Alzheimer's Disease & Dementia
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Combination Drug Therapy for the Treatment of Alzheimer’s Disease

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Published Online: May 15th 2012 European Neurological Review, 2012;7(2):92-102 DOI:
Authors: X Antón Álvarez, Carlos Linares, Eliezer Masliah
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Alzheimer’s disease (AD) is a complex and progressive neurodegenerative disorder resulting in continuous deterioration of cognition, daily living abilities and motor functions and consequently has a huge social and familial burden. To date, the drugs approved for AD treatment provide only modest symptomatic effects. At present, the combined therapy with memantine plus one cholinesterase inhibitor (ChEI) is the best option for the treatment of moderate-to-severe AD. This combination has demonstrated higher clinical efficacy than monotherapy with ChEIs, with similar safety and tolerability in several randomised-controlled clinical trials (RCTs). Recent long-term observational studies have shown that combination therapy slows the rate of cognitive and functional deterioration, delays the placement of patients in nursing homes and also provides evidence that it is more effective when initiated early. None of the drugs for AD tested in Phase III trials show evidence of disease modification. A few studies have shown that the newer drugs, particularly anti-amyloid and neurotrophic agents, may provide improved disease-modifying treatments of AD in the near future. Meanwhile, combination therapy with available drugs is the most effective AD treatment.


Alzheimer’s disease, combination therapy, memantine, disease-modifying treatments, cholinesterase inhibitor


Alzheimer’s Disease – A Complex Neurodegenerative Disorder with a Multifactorial Pathogenesis
Alzheimer’s disease (AD), the main cause of dementia, is a neurodegenerative disorder characterised by a progressive decline of cognitive functions (memory, language, praxis, judgement and thinking, orientation and executive functions), increasing disabilities in daily living function and the presence of behavioural and psychological symptoms.1–3 In the late to end-stages of AD, motor functions also deteriorate and thus AD causes a continuous loss of mental and physical autonomy in patients and produces a parallel increase in dependency and burden on carer-givers as the disease progresses.

The pathogenic process of AD is complex and may start decades before the condition is diagnosed (see Figure 1). Early molecular alterations give rise to structural changes, which precede the onset of the first symptoms and the later development of the full clinical picture, usually required for diagnosis and treatment. AD aetiopathogenesis is multifactorial and may include genetic mutations and/or risk factors,4,5 abnormal processing and deposition of beta-amyloid (Abeta) and tau proteins,6,7 inflammation mechanisms,8–10 deficits of neurotrophic factors,8,11,12 metabolic dysfunctions,13–15 oxidative stress,15,16 excitotoxicity17,18 and alterations in neurotransmitters such as acetylcholine, noradrenaline, serotonine and glutamate.18–20 These pathogenic factors influence the development of the typical AD neuropathology (senile plaques, neurofibrillary tangles, synaptic loss and neuronal apoptosis-degeneration) underlying cognitive impairment and other dementia symptoms (see Figure 1).21,22 Progressive impairment of cognition reduces the abilities of AD patients to recall events, to deal with complex mental activities, to stay orientated, to plan and execute tasks and to communicate and interact with others.

The Need for Multimodal Intervention in Alzheimer’s Disease
Drugs currently approved for the treatment of AD, i.e. cholinesterase inhibitors (ChEIs) and memantine, are intended tocounteract the pathological consequences of neurotransmitter alterations associated with the disease. Donepezil, galantamine and rivastigmine (ChEIs) enhance cholinergic neurotransmission by inhibiting cholinesterase activity and constitute the first-line standard therapy for mild-to-moderate AD.23,24

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Article Information:

The authors have no conflicts of interest to declare.


X Antón Álvarez, Fundación Antidemencia Al Andalus, PO Box 7010, 15002-A Coruña, Spain. E:


The publication of this article was funded by Merz Pharmaceuticals GmbH. The views and opinions expressed are those of the authors and not necessarily those of Merz Pharmaceuticals GmbH.




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