Opportunities and challenges in developing Alzheimer disease therapeutics

Alzheimer disease (AD) is a chronic, progressive disorder with an average disease progression of 7-10 years. However, the histopathological hallmark lesions of this disease, the extracellular Aβ plaques and the intraneuronal neurofibrillary tangles, start as early as childhood in the affected individuals. AD is multifactorial and probably involves many different etiopathogenic mechanisms. Thus, while AD offers a wide window of opportunity that practically includes the whole life span of the affected individuals, and numerous therapeutic targets, the multifactorial nature of this disease also makes the selection of the therapeutic targets an immensely challenging task. In addition to β-amyloidosis and neurofibrillary degeneration, the AD brain also is compromised in its ability to regenerate by enhancing neurogenesis and neuronal plasticity. An increasing number of preclinical studies in transgenic mouse models of AD show that enhancement of neurogenesis and neuronal plasticity can reverse cognitive impairment. Development of both drugs that can inhibit neurodegeneration and drugs that can increase the regenerative capacity of the brain by enhancing neurogenesis and neuronal plasticity are required to control AD.