Journal of Alzheimer s Disease

Small, David H.

doi: 10.3233/JAD-2001-3301pmid: 12214047

David H. Small

doi: N/Apmid: N/A

The biogenesis and degradation/clearance of A$\beta$ amyloid lies at the centre of the pathogenesis of Alzheimer's disease. Quantification of the various metabolic pools of A$\beta$ in the brains and in the periphery may aid in diagnosis, prognosis and the elucidation of the natural history of this disorder. Estimation of the A$\beta$ levels using immunoassays (ELISA and the western blots) are complementary techniques which are now being applied in humans and experimental models. The various forms of A$\beta$ in differing cellular compartments are now being assayed, and a picture of the natural history of Alzheimer's disease is beginning to emerge.

Storey, Elsdon; Kinsella, Glynda J.; Slavin, Melissa J.

doi: 10.3233/JAD-2001-3302pmid: 12214048

Neuropsychological assessment potentially subserves several functions in subjects in whom Alzheimer's disease (AD) is suspected. Such assessment can detect the presence of brain disease once significant neuronal disruption has occurred. Analysis of the pattern and evolution of cognitive deficits allows inferences to be drawn regarding the likely underlying pathology. Neuropsychological assessment enables delineation of the particular cognitive strengths and weaknesses of individual patients, facilitating the construction of individual management programs. Lastly, cognitive testing provides a cost-effective means of monitoring disease progression and the effects of treatment. This review describes the typical pattern and evolution of cognitive deficits in AD, outlines a number of variant presentations, discusses the differential diagnosis from other dementias, and addresses the issue of progression to clinically probable AD in the cognitively impaired, non-demented elderly.It is anticipated that biomarkers for AD will complement neuropsychological assessment by enabling disease detection before unequivocal cognitive deterioration has ensued, and by improving the accuracy of clinical diagnosis of dementia type. The development of reliable biomarkers will also enable improvements in the sensitivity and accuracy of neuropsychological assessment in AD to be made, more quickly and efficiently than is currently possible using longitudinal studies.

Elsdon Storey ; Glynda J. Kinsella ; Melissa J. Slavin

doi: N/Apmid: N/A

Neuropsychological assessment potentially subserves several functions in subjects in whom Alzheimer's disease (AD) is suspected. Such assessment can detect the presence of brain disease once significant neuronal disruption has occurred. Analysis of the pattern and evolution of cognitive deficits allows inferences to be drawn regarding the likely underlying pathology. Neuropsychological assessment enables delineation of the particular cognitive strengths and weaknesses of individual patients, facilitating the construction of individual management programs. Lastly, cognitive testing provides a cost-effective means of monitoring disease progression and the effects of treatment. This review describes the typical pattern and evolution of cognitive deficits in AD, outlines a number of variant presentations, discusses the differential diagnosis from other dementias, and addresses the issue of progression to clinically probable AD in the cognitively impaired, non-demented elderly. It is anticipated that biomarkers for AD will complement neuropsychological assessment by enabling disease detection before unequivocal cognitive deterioration has ensued, and by improving the accuracy of clinical diagnosis of dementia type. The development of reliable biomarkers will also enable improvements in the sensitivity and accuracy of neuropsychological assessment in AD to be made, more quickly and efficiently than is currently possible using longitudinal studies.

Growdon, John H.

doi: 10.3233/JAD-2001-3303pmid: 12214049

Incorporating biomarkers into clinical drug trials for Alzheimer's disease (AD) could 1) increase the homogeneity of patients through improved diagnosis, 2) establish surrogate outcome measures for drug efficacy, 3) test pharmacogenetic bases of drug response, and 4) verify proposed mechanisms of drug action. Among biological correlates of AD, those with the greatest potential to improve diagnostic accuracy are genetic abnormalities that cause AD or increase the risk of AD; characteristic changes in amyloid derivatives and tau and blood in CSF; and neuroimaging detection of brain atrophy and reduction in brain metabolism and blood flow. Although there are no AD biological markers that qualify as true surrogate endpoints in clinical drug trials, indices of brain atrophy show promise as a technique to track progression of dementia and as a measure of treatment efficacy. Anti-amyloid strategies for treatment are the leading candidates for the next generation of Alzheimer therapies. Predicted changes in amyloid derivative levels in CSF can help verify drug activity and illuminate the mechanism of action.

John H. Growdon

doi: N/Apmid: N/A

Incorporating biomarkers into clinical drug trials for Alzheimer's disease (AD) could 1) increase the homogeneity of patients through improved diagnosis, 2) establish surrogate outcome measures for drug efficacy, 3) test pharmacogenetic bases of drug response, and 4) verify proposed mechanisms of drug action. Among biological correlates of AD, those with the greatest potential to improve diagnostic accuracy are genetic abnormalities that cause AD or increase the risk of AD; characteristic changes in amyloid derivatives and tau and blood in CSF; and neuroimaging detection of brain atrophy and reduction in brain metabolism and blood flow. Although there are no AD biological markers that qualify as true surrogate endpoints in clinical drug trials, indices of brain atrophy show promise as a technique to track progression of dementia and as a measure of treatment efficacy. Anti-amyloid strategies for treatment are the leading candidates for the next generation of Alzheimer therapies. Predicted changes in amyloid derivative levels in CSF can help verify drug activity and illuminate the mechanism of action.

Rogaeva, Ekaterina; Tandon, Anurag; St. George-Hyslop, Peter H.

doi: 10.3233/JAD-2001-3304pmid: 12214050

Abbreviations: AD, Alzheimer's disease; AβPP, amyloid β protein precursor; BACE, β-site AβPP cleaving enzyme; PS1, presenilin-1; PS2, presenilin-2; APOE, apolipoprotein E; LRP, low density lipoprotein receptor-related protein; SNPs, single-nucleotide polymorphisms; A2M, α-2-macroglobulin. Alzheimer's disease (AD) is the most common neurodegenerative disorder associated with dementia in the elderly population. Its clinical symptoms are manifest with increasing prominence during mid- to late stages of adulthood. In the absence of precise biological indicators that precede or accompany the cognitive decline, diagnostic confirmation of AD requires postmortem detection of histopathological characteristics such as amyloid plaques, neurofibrillary tangles, and extensive cortical atrophy. While the etiology of AD remains incompletely understood, it was recognized early on that the observed familial aggregation of AD implied the presence of one or more inherited susceptibility markers that could be useful in diagnosis and treatment. To date, genetic analyses of these pedigrees have resolved four independent genetic loci linked with inherited susceptibility to AD.

Ekaterina Rogaeva ; Anurag Tandon ; Peter H. St George-Hyslop

doi: N/Apmid: N/A

Abbreviations: AD, Alzheimer's disease; A \beta PP, amyloid \beta protein precursor; BACE, \beta -site A \beta PP cleaving enzyme; PS1, presenilin-1; PS2, presenilin-2; APOE, apolipoprotein E; LRP, low density lipoprotein receptor-related protein; SNPs, single-nucleotide polymorphisms; A2M, \alpha -2-macroglobulin. Alzheimer's disease (AD) is the most common neurodegenerative disorder associated with dementia in the elderly population. Its clinical symptoms are manifest with increasing prominence during mid- to late stages of adulthood. In the absence of precise biological indicators that precede or accompany the cognitive decline, diagnostic confirmation of AD requires postmortem detection of histopathological characteristics such as amyloid plaques, neurofibrillary tangles, and extensive cortical atrophy. While the etiology of AD remains incompletely understood, it was recognized early on that the observed familial aggregation of AD implied the presence of one or more inherited susceptibility markers that could be useful in diagnosis and treatment. To date, genetic analyses of these pedigrees have resolved four independent genetic loci linked with inherited susceptibility to AD.

McLean, Catriona A.; Beyreuther, Konrad; Masters, Colin L.

doi: 10.3233/JAD-2001-3305pmid: 12214051

The biogenesis and degradation/clearance of Aβ amyloid lies at the centre of the pathogenesis of Alzheimer's disease. Quantification of the various metabolic pools of Aβ in the brains and in the periphery may aid in diagnosis, prognosis and the elucidation of the natural history of this disorder. Estimation of the Aβ levels using immunoassays (ELISA and the western blots) are complementary techniques which are now being applied in humans and experimental models. The various forms of Aβ in differing cellular compartments are now being assayed, and a picture of the natural history of Alzheimer's disease is beginning to emerge.

McLean, Catriona A. ; Beyreuther, Konrad ; Masters, Colin L.

doi: N/Apmid: N/A

The biogenesis and degradation/clearance of Aβ amyloid lies at the centre of the pathogenesis of Alzheimer’s disease. Quantification of the various metabolic pools of Aβ in the brains and in the periphery may aid in diagnosis, prognosis and the elucidation of the natural history of this disorder. Estimation of the Aβ levels using immunoassays (ELISA and the western blots) are complementary techniques which are now being applied in humans and experimental models. The various forms of Aβ in differing cellular compartments are now being assayed, and a picture of the natural history of Alzheimer’s disease is beginning to emerge.