The general drug discovery pipeline is depicted in Fig. 1. Animal models – or laboratory animals in general – play an essential role in various stages of the drug discovery pipeline. In target discovery and validation, molecular targets pivotal to the disease process are studied. A target may be a receptor, proteins (enzymes), DNA, RNA, or ribosomes. In addition, the “drugability” of a target, which may be influenced by cellular location, development resistance, transport mechanisms, side effects, and toxicity, is assessed. Assay development encompasses the development of valid model systems, both in vitro and in vivo. This stage has known a major boost with the development of transgenesis and gene targeting techniques, but is, nevertheless, still the bottleneck of the drug discovery pipeline, since all models are partial and for some human diseases (e.g., hepatitis C infection) adequate models are still completely lacking. When converging hits-to-leads, animals are used to assess the potency (ED50) and dose-response curve of a compound. The mechanism of drug action is studiedin vitro, on whole-cell bases systems and in animal models. During lead optimization, different species are used to study pharmacokine­tics, pharmacodynamics, absorption, distribution, metabolism, and excretion, as well as to optimize formulation and delivery of the lead. All nonclinical data are compiled during the development stage. If required, some additional preclinical studies may be initiated before proceeding to the clinical phases.

Valid animal models are indispensable to the drug discovery and development pipeline. In particular, animal models have a key role to play in target discovery and validation, which require proof that a molecular target is pivotal to the disease process, and that modulation of that target has therapeutic effect. The development of relevant transgenic (knock-out/in) or chemical knock-out models are vital to this stage. Additionally, the use of valid animal models for a specific human condition allows appraisal of the preclinical efficacy of candidate drugs.

The quality and utility of any animal model should be assessed through rigorous validation. A valid model resembles the human condition in etiology, pathophysiology, symptomatology, and response to therapeutic interventions. As a result, homologous models with etiology and symptomatology identical to the human condition exhibit the highest level of validity. In isomorphic ­models, symptomatology is not provoked by the same factors as in the human condition, leading to reduced validity (2).

The conclusions drawn from animal models largely depend on the validity of the model in representing the human condition. The following perspectives are commonly used in the characterization of a model’s validity. Face validity refers to the resemblance between model and situation or process being modeled. It refers to the phenomenological similarity between the model and the human condition. Similarity of symptoms is most commonly used to assess face validity.

Predictive validity is an empirical form of validity that represents the extent to which the performance of the animal model in a test predicts the performance in the condition being modeled. This level of validation, therefore, necessitates parallel development of clinical measures for meaningful comparisons between model and man. In a more narrow sense, this term is sometimes used to indicate pharmacological isomorphism, i.e. the model’s ability to identify compounds with potential therapeutic effects in the human condition. Construct validity refers to the theoretical clarification of what a test measures or a model is supposed to mimic. Because a given condition may manifest itself in different ways in different species, the behavior used in the animal model may not match that of humans, yet the test or model may still be valid. Construct validation is useful in the incessant process of further developing and refining an animal model. Etiological validity is closely related to construct validity, and refers to identical etiologies of phenomena in the model and the human condition. Models with high etiological validity are most valuable in drug development and discovery.

The more levels of validity a model satisfies, the greater its value, utility, and relevance to the human condition. A “perfect” model would account for etiology, symptomatology, treatment, and physiological basis. Animal models in general do not meet all of these criteria.

The key etiological and symptomatic features of AD that would ideally be replicated in an animal model of the disease are outlined in the following paragraphs. In reality, most animal models are partial models, focusing only on restricted aspects of a disease, and modeling the complete condition is often not pursued.

As the prototype of cortical dementias, AD presents with prominent cognitive deficits. Initially, patients display limited forgetfulness with disruption of memory imprinting, evolving to short-term memory disruption, and with disease progression, long-term memory deficits. Most cortical dementias are characterized by the early-stage development of anomia progressing towards aphasia with perseverations and paraphasia. In addition, patients exhibit agnosia, including prosopagnosia or face blindness (representing a major burden for family members), as well as temporal and spatial disorientation. In a more advanced stage, apraxia results in executive dysfunctioning and, hence, the increasing helplessness of the AD patient (3). Besides cognitive deterioration, patients display noncognitive symptoms, such as anxiety, depression, aggression, agitation, hallucinations, circadian rhythm disturbances, and wandering. In contrast with cognitive symptomatology, these noncognitive symptoms – commonly referred to as behavioral and psychological signs and symptoms of dementia (BPSD) – do not exhibit a progressive course. The impact of BPSD is emphasized by the fact that they increase patient suffering, impose tremendous strain on family members and caregivers (often motivating institutionalization), and increase the financial burden on the family and society (3,4).

The histopathological hallmarks of AD brain are extracellular amyloid plaques and intracellular neurofibrillary tangles (NFT), accompanied by decreased synaptic density, which eventually leads to widespread neurodegeneration, loss of synapses, and ­failure of neurotransmitter pathways, particularly those of the cholinergic system. Clinical, epidemiological, and biochemical research over roughly the past 2 decades has significantly increased our knowledge of the pathological and molecular cascades underlying AD, uncovering potential biomarkers for disease progression or early diagnosis and revealing new drug targets. For a therapeutic intervention to slow down or halt disease progression – that is, to be disease-modifying – it must interfere with these central pathophysiological pathways. The following key pathways are being extensively scrutinized in AD rodent models.

In general, animal models of human disease can be classified into spontaneous, induced, negative, and orphan models, although the two latter types are not relevant when considering dementia models. Although spontaneous models are presumed to develop their condition without experimental manipulation, selective bree­ding is often necessary to establish and maintain the mutant line. Induced models display conditions as a result of artificial manipulation. Particularly for psychiatric and neurological conditions, few spontaneous models exist, and experimentally induced pathology is often necessary (3). Although models based on many different species, including primates and other mammals, as well as invertebrates, have contributed to the wider field of AD research, rodent models are predominant in drug discovery. The different species and types of models available for dementia-related research will be dealt with in a different chapter of this volume.