Alzheimer's at 100

A century ago, Alois Alzheimer first described his eponymous condition. Bushra A Khawaja and Basil H Ridha look at how our understanding has since changed

Alzheimer's disease is a neurodegenerative disorder, characterised clinically by progressive global cognitive decline. It is the commonest cause of dementia (85% of all causes), affecting several cognitive domains and results in considerable physical and psychosocial distress to patients, their carers, and society as a whole.

SIMON FRASER/NEWCASTLE RVI/SPL
My cortex is not the only thing missing

The prevalence of Alzheimer's disease increases exponentially with age, and the number of affected people is projected to increase to 9.9 million by 2040, as the ageing population grows.^w1

The past

The symptoms of Alzheimer's disease were first described in the early 1900s by Emil Kraepelin, a German psychiatrist, who postulated that a specific brain pathology underlies each of the major psychiatric disorders. The neuropathological features were later described by Alois Alzheimer, another German psychiatrist, who worked in Kraepelin's laboratory.

Alzheimer, who had an interest in neuropathology, did an autopsy on the brain of a woman who died in 1906, aged 51 years, with a five year history of progressive cognitive impairment. She had developed hallucinations, delusions, and severely impaired social functioning, and was eventually admitted to an asylum for "delirium and frenzied jealousy of her husband."^w2

Alzheimer found "miliary bodies" and "dense bundles of fibrils," which still define the condition.^w2 He boldly asserted a correlation between the clinical symptoms of this mental disorder and the physical pathology. By the 1960s, autopsies of the brains of elderly people who had dementia showed that senility was not simply owing to ageing, but was, Alzheimer's disease.^w2

100 years on

We still don't know the cause of Alzheimer's disease. It is incurable, and death is expected within 5-12 years. No definitive laboratory marker or neuroimaging for diagnosis in life exists, with the rare exceptions of pathological confirmation from brain biopsy or detection of known genetic mutations in familial forms of the disease. Otherwise, a clinical diagnosis only of probable Alzheimer's disease is made after excluding other causes of cognitive impairment, often after a prolonged follow-up showing progressive cognitive decline.

Several advances have furthered the initial clinical and pathological findings of Kraepelin and Alzheimer, however. The miliary bodies are amyloid plaques, made of beta amyloid peptide, and the dense bundles of fibrils are neurofibrillary tangles consisting of hyperphosphorylated τ protein. These features have been incorporated into objective criteria for defining and staging Alzheimer's disease histopathologically. w3

The development of neuropsychology, with objective cognitive tests, has enabled more accurate mapping of the cognitive impairment and tracking of clinical progression. One of the most useful bedside cognitive tests devised is the widely used mini mental state examination.^w4

The hope for future disease modifying treatments has raised the need to identify people at increased risk of developing the disease. This led to the concept of mild cognitive impairment,w5 w6 a transitional stage between normal ageing and Alzheimer's disease. People with mild cognitive impairment have a 50% risk of its conversion to Alzheimer's disease over five years of follow-up.

Two classes of symptomatic treatment are available. Cholinesterase inhibitors, like rivastigmine, based on the cholinergic deficit theory of Alzheimer's disease, are of modest benefit in patients with mild to moderate disease. Also, the glutamate neurotoxicity theory has led to the development of memantine, an N-methyl-D-aspartic acid (NMDA) receptor antagonist, which has a modest benefit in moderate to severe disease.

Although age is the strongest risk factor for the development of Alzheimer's disease, several genetic factors have been implicated. Mutations in the genes coding for the amyloid precursor protein, presenilin 1 and presenilin 2, leading to autosomal dominant pattern of inheritance of early onset Alzheimer's disease have provided support to the amyloid cascade theory of pathogenesis. Transgenic animal models carrying the amyloid precursor protein mutations have been instrumental in understanding the pathophysiology and developing potential disease modifying agents. Also, the consistent finding of an association between apolipoprotein E4 allele and sporadic Alzheimer's disease has highlighted the potential role of cholesterol metabolism in the disease.

The future

The exponential increase of research projects into all aspects of Alzheimer's disease is promising.

An important technical development has been the design of radioactive ligands, such as the Pittsburgh compound B, which specifically bind to beta amyloid plaques. This can be safely injected and then visualised using positron emission tomography.^w7

The amyloid cascade hypothesis, with the central role of amyloid beta peptide deposition in the pathogenesis of Alzheimer's disease, has led to the development of potential disease modifying agents that focus on the removal of amyloid deposits. One mechanism is via antibodies that target the plaques, removing them with immune mechanisms. Initial active vaccination with beta peptide as antigen, from work on animal models of Alzheimer's disease is promising. But a clinical trial of active vaccination in humans was stopped because of the development of immune meningoencephalitis in a small proportion of patients.^w8 A clinical trial of passive vaccination is currently underway.

With much research concentrating on the molecular and pharmacological aspects of Alzheimer's disease, it is important not to forget the psychosocial impact on patients and their carers. Even today, constant social and psychological support continues to form the mainstay of management, alongside other pharmacological advancements.

Bushra A Khawaja, fourth year medical student, Royal Free University College London Medical School, London WC1E 6BT
Email: b.khawaja@ucl.ac.uk
Basil H Ridha, clinical research fellow, Dementia Research Centre, London SW8 2HB
Email: bridha@dementia.ion.ucl.ac.uk

We thank Bahman Nedjat-Shokouhi for his contribution to this article.

Competing interests: None declared.

studentBMJ 2006;14:353-396 October ISSN 0966-6494

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