Combination Drug Therapy for the Treatment of Alzheimer’s Disease

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 excitotoxicity^17,18 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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