**1. Introduction**

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The prevalence of Alzheimer's disease (AD), the most common form of dementia, is rising rapidly worldwide. A seemingly imminent epidemic is predicted to have wide reaching societal and economic consequences, becoming the leading health issue for many countries by the middle of this century. This epidemic is driven by an ageing world population in combination with a lack of disease modifying treatments or preventive strategies. The popular amyloid cascade hypothesis suggests that AD is precipitated by the dysregulated metabolism of the amyloid precursor protein resulting in the accumulation of the betaamyloid peptide (A) in the brain. This hypothesis is the basis for most experimental treatments currently in clinical trials. However, not all evidence supports a precipitating role of abnormal A accumulation in the common forms of AD.

The completion of the human genome project in 2001 has ushered in a dramatic increase in the technologies available to biologists and these have been applied to understanding the pathogenesis of complex disorders, like AD. Genome-wide association and expression (transcriptomic) studies are now commonplace creating a more immediate and dynamic, but invariably more complex, research environment.

Transcriptomic studies in particular have the potential to greatly influence our understanding of complex diseases like AD, but to date they have provided quite discordant results. There are a number of potential reasons for this including our incomplete understanding of the complex nature of the human brain at the molecular level. It is now known that the evolutionary advances in our cognitive capacity have largely originated at the level of transcription with substantial increases in both coding and non-coding RNA variants. Until recently transcriptomic platforms only assayed a proportion of the coding RNA species, but with the introduction of next generation sequencing the whole transcriptome, both coding and non-coding, can now be investigated.

In this chapter we undertake a review of the clinical and pathological characteristics of AD before considering the impact of new technologies on AD research and their future role in finding a cure for this important disease.

Alzheimer's Disease: Approaches to Pathogenesis in the Genomic Age 391

textbook edited by Nissl and Alzheimer (Perusini, 1909). Alzheimer himself only published a detailed clinical and pathological report in 1911 along with his findings from a second case (Johan F) (Alzheimer, 1911). Interestingly Alzheimer described Auguste D as having both the pathologies that we now know as plaques and tangles in her cerebral cortex but Johan F as having only plaques. Graeber and colleagues re-examined Alzheimer's original sections 90 years later and confirmed the original histopathological findings for Johann F (Graeber *et al.,* 1997) and Auguste D (Graeber *et al.,* 1998). In accordance with Kraepelin's original classification the term Alzheimer's disease or Alzheimer's presenile dementia continued to be exclusively used for a rare disease of mid-life until the 1970's when neuropathologists realised that the more common senile dementia and the type described by Alzheimer were

The mean age at onset of AD is around 75 years of age and the overall prevalence is about 1% in most developed nations. If AD prevalence is divided into different age bands then we see a rapid increase from 1% in the 60-64 year age group to greater than 25% in individuals

A comprehensive estimate of worldwide prevalence was recently reported with age- and gender-specific prevalence and projections out to 2050 (Alzheimer's Disease International, 2009). This suggested that the current worldwide burden of 35.6 million dementia sufferers would nearly double every 20 years, to 65.7 million in 2030, and 115.4 million in 2050. The

Alzheimer's Disease International (ADI) has addressed the current cost of dementia worldwide and predicted its future economic impact (Alzheimer's Disease International, 2010). They suggested that the currents cost of US\$604 billion would increase by 85% to US\$1000 billion by 2030. They noted considerable disparity between high-income and lowincome countries largely due to formal care facilities in the former, rather than direct health costs. Direct health costs amounted to only 16% of the average \$32,000 per annum costs in the USA. ADI considered that stigmatisation played a role here where cognitive decline was often the precipitant for institutionalisation as opposed to individuals with severe physical

In terms of care-giving an important indirect effect of AD and dementia that may often be missed in such reports is the physical and psychological toll on the caregivers themselves. It is estimated that a person with dementia requires more than 7 hours of close supervision per day (Wimo *et al.,* 2007). Caregivers are commonly spouses or first-degree relatives, and for long periods of time will be as socially isolated as the patients themselves. They are estimated to experience between a three- and 40-fold increase in their risk of major depression (Cuijpers, 2005). Caregivers who choose to support a dementia patient at home also are likely to suffer a huge financial burden, through lost of income, disability-friendly renovations and the hiring of respite care. These costs are only partially off set by

The term dementia refers to the main clinical manifestation of AD but also occurs with other diseases including frontotemporal dementia (FTD), vascular dementia (VaD) and dementia

authors attributed this increase to population growth and demographic ageing.

disabilities who are often supported at home by community services.

government allowances or pensions in most cases.

**2.4 Clinical findings** 

indistinguishable (Terry and Katzman, 1983).

over 85 years of age (Jorm and Jolley, 1998).

**2.3 Prevalence and cost** 
