**2.2 The history of AD**

Emil Kraepelin first used the name Alzheimer's disease in 1910 in recognition of Alois Alzheimer (1864-1915), the German psychiatrist and neuropathologist, who had originally described the clinical and pathological features of the disease. Kraepelin was keen to make the distinction between the presenile form of dementia (described by Alzheimer) and the more common senile variant.

Alzheimer's findings were originally published in 1907, in the form of a conference abstract where he described a delusional woman (Auguste D) who had slowly lost her cognitive function and died at 55 years of age (Alzheimer, 1907). According to a later translation of the original manuscript Auguste D suffered from reduced comprehension and memory as well as psychotic symptoms including paranoia that resulted in her psychosocial impairment (Maurer *et al.,* 1997). The first formal description of Auguste D was by Perusini in 1909 in a 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 indistinguishable (Terry and Katzman, 1983).

### **2.3 Prevalence and cost**

390 Neuroscience – Dealing with Frontiers

The term dementia encapsulates a number of separate diseases that clinically manifest as a progressive decline in cognitive function. Alzheimer's disease (AD) is the most common form of dementia accounting for approximately 60% of all cases. It is estimated that the current 36 million sufferers worldwide will increase to 115 million by 2050 (Alzheimer's Disease International, 2009). In countries like Australia, dementia will become the number one health cost by the middle of this century exceeding both heart disease and cancer (Access Economics, 2009). These surprising predictions result from the additive effects of an ageing world population, the duration of the disease and the extended period where the patient is totally dependent on caregivers. The societal trend in Western countries towards professional aged care services accounts for the majority of the current and predicted costs. More importantly, AD is a cruel disease that robs patients of their sense of self and places considerable physical and psychological strain on caregivers, who are often isolated from society themselves. As the currently available treatments only provide transient improvement, an AD epidemic will only be halted with the development of new therapies. It has been predicted that a novel therapeutic agent that delays disease onset and progression by just one year would result in nine million fewer cases by 2050 (Brookmeyer

The other approach to reducing the worldwide burden of AD is prevention. This would be based on either avoiding identified risk factors or augmenting the impact of protective factors. Unfortunately finding such factors through epidemiological studies has proved

The completion of the human genome project in 2001 ushered in a dramatic increase in the technologies that have subsequently been applied to understanding the pathogenesis of complex disorders, like AD. Genome-wide association and expression studies are now commonplace in AD research creating a more immediate and dynamic research environment. The application of these technologies to clinical, pathological and epidemiological studies of AD is starting to bear fruit although effective treatments are not

Emil Kraepelin first used the name Alzheimer's disease in 1910 in recognition of Alois Alzheimer (1864-1915), the German psychiatrist and neuropathologist, who had originally described the clinical and pathological features of the disease. Kraepelin was keen to make the distinction between the presenile form of dementia (described by Alzheimer) and the

Alzheimer's findings were originally published in 1907, in the form of a conference abstract where he described a delusional woman (Auguste D) who had slowly lost her cognitive function and died at 55 years of age (Alzheimer, 1907). According to a later translation of the original manuscript Auguste D suffered from reduced comprehension and memory as well as psychotic symptoms including paranoia that resulted in her psychosocial impairment (Maurer *et al.,* 1997). The first formal description of Auguste D was by Perusini in 1909 in a

**2. Alzheimer's disease** 

**2.1 Overview** 

*et al.,* 2007).

extremely difficult to date.

necessarily close at hand.

**2.2 The history of AD** 

more common senile variant.

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

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 authors attributed this increase to population growth and demographic ageing.

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 disabilities who are often supported at home by community services.

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 government allowances or pensions in most cases.

#### **2.4 Clinical findings**

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

Alzheimer's Disease: Approaches to Pathogenesis in the Genomic Age 393

The definition of preclinical AD remains a research-only paradigm based on the promise that biomarkers faithfully reflect the underlying pathophysiological processes (Sperling *et al.,* 2011). As will be discussed below this preclinical diagnostic paradigm is firmly based on

The review of the clinical diagnostic criteria was prompted in part by increasing reports of variations in the classic presentation of AD. It has even been suggested that the term Alzheimer's syndrome is more appropriate than AD (Zellner *et al.,* 2009). In addition to the classic amnestic presentation of AD described above, a "visual variant" of AD, often called posterior cortical atrophy, a "language variant" called logopenic/phonological aphasia (Gorno-Tempini *et al.,* 2011) and a frontal/behavioural variant are occasionally observed (Johnson *et al.,* 1999). The latter two are also considered sub-categories of frontotemporal dementia hinting that there might be considerable overlap in clinicopathological correlates between the current clinical dementia categories. This is supported by a recent study that found AD to be the primary pathological diagnosis in a range of focal cortical syndromes including 50% of corticobasal disease and 44% progressive non-fluent aphasia, another language variant of frontotemoporal dementia (Alladi *et al.,* 2007). This clinical or phenotypic heterogeneity in AD suggests variation in both aetiology and pathogenesis and

There are two classes of drugs that are currently used to treat moderate to severe cases of AD. They are the acetylcholinesterases inhibitors (ChEIs) and glutaminergic receptor antagonists. The cholinergic (acetylcholine producing) neurons of the basal forebrain nuclei such as the nucleus basalis of Meynert are among the earliest lost in AD (Cullen and Halliday, 1998). These neurons synapse in the prefrontal cortex and the hippocampus where they release

Acetylcholinesterases are enzymes responsible for the rapid breakdown of acetylcholine in the synaptic cleft. ChEIs are postulated to maximise the residual acetylcholine modulating these memory circuits in the AD brain and there are three types in current use donepezil, rivastigmine and galantamine. Meta-analyses of randomised control trials for the three ChEIs suggest that all show moderate improvements in cognitive function over placebo but the incidence of adverse events is lowest for donepezil (Birks, 2006; Hansen *et al.*, 2008)

The other drug in common use is called memantine, a low affinity glutamate NMDA receptor antagonist. The postulated mechanism of action for memantine is the prevention of glutamate-mediated excitatory neurotoxicity (McShane *et al.,* 2006). As with the ChEIs, meta-analyses report a significant but marginal improvement (Raina *et al.,* 2008) with particular attenuation of behavioural symptoms (Gauthier *et al.,* 2008). Memantine is less efficacious in mild to moderate compared to severe AD (MMSE >15) (McShane *et al.,* 2006;

Unfortunately there is no evidence that either of these treatments significantly alters disease progression (Golde *et al.,* 2011). Hence there is enormous research effort aimed at finding alternative treatment strategies, some of which have already reached Phase II and III human

clinical trials. These potential treatments are discussed below.

one, albeit prominent, working hypothesis for AD pathogenesis.

the potential ramifications of this will be discussed in greater detail below.

acetylcholine to modulate circuits involved in learning and memory (Gold, 2003).

**2.6 Clinical heterogeneity** 

**2.7 Current treatment options** 

Schneider *et al.,* 2011).

with Lewy bodies (DLB). Dementia is a progressive decline in cognition that impairs social and/or occupational function. The deficits in a particular individual will reflect the regions in which neuronal loss occurs.

AD sufferers will usually present to a general physician because of their own concern about deteriorating cognition or the concerns of an informant (often their spouse or work colleague). A general physician may refer the patient to a specialist geriatrician or neurologist but many patients remain under the primary care of their general practitioners. The loss of short-term memory is often the earliest cognitive phenotype for AD (Dubois and Albert, 2004).
