Long-term treatment response, predictors and biochemical markers in Alzheimer’s disease

Abstract: Alzheimer’s disease (AD) is clinically characterised by an insidious onset with progressive symptoms of memory impairment, dysphasia, dyspraxia, dygnosia and visuospatial difficulties. Degeneration of neurons in specific regions of the brain, formation of senile plaques and neurofibrillary changes are some of the neuropathological features of the disease. As a result of the degenerating process a deficiency in cholinergic function occurs in AD. This has been a target for therapy since the cholinesterase inhibitors (ChEIs) (tacrine, donepezil, rivastigmine, galantamine) were introduced as treatments for AD. Multiple short-term randomised clinical trials of ChEI treatment show beneficial effects on cognition, global functioning and activities of daily living in AD. Whether the effects of long-term ChEI treatment in a routine clinical setting are equally positive remains to be investigated. In the present study patients from naturalistic settings were investigated in long-term treatment studies (tacrine-study and The Swedish Alzheimer Treatment Study, SATS). Patients were repeatedly assessed with cognitive scales and global ratings over 3-5 years. A positive response to treatment was described in different response models. At 6 months 3/4 of the patients and at 3 years 1/3 were better or unchanged. Treatment for more than a year and positive response to tacrine treatment delayed nursing-home placement but did not influence survival. CSF T-tau and P-tau were possible markers for disease severity and P-tau for the abundance of symptoms in AD. A fast pre-treatment progression rate was a positive predictor for response to ChEI treatment even after adjusting for disease severity, another positive predictor of response. Baseline factors such as age, gender, CSF biomarkers and APOE genotype did not predict response to treatment. Dropout in these naturalistic settings was lower than expected. ChEI treatment changed the progression of the disease for more than 6 months and stabilised groups of patients for even longer