Alzheimer's disease(AD)

A progressive neurodegenerative form of dementia. In the early stages it is marked by a memory deficit. Patients have increasing difficulty in learning new information and retaining it over a delay. Patients typically forget recent events and become more repetitive. As the disease progresses, patients experience difficulty with everyday tasks that require concurrent manipulation of information. Subsequently language and spatial difficulties emerge. Behavioural changes, such as apathy, delusions, and agitation, occur often in AD. Ultimately patients are no longer able to manage basic activities of daily living and require total care. The course of the disease from onset to death can be variable but may average 10–12 years.

When Alois Alzheimer described the post-mortem findings on a lady suffering from dementia in 1907, the neuropathology was insufficient to define a distinct disorder. Since that time, clinical criteria have been developed to define groups of elderly patients and these groups have been examined for clinicopathological correlates of dementia. These studies have made it possible to focus on the structure, composition, and molecular biology of the neurofibrillary tangle. The outcome of this research programme has been to identify a normal 'tau protein' that undergoes abnormal processing in AD. This results in aggregates of tau that are harmful to neurons. A therapeutic strategy to prevent this process offers the potential to combat the progression of the disease in patients with Alzheimer's disease.

1. The heterogeneity and pathological basis of dementia
2. Clinical diagnosis
3. Pathology
4. Molecular composition of the PHF
5. Therapeutic potential

1. The heterogeneity and pathological basis of dementia

Dementia has many causes and the neurodegenerative forms of the disease are both clinically and pathologically heterogeneous. The most common form of dementia, AD, can be caused by mutations in a number of proteins. Such cases are largely indistinguishable from the more common, sporadic form of the disease that occurs later in life and as yet have no identified genetic basis. A constant feature of AD is the neurofibrillary, tau protein pathology that is temporally associated with the clinical symptoms of dementia. Since the finding that mutations in the tau protein can cause related forms of dementia, renewed interest in tau pathology has two incentives. First, there is the therapeutic potential for preventing tau aggregation. Second, the mechanism of tau aggregation may be a generic process common to a number of distinct neurodegenerative disorders that are characterized by the aggregation of different proteins.

The progressive increase in the population over the age of 65 relative to the rest of the population is a feature of all industrialized societies. This demographic transformation has resulted, in the main, from increased longevity or life expectancy at birth and reduced fertility. In the UK, for example, there is a projected 80 per cent increase in the over-65 population between 1965 and 2025. The prevalence of dementia increases as an exponential function of age, with a representative estimate of around 8 per cent of the over-65 population.

More than 50 medical, psychiatric, and neurological conditions are associated with dementia. AD is the major cause of dementia in the elderly, although the reported frequency of other types of dementia has increased as the result of improvements in their diagnosis. These include a variety of disorders including: vascular dementias, dementia with Lewy bodies, Parkinson's disease, Pick's disease, corticobasal degeneration, progressive supranuclear palsy, Huntington's disease, Creutzfeldt–Jakob disease (CJD), and chromosome 17-linked frontotemporal dementias. The delineation and clinical diagnosis of these disorders rest on the presence of a characteristic pattern of deficit that arises from the involvement of particularly vulnerable areas of the cerebral cortex, e.g. the medial temporal lobe and hippocampus to AD and the anterior temporal and frontal lobes to Pick's disease. Diagnostic criteria have been improved in the light of clinicopathological studies and, in the case of CJD, for example, by the identification of specific genetic determinants of the phenotypic variability.

2. Clinical diagnosis

The concept of dementia has evolved in recent years from the rather non-specific notion of an organic brain syndrome to a more specific concept. During the first half of the 20th century, all mental disorders of the elderly were considered as different manifestations of senile degeneration of the brain. At that time, nobody had associated the various symptoms of dementia, depression, and paranoia with any particular brain pathology. To do this, 'operational criteria' were developed to classify elderly people into five clinical groups: affective psychosis, senile dementia (or Alzheimer's disease), late paraphrenia, confusional–delirious states, and vascular dementia. The classification was further enhanced with a range of neuropsychological tests. These studies also defined social and familial problems of the elderly in the community which, in turn, paved the way for the development of domicillary social services and psychogeriatric assessment units, the first of which was established in Newcastle in the 1970s.

3. Pathology

The relationship between measures of cognitive function and quantitative measures of brain pathology was first examined in Newcastle in the 1960s. The presence of abundant neurofibrillary tangles (NFTs) in the cerebral cortex proved to be diagnostic of AD. Although some NFTs were present in the hippocampus of normal elderly persons, the number in AD was almost twenty times as great. Approaches to prevent the accumulation of insoluble NFTs in the brain are important, as it is this very pathology that is intimately linked with clinical symptoms. These endeavours encouraged molecular biologists into the study of AD, and the discovery of the composition of the pathological hallmarks that underlie the disease, namely NFTs and neuritic senile plaques. The tangles that form within neurons are composed of paired helical elements (PHFs). These PHFs are made up almost entirely of tau protein. Senile plaques are composed of extracellular deposits of amyloid β-protein interspersed with dystrophic neurites packed with tau-containing PHFs.

Factors that predispose individuals to an increased risk of acquiring AD include the following: increased age, family history, head trauma, and Down's syndrome. Mutations in three genes have been identified which co-segregate with disease in families with the less common, early-onset forms of AD: the amyloid β-protein precursor gene and two presenilin protein genes. A genetic factor in as many as half of the early, autosomal-dominant AD cases has yet to be found. A polymorphism in the apolipoprotein E gene can account for as much as 60 per cent of the susceptibility to AD; inheritance of an APOE β4 allele, however, does not reliably predict whether or when a carrier will develop AD. While various mutations are associated with slight differences in clinical presentation, the pathological changes at autopsy are relatively insignificant and the neurofibrillary pathology is invariably constant.


Fig.1.a The pathological hallmarks of AD are the neurofibrillary tangle and neuritic plaque. b. Neurofibrillary pathology is composed of insoluble, fibrous accumulations of tau protein. c. Tau proteins exist as a family of proteins up to 441 amino acids in length. Mutations associated with other tau-based dementias are clustered largely around a repeated domain of the protein that is indicated by four filled boxes.

4. Molecular composition of the PHF

The clinicopathological findings indicated the importance of the neurofibrillary tangle in the aetiology of Alzheimer's disease and led to a project designed to understand the structure and composition of the tangle. Image reconstruction techniques, developed by Aaron Klug in the MRC Laboratory for Molecular Biology, were applied to tangles purified from Alzheimer brains. The constituent PHFs are made up of a double-helical stack of subunits with the overall appearance of a ribbon twisted into a left-handed helix, each consisting of two symmetrical C-shaped subunits with three domains.

The core of the PHF consists of short, truncated tau molecules that represent fragments derived by proteolysis of the microtubule-associated tau protein. Tau normally serves in the assembly and stabilization of axonal microtubules that are necessary for the transport of vesicles along axons. In Alzheimer's disease, normal, full-length tau disappears, while aggregates of truncated tau accumulate as PHFs within the neuronal cell bodies and dendrites.

It has also been possible to trace the progressive development of the tangle in the brain by immunohistochemistry. In the first stage, amorphous aggregates of truncated tau assemble in the neuron. As tau molecules become truncated the aggregates that form become increasingly more resistant to degradation and neuronal dysfunction commences. When the expanding tangle bursts through the cell membrane, it becomes a 'ghost' tangle representing the tombstone of a neuron that has been destroyed. These steps arise by aggregation and proteolysis of the tau protein molecules in affected neurons. The extent of tau pathology is intimately correlated with cognitive impairment and commences even before the overt appearance of tangles and plaques.

Recently, mutations in the tau gene have been found that co-segregate with a number of familial dementias associated with a variety of phenotypes that can be broadly categorized as frontotemporal dementias. Although mutations have not been found in AD, the discovery that tau mutations are associated with dementia in the absence of Aβ pathology further asserts the view that tau pathology need not be a secondary consequence of altered APP metabolism. The regional distribution, ultrastructural, and biochemical characteristics of the tau deposits in these frontotemporal dementias differentiate them from those present in AD. In many families no Aβ deposits are present, indicating that FTDP-17 is a disorder distinct from AD. This implies that the tau aggregation in the brain per se is not dependent upon prior deposition of Aβ. Conversely, it implies that intraneuronal tauopathy does not necessarily lead to the deposition of Aβ. If tau and amyloid pathologies are linked in AD, then some other factor(s) is required to account for the association between these two deposits in the brain in AD.

5. Therapeutic potential

The shortened fragment of tau protein that accumulates in PHFs in AD neurons is able to capture normal full-length tau in vitro and impose upon it a conformational change that enhances the subsequent capture of further tau molecules. This sequence of events bears resemblance to the pathological process demonstrated by Stanley Prusiner for the prion disorders. In Alzheimer's disease, it proceeds in an exponential fashion, leading to the formation of PHFs and thence tangles. The recent identification of diaminophenothiazine compounds that selectively inhibit tau aggregation without affecting the normal tau–tubulin interaction offers great therapeutic potential not only for Alzheimer's disease but also perhaps for other disorders characterized by protein aggregation.

Alzheimer's disease and the related tauopathies constitute a diverse and heterogeneous group of dementing disorders. There is no single pathway that can explain the pathogenesis of all these disorders. Central to all of them is the ability of tau protein to form proteolytically resistant aggregates. Neurodegeneration might arise as a result of cytoskeletal destruction or be due to the toxicity of the aggregated tau. The proof that protein aggregation causes neurodegeneration will be demonstrated if agents that prevent aggregation are able to prevent the progression of these diseases.

(Published 2004)

— Claude M. Wischik/Charles R. Harrington/Martin Roth

Bibliography
• Blessed, G., Tomlinson, B. E., and Roth, M. (1968), 'The association between quantitative measures of dementia and of senile change in the cerebral grey matter of elderly subjects'. British Journal of Psychiatry, 114.
• Roth, M. (1955). 'The natural history of mental disorder in old age'. Journal of Mental Science, 101.
• — —  Tomlinson, B. E., and Blessed, G. (1967). 'The relationship between quantitative measures of dementia and the degenerative changes in the cerebral grey matter of elderly subjects'. Proceedings of The Royal Society of Medicine. 60.
• Wischik, C. M., Novak, M., Thøgersen, H. C., et al. (1988). 'Isolation of a fragment of tau derived from the core of the paired helical filament of Alzheimer disease'. Proceedings of the National Academy of Sciences of the USA, 85.
• — —  Edwards, P. C., Lai, R. Y. K., Roth, M., and Harrington, C. R. (1996). 'Selective inhibition of Alzheimer disease-like tau aggregation by phenothiazines'. Proceedings of the National Academy of Sciences of the USA, 93.

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