Effects of Risperidone and Galantamine Treatment on Alzheimer’s Disease Biomarker Levels in Cerebrospinal Fluid

INTRODUCTION

Neuropsychiatric symptoms (NPS) are a prominent feature of Alzheimer’s disease (AD) and other dementias and include symptoms such as apathy, depression, psychosis, and agitation [1]. NPS have a major negative impact on the patient’s quality of life and constitute the most important determinant of caregiver burden [1, 2]. The pathogenesis of NPS is largely unknown but likely a consequence of complex interaction between biological and environmental factors [3]. Recent research, including neuroimaging, neuropathology, and neurochemical studies indicate that specific NPS are associated with the underlying AD pathology in distinct cerebral regions [3–7].

The biomarker correlates of pathological changes in AD can be measured in vivo using cerebrospinal fluid (CSF) levels of total-tau (T-Tau) reflecting axonal degeneration, phosphorylated-tau (P-Tau) associated with the amount of intracellular tangles or extracellular protein levels during cell-to-cell transmission, and the 42 amino acid isoform of amyloid-β protein (Aβ_1-42) reflecting cortical amyloid burden [8, 9]. Furthermore the ratio of Aβ_42/40 is used as it normalizes Aβ₄₂ levels for total Aβ production and thereby increases diagnostic accuracy [10].

Association of NPS and CSF markers may provide insight with the mechanisms of NPS, but few studies of these relationships exist. We recently showed that agitation was associated with high levels of T-Tau and P-Tau [11]. However, we are not aware of previous studies of the association between CSF markers and the course of NPS.

Atypical antipsychotics and acetylcholinesterase inhibitors (AChEI) are used in the treatment of NPS [12], although the evidence regarding their efficacy is inconsistent. In a recent randomized trial, we found that galantamine, an AChEI, and risperidone, an atypical antipsychotic, treatments were equally effective in treating several NPS domains, although risperidone was more effective than galantamine for irritation and agitation. However, a positive effect on cognition was observed in the galantamine but not in the risperidone group [13]. This is the original trial that this secondary trial is based on in which the primary end points were change in rating scales of NPS between baseline and follow-up.

Antipsychotics have potentially severe adverse effects including cerebrovascular events, increased mortality, and cognitive impairment [14, 15]. In an earlier autopsy study, antipsychotics were associated with increased neurofibrillary tangles in the brain, which could possibly explain the increased cognitive decline associated with the treatment [16]. In contrast, there are some indications that AChEIs may reduce the amount of cortical Aβ in people with dementia [17]. Currently there is limited information to whether treatment with AChEIs and antipsychotic agents influence AD pathologies in vivo as measured with relevant CSF biomarkers.

This is an exploratory analysis of the potential effects of commonly used drugs on the profile of CSF AD biomarkers due to the gap in knowledge in this area and the emerging evidence of decreased cognition and increased mortality in elderly people with dementia treated with antipsychotics. Our primary aim of this randomized controlled trial was to investigate whether treatment with an AChEI (galantamine) or an antipsychotic agent (risperidone) affects CSF levels of the AD biomarkers T-Tau, P-Tau, Aβ_1 - 42, and Aβ_42/40. We hypothesized that galantamine would reduce and risperidone would increase the AD type CSF pattern, i.e., reduced Aβ_1-42 and increased total and P-tau. Secondly, we wanted to examine the possible role of these biomarkers for predicting the course of NPS, hypothesizing that more pathological biomarkers at baseline are associated with increased NPS at follow up.

MATERIAL AND METHODS

RESULTS

Clinical and demographic characteristics are shown in Table 1. Both treatment groups were matched in clinical and demographic characteristics at baseline. Furthermore, as can be seen in Table 2, the two groups did not differ significantly for the CSF markers at baseline.

DISCUSSION

The primary aim of this study was to investigate whether treatment with galantamine and risperidone displayed any evidence of disease-modifying effects as measured by AD biomarkers in CSF. Secondly, we wanted to examine the possible role of these biomarkers for the course of NPS, hypothesizing that more pathological biomarkers at baseline are associated with increased NPS at follow up.

We observed significantly lower levels of Aβ_1-42 at follow-up compared to baseline in the risperidone group, but not in the galantamine group, which to some extent is consistent with our hypothesis. Although there was no difference in between group comparison, which could be attributed to small sample size and low power, this finding suggests a possible negative role of risperidone usage on amyloid pathology. Furthermore, this finding was not evident when including only patients diagnosed with AD and mixed AD. Based on earlier autopsy studies [16], we hypothesized that CSF patterns of dementia biomarkers T-Tau, P-Tau, Aβ_1-42, and Aβ_42/40-ratio would show a worsening of AD-type pathology among patients treated with risperidone. Taken together, our findings suggest that risperidone may worsen amyloid pathology in people with dementia and NPS, but did not seem to influence tau pathology as reflected in CSF measures.

Conversely, we hypothesized that treatment with galantamine could reduce AD-type pathology, in particular a relative increase of Aβ_1-42, given that an earlier autopsy study had indicated treatment with AChEI could reduce Aβ [17]. This study does not support our hypothesis that galantamine could reduce AD-type pathology, which is in line with an earlier CSF studies showing no effect of AChEI on AD biomarkers [25]. Several possible explanations for these negative findings exist. Effects of risperidone and galantamine may be mediated exclusively through transmitter effects producing symptomatic changes without disease modification. Alternatively, it is possible that a disease modifying effect on AD-type pathology by these drugs may take longer time to develop than the 12-week treatment in this study. In addition, the number of patients in each treatment group was relatively low and thus the power to detect statistical difference was relatively low. Patients were at relatively advanced stage of dementia, and it is possible that drug-effect on the AD pathology is stronger in the earlier disease stages. Several studies have indicated that treatment with antipsychotics worsen cognition in AD [26, 27], which would suggest that they accelerate the pathological process causing cognitive impairment in AD. However, this effect may also be due to the anticholinergic or anti-histaminergic effects, or sedation. Recently another atypical antipsychotic drug Olanzapine was shown to exhibit neurotoxic effects by influencing autophagy, demonstrated both in vivo and in vitro. Thus, the potential negative effect of risperidone on AD pathology may be mediated through an effect on autophagy in the neurons.

A possible explanation of the association between risperidone and decreased levels of Aβ_1-42 could possibly be a natural decrease of the biomarker during progress of the disease. However, earlier studies have shown that Aβ_1-42 is stable over a time period of at least 6 months when treated with AChEI [25]. Compared to earlier studies the mean levels of AD biomarkers in our study population at baseline displayed a quite severe CSF profile suggesting pronounced AD pathology [29], indicating that further changes due to the disease progression are less likely. Furthermore, a 12-week period may be too short period to observe a natural decrease of Aβ_1-42 of due to disease progression. We therefore believe that the observed reduction in Aβ_1-42 in the risperidone group may represent a negative drug effect.

The potential role of T-Tau, P-Tau, Aβ_1-42, and Aβ_42/40-ratio as markers for disease progression is currently undetermined. For our secondary objective, we tested whether CSF markers may predict the course of NPS and found some indications that the course of some specific neuropsychiatric symptoms was associated with baseline CSF markers. We recently reported that tau-mediated pathology was associated with increased agitation in AD [11]. In this study, low Aβ_1-42 at baseline was associated with improvement of irritability during treatment. Aβ_1-42, Aβ_42/40, and P-Tau were significant correlates of change in appetite and eating disorders. Some studies suggest that these biomarkers, due to their intra-individual stability over time are valuable as surrogate markers in clinical trials and can be used for detection of pathophysiological changes caused by disease-modifying drugs [25, 31]. Contrary, some studies suggest that they have limited value as markers for disease progression and treatment efficacy [32].