Clinical Findings and Genetic Basis of Alzheimer Disease

Author: L. T. Middleton
Submitted: Wednesday 8th of September 2010 08:33:46 AM
Submitted by: egf
Educational levels: expert, qc1, qc2, qc3



The world’s population is ageing at an increasing pace and by year 2047 the number of older people (aged +60) is expected to exceed the number of children (aged 0-15), worldwide. In 2000, it was estimated that there were 4 million Europeans suffering from Alzheimer’s disease (AD) and this figure has been projected to almost triple by the year 2050. About 40% of people over 85 years suffer from AD. The disease is therefore seen as a major public health issue, with important health-related and socioeconomic consequences. There are currently no effective preventive measures or disease modifying therapies for neurodegenerative diseases and available treatments are purely symptomatic. In recent years, several major studies have started to shed light into the genetic basis and imaging and biological biomarkers that are aimed to predict the risk of developing the disease, with the ultimate goal of discovery and development of new preventive and disease modifying therapies. AD, a complex and genetically heterogeneous disease, is frequently divided into early onset and late onset forms, with the dividing line being 60-65 years of age. The neuropathologic landmarks of AD is the presence of abnormal deposits of amyloid (fibrillary Aβ) plaques and neurofibrillary tangles (NFTs) formed by phosphorylated tau associated with signs of neurodegeneration (atrophy, neuronal loss and gliosis). Neurodegeneration and NFTs are neuronal processes whilst Aβ plaques are extracellular and usually more widespread. It has recently been shown that in APOE4 carriers, Aβ deposition occurs decades before the potential age of onset of AD and clinical symptoms seem to be more closely linked to NFTs and neurodegeneration. Early onset autosomal dominant forms are caused by mutations in three genes, identified in the early 90s: the Amyloid Precursor Protein (APP) gene and the Presenile-1 (PS1) and Preseniline-2 (PS2) genes. APP is normally cleaved at the β and γ- secretase sites, producing the 40-42 aminoacid, Aβ peptide. The abnormally high deposition of the insoluble fibrillar form of this peptide is one of the neuropathologic cornerstones of AD. Point mutations clustered around the secretase sites and duplication, leading to excessive production of Aβ have been shown to cause autosomal dominant early onset AD. Mutations in PS1 (chrom 14) and PS2 also cause autosomal dominant AD. Of note, PS1 is known to be part of the molecular mechanisms of the γ- secretase cleavage of APP. Although mutations in these three genes represent <2% of all AD, their identification has paved the way in elucidating the basis of the pathogenic mechanisms of the disease, i.e. the Amyloid cascade: Aβ peptide monomers bind other peptides, form oligomers, ultimately leading to the accumulation of amyloid aggregates (amyloid or senile plaques). By still unclear mechanisms but possibly as a result of Aβ oligomers’ toxicity, there is concurrent tau phosphorylation and aggregation, neuroinflammation, synaptic dysfunction, cell death and brain atrophy. In contrast, susceptibility for the late onset form of AD (LOAD) shows no apparent familial aggregation (hence it is also known as sporadic). Based on the Amyloid hypothesis, susceptibility genes would be expected to be part of pathways involved in the production, aggregation and removal of Aβ, as well as in other contributing pathogenic mechanisms. The ε4 polymorphism of the APoE gene (chrom 19) has been consistently associated with LOAD. In families with LOAD and APP mutations, each APOE4 allele can lower the age of onset of dementia. In the absence of family history, one APOE4 allele is associated to two-threefold increased risk, whereas two alleles increases the risk to fivefold and each APOE4 allele lowers the age of onset in a dose- dependant fashion. The population attributable risk associated with APOE4 is estimated at 20%. Long poly-T polymorphisms on an adjoining gene (TOMM40) have recently been shown to be in linkage dysequilibrium with APOE4 and also confer a similar increase of risk. d risk of AD. TOMM40 is part of the mitochondrial protein import machinery. in 2009, two large international genome-wide association studies have reported three additional susceptibility risks that have been replicated in a third US study. The combined studies provided evidence that CLU (Clusterin), PICALM (Phospatidylinositol-binding clathrin-assembly protein) and CR1 (complement component 3b/4b receptor1) might be involved, in ways that may be synergistic to APOE4, in mechanisms of amyloidogenesis and Aβ clearance. Several risk factors have been implicated in AD. Ageing, maternal age, head injury, depression, diabetes and cerebrovascular disease have been consistently associated with an increased risk for AD. Proposed mechanisms include concurrent occurrence, oxidative stress, and overproduction of advanced glycosylated end products, mitochondrial abnormalities and insulin resistance/hyperinsulinemia. Several important studies have been initiated in the last few years, aimed at evaluating the role of imaging (PIB and FDG PET, volumetric MRI) and biological (blood and CSF) biomarkers in assessing and predicting progression to AD in asymptomatic at-risk individuals and in individual with mild cognitive impairment (MCI). The $450M ADNI study (North American Alzheimer’s Disease Neuroimaging Initiative) reported their initial findings in 2009. Their results suggest that Aβ deposition (as evidenced by PIB-PET) is the primary event, followed by Aβ induced hippocampal atrophy, which leads to a decline in episodic memory and cognitive performance. Once positive, PIB imaging remains unchanged, whilst serial MRI and FDG-PET studies continue progressing, with signs of hypo metabolism, increase in ventricular volume and brain atrophy, suggesting progressive neurodegeneration. Low CSF concentrations of Aβ42, increased tau/ phosphorylated tau and tau/ Aβ42 ratio were found to be consistently associated with early signs of AD dementia, with the Aβ42 returning to normal values as the disease progresses. With the caveat of significant interpersonal variability, these data suggest that the combination of genetic susceptibility factors, imaging and CSF data might prove useful in predicting the likelihood of transition to AD from MCI.


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L. T. Middleton . Clinical Findings and Genetic Basis of Alzheimer Disease . EUROGENE portal. September 2010. online:


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