Neuroprotective therapeutics for Alzheimer’s disease: progress and prospects Alan M. Palmer MS Therapeutics Ltd, Beechey House, 87 Church Street, Crowthorne, Berkshire RG45 7AW, UK The number of people with Alzheimer’s disease (AD) has never been greater and is set to increase substantially in the decades ahead as the proportion of the population aged 65 years or more rises sharply. There is therefore an urgent need for safe and effective pharmacotherapy to help combat the corresponding and substantial increase in disease burden. Increased understanding of disease aetiology and pathophysiology, particularly in relation to the loss of vulnerable neurons and the formation of plaques and tangles, has increased hope for medications that can slow (or perhaps even halt) the course of the disease. In this article I review the neurobiological basis of AD, current progress towards neuroprotective thera- peutics, and prospects for the future. Introduction Alzheimer’s disease (AD) is a progressive neurodegenera- tive disorder that affects daily living through memory loss and cognitive impairment [1]. Early symptoms include disturbances in short-term memory, attention, spatial ori- entation, personality and language, often in conjunction with confusion and unexplained mood swings. Initially these symptoms are very mild and then progress, typically over a period of 8 to 10 years. The symptoms can vary in severity and chronology, but they mirror a gradual expan- sion of degenerative change in the brain, which has been described to occur in six stages [2]. Neurodegeneration commences in the entorhinal cortex with pyramidal cell loss, neurofibrillary tangles and neuropil threads, and then spreads in an anatomically defined pattern to other brain regions, particularly the hippocampus and parietal and temporal regions of the neocortex (Figure 1). A minority of AD patients (predominantly those with onset before 65 years of age) have a familial form of the disease that is largely attributable to mutations in three genes: amyloid precursor protein (APP), presenilin 1 (PSEN1), or presenilin 2 (PSEN2) [3]. However, in the majority (>95%) of AD cases (those aged 65 years and above) the disease does not follow Mendelian inheritance, despite showing significant heritability. There are a number of genetic risk factors for AD. The strongest genetic risk is the presence of the e4 allele of the apolipoprotein E gene (APOE), but increased risk for AD is also associated with genes linked to cytokines, chemokines, and nitric oxide synthases [4]. However, age is the major risk factor for AD, with disease prevalence increasing exponentially after age 65: one in ten people over 65 years of age, and nearly half of those 85 or older, have AD [5]. With people living longer and the baby-boomer generation now reaching age 65, the world population of those aged 65 or more is set to increase substantially in the decades ahead (with one billion more people between 2000 and 2050 [6]), and the burden of AD is thus set to increase substantially. In 2006 the worldwide prevalence of AD was 26.6 million, and this is projected to increase to about 100 million by 2050. It has been estimated that about 43% of cases will require a high level of care (equivalent to that of a nursing home), and this will present a major challenge to the funding and implementation of healthcare. Effective medications have the potential to have a major impact upon this increased burden of care for AD. A neuroprotective therapeutic that can delay both disease onset and progression by a modest 1 year would result in 9.2 million fewer cases of disease in 2050, with most of this decline representing reduced numbers of patients requiring high-level care [7]. This review considers the progress that has been made in the development of neuroprotective therapeutics for AD and the prospect for such compounds becoming medica- tions to slow the cascade of neurodegenerative changes associated with AD. The neurobiological basis of AD The discovery and development of neuroprotective thera- peutics for AD is largely dependent on understanding the biological basis of its aetiology and pathogenesis. Although our understanding is far from complete, great strides have been made over recent decades. The disease is characterised by three cardinal changes in the brain: (i) the formation of dystrophic neurites around a central core of amyloid (plaques), (ii) the formation of abnor- mal filaments (neurofibrillary tangles) made up of a highly phosphorylated form of the microtubule-associated protein tau (designated MAPT) in the perikaryia of certain neurons, accompanied by neuropil threads in axons and nerve term- inals, and (iii) loss of vulnerable neurons, principally pyra- midal, cholinergic, noradrenergic and serotonergic neurons [8] (Figure 1). Plaques Two major breakthroughs regarding the aetiology of AD came with the discoveries that (i) amyloid deposits of Ab,a Review Corresponding author: Palmer, A.M. (alan.palmer@mstherapeutics.com) 0165-6147/$ – see front matter ß 2010 Elsevier Ltd. All rights reserved. doi:10.1016/j.tips.2010.12.007 Trends in Pharmacological Sciences, March 2011, Vol. 32, No. 3 141