Disease relevance of Alzheimer Disease

• We also found that the concentration of PreA4 in the brain tissue of two adults with Down's syndrome (100 and 190 pmol per gram) was higher than that in the brain tissue of either 26 patients with Alzheimer's disease (64.4 +/- 17.3 pmol per gram) or 17 elderly controls with neurologic disease (68.5 +/- 26.3 pmol per gram) [1].
• Genetic studies on Alzheimer's disease (AD), a devastating neurodegenerative disorder, have identified the apolipoprotein E (APOE) gene as a strong susceptibility marker for AD [2].
• We report duplication of the APP locus on chromosome 21 in five families with autosomal dominant early-onset Alzheimer disease (ADEOAD) and cerebral amyloid angiopathy (CAA) [3].
• Deregulated Ca(2+) levels result in aberrant proteolysis by calpains, which contributes to tissue damage in heart and brain ischemias as well as neurodegeneration in Alzheimer's disease [4].
• Loss-of-function mutations in TYROBP (DAP12) result in a presenile dementia with bone cysts [5].
• As such, glucosamine may facilitate the process of amyloidosis, and /or provide neuroprotection in the Alzheimer disease brain [6].

Psychiatry related information on Alzheimer Disease

• Variants of the apolipoprotein E allele appear to account for most cases of late-onset Alzheimer's disease, and persons with two copies of the epsilon 4 allele appear to have an especially high risk of dementia [7].
• We measured high-affinity, sodium-dependent glutamate transport in synaptosomes from neural tissue obtained from 13 patients with ALS, 17 patients with no neurologic disease, and 27 patients with other neuro-degenerative diseases (Alzheimer's disease in 15 patients and Huntington's disease in 12 patients) [8].
• Studies in three different transgenic mouse models suggest that the amyloid beta-protein contributes to memory loss in Alzheimer disease [9].
• INTERPRETATION: These findings suggest that dementia and its two major subtypes Alzheimer's disease and vascular dementia are associated with atherosclerosis and that there is an interaction between apolipoprotein E and atherosclerosis in the aetiology of Alzheimer's disease [10].
• Levels of high-density lipoprotein cholesterol were found to be significantly lower in 5 men with multi-infarct dementia than in 12 men with senile dementia of the Alzheimer type [11].

High impact information on Alzheimer Disease

• These include maintenance of cell polarization, antigen presentation, glucose transport, atherosclerosis, Alzheimer's disease, and the endocytosis of toxins and viruses [12].
• From Alois Alzheimer's description of Auguste D.'s brain in 1907 to George Glenner's biochemical dissection of beta-amyloid in 1984, the "amyloid hypothesis" of Alzheimer's disease has continued to gain support over the past two decades, particularly from genetic studies [13].
• Mutations in PS-1 associated with Alzheimer's disease interfere with CBP proteolysis, leading to abnormal transcription [14].
• Presenilin1 (PS1), a protein implicated in Alzheimer's disease (AD), forms complexes with N-cadherin, a transmembrane protein with important neuronal and synaptic functions [15].
• To determine the relation between brain responses to tasks requiring memory and the genetic risk of Alzheimer's disease, we performed APOE genotyping and functional magnetic resonance imaging (MRI) of the brain in older persons with intact cognition [16].

Chemical compound and disease context of Alzheimer Disease

• Tacrine in Alzheimer's disease [17].
• These data show that A beta is neurotoxic in vivo and suggest that apoptosis may be responsible for the accompanying neuronal loss, the principal underlying cellular feature of Alzheimer's disease [18].
• Glutamate/aspartate-releasing neurons in Alzheimer's disease [19].
• We treated 17 patients who had moderate to severe Alzheimer's disease with oral tetrahydroaminoacridine (THA), a centrally active anticholinesterase, in a three-phase study [20].
• Choline in Alzheimer's disease [21].
• Proteins involved in brain cholesterol metabolism may affect the pathogenesis of Alzheimer's disease [22].

Biological context of Alzheimer Disease

• The addition of information about the APOE genotype increased the overall specificity to 84 percent in patients who met the clinical criteria for Alzheimer's disease, although the sensitivity decreased [23].
• A locus for familial early-onset Alzheimer's disease on the long arm of chromosome 14, proximal to the alpha 1-antichymotrypsin gene [24].
• In several pedigrees of early onset familial Alzheimer's disease (FAD), point mutations in the beta-amyloid precursor protein (APP) gene are genetically linked to the disease [25].
• Identification, biogenesis, and localization of precursors of Alzheimer's disease A4 amyloid protein [26].
• These findings, with previous studies which show that heparin stimulates tau phosphorylation by a number of protein kinases, indicate that sulphated glycosaminoglycans may be a key factor in the formation of the neurofibrillary lesions of Alzheimer's disease [27].

Anatomical context of Alzheimer Disease

• The gene coding for the amyloid protein, a component of neuritic plaques found in brain tissue from patients with Alzheimer's disease, has been localized to chromosome 21, and neighbouring polymorphic DNA markers segregate with Alzheimer's disease in several large families [28].
• Neuronal degeneration in the hippocampus, a region of the brain important for acquisition of memory in humans, occurs in various pathological conditions, including Alzheimer's disease, brain ischaemia and epilepsy [29].
• Accumulation of the amyloid-beta protein (Abeta) in the cerebral cortex is an early and invariant event in the pathogenesis of Alzheimer's disease [30].
• Peripherally administered antibodies against amyloid beta-peptide enter the central nervous system and reduce pathology in a mouse model of Alzheimer disease [31].
• Here we report the detection of amyloid beta-protein deposits in non-neural tissues and blood vessels of Alzheimer's disease patients, including skin, subcutaneous tissue and intestine [32].

Gene context of Alzheimer Disease

• However, since increased levels of PreA4 are not present in Alzheimer's disease, additional factors must account for the amyloid deposition in that disorder [1].
• In patients with Alzheimer's disease, amyloid fibrils that are aggregates of A4 protein subunits are deposited in the brain [1].
• A specific isoform of apolipoprotein E has been associated with the accelerated rate of disease expression of sporadic Alzheimer's disease (AD) and late-onset familial AD (FAD) [33].
• Disease-linked mutations in these genes result in increased production of the 42-amino-acid form of the peptide (Abeta42), which is the predominant form found in the amyloid plaques of Alzheimer's disease [34].
• In addition, some isoform-specific interactions of apolipoprotein E have been demonstrated with the defining pathological lesions of Alzheimer's disease, the neurofibrillary tangle and neuritic plaque [35].
• Cholesterol and lipoprotein gene cascades in Alzheimer's disease [36]
• Genes   and environmental   risk factors involved in Alzheimer's Disease

Analytical, diagnostic and therapeutic context of Alzheimer Disease

• Positron-emission tomography (PET) has identified specific regions of the brain in which the rate of glucose metabolism declines progressively in patients with probable Alzheimer's disease [7].
• A double-blind, placebo-controlled multicenter study of tacrine for Alzheimer's disease. The Tacrine Collaborative Study Group [37].
• CONCLUSIONS: APOE genotyping does not provide sufficient sensitivity or specificity to be used alone as a diagnostic test for Alzheimer's disease, but when used in combination with clinical criteria, it improves the specificity of the diagnosis [23].
• To investigate the deposition of amyloid in these diseases, we used a radioimmunoassay to measure levels of the amyloid precursor (PreA4) in the serum of 17 patients with Down's syndrome, 15 patients with Alzheimer's disease, and 33 normal elderly controls [1].
• Here we show that vaccination with A beta protects transgenic mice from the learning and age-related memory deficits that normally occur in this mouse model for Alzheimer's disease [38].

References