Elsevier

The Lancet

Volume 368, Issue 9533, 29 July–4 August 2006, Pages 387-403
The Lancet

Seminar
Alzheimer's disease

https://doi.org/10.1016/S0140-6736(06)69113-7 Get rights and content

Summary

Alzheimer's disease is the most common cause of dementia. Research advances have enabled detailed understanding of the molecular pathogenesis of the hallmarks of the disease—ie, plaques, composed of amyloid β (Aβ), and tangles, composed of hyperphosphorylated tau. However, as our knowledge increases so does our appreciation for the pathogenic complexity of the disorder. Familial Alzheimer's disease is a very rare autosomal dominant disease with early onset, caused by mutations in the amyloid precursor protein and presenilin genes, both linked to Aβ metabolism. By contrast with familial disease, sporadic Alzheimer's disease is very common with more than 15 million people affected worldwide. The cause of the sporadic form of the disease is unknown, probably because the disease is heterogeneous, caused by ageing in concert with a complex interaction of both genetic and environmental risk factors. This seminar reviews the key aspects of the disease, including epidemiology, genetics, pathogenesis, diagnosis, and treatment, as well as recent developments and controversies.

Section snippets

Epidemiology and risk factors

Alzheimer's disease is the most common form of dementia, accounting for 50–60% of all cases. The prevalence of dementia is below 1% in individuals aged 60–64 years, but shows an almost exponential increase with age, so that in people aged 85 years or older the prevalence is between 24% and 33% in the Western world.2 Representative data from developing countries are sparse, but about 60% of patients with dementia are estimated to live in this part of the world. Alzheimer's disease is very common

Genetics

From a genetic standpoint, Alzheimer's disease is a heterogeneous disorder with both familial and sporadic forms.

Pathogenesis

At the microscopic level, the characteristic lesions in Alzheimer's disease are senile or neuritic plaques and neurofibrillary tangles (figure 1) in the medial temporal lobe structures and cortical areas of the brain, together with a degeneration of the neurons and synapses. Several pathogenic mechanisms that underlie these changes have been studied, including Aβ aggregation and deposition with plaque development, tau hyperphosphorylation with tangle formation, neurovascular dysfunction, and

Clinical features

Alzheimer's disease is a slowly progressive disorder, with insidious onset and progressive impairment of episodic memory; instrumental signs include aphasia, apraxia, and agnosia, together with general cognitive symptoms, such as impaired judgment, decision-making, and orientation.

The term Alzheimer's disease was originally reserved for individuals with presenile onset of symptoms, whereas the expression senile dementia was used when onset was after 65 years of age. Largely on the basis of

Diagnosis

The medical history together with the clinical, neurological, and psychiatric examination serves as the basis in the diagnostic work-up. In very early cases, neuropsychological testing can help to obtain objective signs of memory disturbances. Laboratory studies, such as thyroid-function tests and serum vitamin B12, are necessary to identify secondary causes of dementia and coexisting disorders that are common in elderly people.

Neuroimaging, CT and MRI, plays an important part in the diagnosis

Treatment

Knowledge of the neurotransmitter disturbances in Alzheimer's disease has led to the development of drugs with symptomatic effects, which are approved in many countries. Research advances in the molecular pathogenesis of Alzheimer's disease have also led to new drug candidates with disease-modifying potential, which have now come to testing in clinical trials. Epidemiological data have suggested additional drug candidates, some of which have been investigated in randomised trials.

Future prospects

The past two decades of Alzheimer's disease research have resulted in detailed knowledge of the molecular mechanism of Aβ production and aggregation. With the amyloid cascade hypothesis serving as the foundation, and the Alzheimer's disease transgenic mouse models as the tools for testing, anti-Aβ drug candidates have been developed. Several phase II clinical trials are now ongoing or under planning. The key question that will determine whether these will be successful is not only whether the

Search strategy and selection criteria

We searched PubMed for English language articles on Alzheimer's disease using the keyword “Alzheimer” alone or together with other keywords including: “amyloid”, “CSF”, “CT”, “diagnosis”, “epidemiology”, “genetic”, “imaging”, “MRI”, “PET”, “risk factors”, “tau”, “therapy”, “transgenic”, “treatment”, and several other keywords relevant to every section. We largely selected publications in the past 5 years, but did not exclude important older publications. Selection criteria also included a

References (184)

  • KM Webber et al.

    The cell cycle in Alzheimer disease: a unique target for neuropharmacology

    Mech Ageing Dev

    (2005)
  • PS Aisen

    The potential of anti-inflammatory drugs for the treatment of Alzheimer's disease

    Lancet Neurol

    (2002)
  • GE Gibson et al.

    Oxidative stress in Alzheimer's disease

    Neurobiol Aging

    (2005)
  • PH Reddy et al.

    Are mitochondria critical in the pathogenesis of Alzheimer's disease?

    Brain Res Brain Res Rev

    (2005)
  • GK Wilcock et al.

    Plaques, tangles and dementia. A quantitative study

    J Neurol Sci

    (1982)
  • C Brayne et al.

    Normal ageing, impaired cognitive function, and senile dementia of the Alzheimer's type: a continuum?

    Lancet

    (1988)
  • S Gauthier et al.

    Mild cognitive impairment

    Lancet

    (2006)
  • MJ de Leon et al.

    Abnormal cortisol response in Alzheimer's disease linked to hippocampal atrophy

    Lancet

    (1988)
  • W Jagust

    Positron emission tomography and magnetic resonance imaging in the diagnosis and prediction of dementia

    Alzheimers Dementia

    (2006)
  • L deToledo-Morrell et al.

    MRI-derived entorhinal volume is a good predictor of conversion from MCI to AD

    Neurobiol Aging

    (2004)
  • C Pennanen et al.

    Hippocampus and entorhinal cortex in mild cognitive impairment and early AD

    Neurobiol Aging

    (2004)
  • K Herholz et al.

    Discrimination between Alzheimer dementia and controls by automated analysis of multicenter FDG PET

    Neuroimage

    (2002)
  • S De Santi et al.

    Hippocampal formation glucose metabolism and volume losses in MCI and AD

    Neurobiol Aging

    (2001)
  • A Nordberg

    PET imaging of amyloid in Alzheimer's disease

    Lancet Neurol

    (2004)
  • K Blennow et al.

    CSF markers for incipient Alzheimer's disease

    Lancet Neurol

    (2003)
  • K Blennow

    Cerebrospinal fluid protein biomarkers for Alzheimer's disease

    Neuro Rx

    (2004)
  • MS Chong et al.

    Preclinical Alzheimer's disease: diagnosis and prediction of progression

    Lancet Neurol

    (2005)
  • O Hansson et al.

    Association between CSF biomarkers and incipient Alzheimer's disease in patients with mild cognitive impairment: a follow-up study

    Lancet Neurol

    (2006)
  • HJ MÖller et al.

    The case described by Alois Alzheimer in 1911. Historical and conceptual perspectives based on the clinical record and neurohistological sections

    Eur Arch Psychiatry Clin Neurosci

    (1998)
  • R Mayeux

    Epidemiology of neurodegeneration

    Annu Rev Neurosci

    (2003)
  • JA Mortimer et al.

    Head circumference, education and risk of dementia: findings from the Nun Study

    J Clin Exp Neuropsychol

    (2003)
  • KA Jellinger

    Head injury and dementia

    Curr Opin Neurol

    (2004)
  • M Gatz et al.

    Role of genes and environments for explaining Alzheimer disease

    Arch Gen Psychiatry

    (2006)
  • A Goate et al.

    Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer's disease

    Nature

    (1991)
  • R Sherrington et al.

    Cloning of a gene bearing missense mutations in early-onset familial Alzheimer's disease

    Nature

    (1995)
  • E Levy-Lahad et al.

    Candidate gene for the chromosome 1 familial Alzheimer's disease locus

    Science

    (1995)
  • RJ Harvey et al.

    The prevalence and causes of dementia in people under the age of 65 years

    J Neurol Neurosurg Psychiatry

    (2003)
  • EH Corder et al.

    Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families

    Science

    (1993)
  • LA Farrer et al.

    Effects of age, sex, and ethnicity on the association between apolipoprotein E genotype and Alzheimer disease: a meta-analysis

    JAMA

    (1997)
  • MR Meyer et al.

    ApoE genotype predicts when–not whether–one is predisposed to develop Alzheimer's disease

    Nature Genetics

    (1998)
  • DM Holtzman et al.

    Apolipoprotein E isoform-dependent amyloid deposition and neuritic degeneration in a mouse model of Alzheimer's disease

    Proc Natl Acad Sci USA

    (2000)
  • JA Prince et al.

    APOE epsilon4 allele is associated with reduced cerebrospinal fluid levels of Abeta42

    Neurology

    (2004)
  • ME Blomqvist et al.

    Towards compendia of negative genetic association studies: an example for Alzheimer disease

    Hum Genet

    (2006)
  • G Blessed et al.

    The association between quantitative measures of dementia and of senile change in the cerebral grey matter of elderly subjects

    Br J Psychiatry

    (1968)
  • CL Masters et al.

    Amyloid plaque core protein in Alzheimer disease and Down syndrome

    Proc Natl Acad Sci USA

    (1985)
  • J Kang et al.

    The precursor of Alzheimer's disease amyloid A4 protein resembles a cell-surface receptor

    Nature

    (1987)
  • C Haass et al.

    Amyloid beta-peptide is produced by cultured cells during normal metabolism

    Nature

    (1992)
  • S Gandy

    The role of cerebral amyloid beta accumulation in common forms of Alzheimer disease

    J Clin Invest

    (2005)
  • R Vassar et al.

    Beta-secretase cleavage of Alzheimer's amyloid precursor protein by the transmembrane aspartic protease BACE

    Science

    (1999)
  • S Lammich et al.

    Constitutive and regulated alpha-secretase cleavage of Alzheimer's amyloid precursor protein by a disintegrin metalloprotease

    Proc Natl Acad Sci USA

    (1999)
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