrophy subtypes of AD, possibly contributing to their differential response to cholinergic treatment. Our findings suggest that future clinical trials should target specific subtypes of AD, or at least report treatment effects stratifying by subtype. Trial registration ClinicalTrials.gov identifier: NCT01163825 . Registered 14 July 2010 - https://clinicaltrials.gov/ct2/show/NCT0116382