Title: Randomised Clinical Trial of Noradrenergic Add-on Therapy with Extended-Release Guanfacine in Alzheimer's Disease
Funder: Department of Health and Social Care

Abstract: Current treatments for AD focus on boosting levels of acetylcholine, a neurotransmitter which is closely associated with normal memory function, and acetylcholine pathways are known to be affected by AD. Although cholinesterase inhibitors are employed in standard practice, their overall effects are relatively modest, leaving patients with considerable cognitive impairment. In addition to cholinergic dysfunction, there is clear evidence of disruption of the locus coeruleus and pathways involving the neurotransmitter noradrenaline in AD. Noradrenaline is closely linked to the mediation of attention (particularly general arousal and vigilance) and attentional impairments have been demonstrated in AD in addition to having been shown to contribute to clinical disability. Guanfacine, a noradrenergic agonist (originally developed as an anti-hypertensive), has been shown to boost attention and planning in animals and healthy volunteers, acting via alpha2A receptors in prefrontal cortex. In a previous proof-of-concept study, we showed that guanfacine reduces attentional deficits following stroke, and in a single case study we also found that guanfacine improved attention in a patient with cognitive impairments secondary to inflammatory disease. Guanfacine has also been shown to improve attention in children with Attention Deficit Hyperactivity Disorder (ADHD) and is approved for this use in the USA. There have been a few small studies assessing the effects of guanfacine as a single agent on cognition in AD and age-associated memory impairment , but these showed no evidence of significant improvement and it was concluded that noradrenergic intervention alone is unlikely to be effective in AD . However, these trials used low doses compared to studies in other neurological populations, and only recruited low participant numbers (5 & 29), and therefore were inadequately powered. In addition, they employed lower doses of guanfacine than in our previous studies in other neurological populations. Critically, there have been no studies to date examining the effectiveness of guanfacine as part of a combination treatment (i.e. in addition to cholinergic therapies) in AD, even though there is a strong theoretical rationale for this. One drawback with the use of standard guanfacine for all these conditions is its tendency to cause drowsiness. In order to combat this potential side effect an extended-release version of the drug (GXR) has been developed and manufactured by Shire pharmaceuticals for use in ADHD, where it has been found to be effective, less likely to lead to sedation, and is licensed for use in the USA. The aim of this proposal is to carry out a double-blinded, randomised placebo-controlled trial of the effects of GXR on cognition, particularly attention, in patients with mild-moderate AD who are stable on cholinergic treatment (the NICE approved drugs donepezil, rivastigmine and galantamine). We will recruit 160 patients with mild-moderate disease, who have been on a stable dose of cholinergic therapy for the preceding 3 months. They will be recruited from memory clinics at Imperial College Healthcare NHS Trust and from West London Mental Health Trust. We will randomise 80 individuals to treatment with GXR plus standard cholinergic therapy and 80 individuals to cholinergic therapy plus placebo. Patients will be treated for a total of 12 weeks (1mg GXR for 1 week followed by 2mg for the remaining 11 weeks), and will be assessed at 0 weeks, 4 weeks, 8 weeks and 12 weeks. They will be tested on a number of standard tests assessing cognition, with a particular emphasis on attentional processes. By comparing performance between the two groups we will be able to ascertain whether GXR, as part of combination therapy with cholinergic drugs, improves cognition, particularly with respect to attention, in mild to moderate Alzheimer s Disease.

Lay abstract: Attention, the act of focusing on relevant information, is affected in Alzheimer s Disease. Attention is linked to the neurotransmitters Acetylcholine and Noradrenaline, and the brain regions that transmit both of these to the rest of the brain are affected by Alzheimer s Disease, leading to reduced transmission of these key substances. Because Acetylcholine is also linked with memory, which is typically affected in Alzheimer s, treatment strategies to decrease symptoms in Alzheimer s have mostly focused on boosting Acetylcholine levels. These form the basis of standard current treatments, and are not very effective. Our proposed study focuses on drugs which increase levels of the other key neurotransmitter, noradrenaline. These have been shown to boost attention in animals and healthy volunteers, and used to treat Attention Deficit Hyperactivity Disorder in children. In previous work we have also shown that one of these drugs, guanfacine, can improve attention in stroke patients. A few studies of guanfacine treatment in Alzheimer s took place around twenty years ago, with very few patients (fewer than 30 in each case) and, crucially, those studies looked at the effects of guanfacine on its own. We want to assess whether guanfacine should be used in addition to NICE-approved drugs which are currently being used to treat Alzheimer s disease, as part of combination therapy, since theory would suggest a greater effect when both types of drug are used together. We plan to recruit 160 patients and treat half of them with guanfacine in addition to standard medication and we will compare them with the other half who will be given placebo in addition to standard medication. We will treat all patients for 12 weeks, with assessments every 4 weeks during this period. By using tests of thinking and attention, we will evaluate whether adding guanfacine to standard therapy improves thinking in Alzheimer s Disease.

Research activity codes: 6.1 PHARMACEUTICALS
Health categories: NEUROLOGICAL