Diagnostic Marker For Alzheimer's Disease Research Articles

Apolipoprotein E in Alzheimer's disease risk and case detection: A case-control study

The objective of this study was to describe the association between the epsilon 4 allele of the apolipoprotein E gene (APOE E4) and Alzheimer's disease (AD) and to evaluate APOE E4 genotyping as a test for AD. The study base of this case-control study included about 23,000 persons 60 year of age or greater (a large health maintenance organization); the demographic characteristics of this group are similar to those of the surrounding area. Analysis focused on 234 Caucasian probable AD patients first identified between 1987 and 1993; and 304 cognitively intact controls of similar age, sex, and race who were randomly selected from the same study base. All cases were examined and diagnosed by study physicians using standard protocols. All subjects participate in continuing annual follow-up testing to verify their cognitive status. APOE genotypes were determined from blood samples using standard laboratory methods. Subject characteristics and diagnoses were obtained from interviews, diagnostic examination, or medical record review. Heterozygous E4 individuals had a crude odds ratio of 3.1 (2.1–4.5) for AD compared to those with no E4, while homozygous E4 subjects had an odds ratio of 34.3 (8.0–146.3) for AD. As an indicator of AD, having one E4 allele showed a sensitivity of 0.52 and a specificity of 0.74. Homozygous E4 genotype had a sensitivity of 0.23 and a specificity of 0.99 (when compared to non-E4 genotypes). Cardiovascular disease differed in cases and controls, but did not confound or modify the APOE E4-AD association. In this study base, the APOE E4 allele was a significant risk factor. However, considering either homozygous or heterozygous E4 genotype as a screen or diagnostic marker for AD would miss many true cases and could misclassify many normals as AD.

High apolipoprotein E ε4 allele frequency in Age‐related memory decline

Many studies have demonstrated a strong association between the presence of one or two epsilon 4 alleles and Alzheimer's disease (AD), although few data are available on the apolipoprotein E (APOE) epsilon 4 frequencies at the preclinical stages of AD. Thus, with a view to determining whether APOE genotyping could be useful in the early detection of AD, we determined the Apoe allele frequencies in patients with memory complaints without dementia (age-related memory decline, ARMD). We found an APOE epsilon 4 allele frequency of 0.315 in the ARMD group, similar to 0.293 in the AD group, in contrast to 0.057 in the control group. Significant differences (t=-2.91, df=25, p=0.008) were found between the Alzheimer's Disease Assessment Scale (ADAS) total scores in the ARMD patients with at least one epsilon 4 allele (mean=24.2) compared with the ARMD patients without the epsilon 4 allele (mean=14.7). Our results suggest that the patients with memory complaints, a high ADAS score, and the presence of one or two APOE-4 alleles could be at high risk for developing AD. Thus, we propose that genotyping in conjunction with the ADAS scale may prove useful as diagnostic markers of AD in the presymptomatic stages.

7 Tau and Ubiquitin as diagnostic markers of Alzheimer disease

7 Tau and Ubiquitin as diagnostic markers of Alzheimer disease

Tetraethylammonium-induced calcium concentration changes in skin fibroblasts from patients with Alzheimer disease.

Potassium (K+) channel dysfunction in fibroblasts was recently proposed as a potential diagnostic marker for Alzheimer disease (AD). We utilized a microspectrofluorometric method with Fura-2AM to measure intracellular free calcium ([Ca2+]i) following depolarization with the K+ channel blocker tetraethylammonium (TEA) in seven AD and seven control fibroblast cultures. Contrary to our expectation, 43% of the AD and 36% of the control fibroblast plated coverglasses responded with an increase in [Ca2+]i on addition of 100 mM TEA. The data suggest that the TEA-elicited [Ca2+]i response is not a useful AD screening test.

Neuron specific enolase in cerebrospinal fluid: a biochemical marker for neuronal degeneration in dementia disorders?

Alzheimer's disease (AD) is the most common disease causing dementia. Today the clinical diagnosis of AD is made by way of exclusion, and no biochemical markers are available to assist the clinical diagnosis. We examined the potential of neuron-specific enolase (NSE) in cerebrospinal fluid (CSF) as a diagnostic marker for AD. NSE was determined with a monoclonal antibody two-site immunoradiometric assay (IRMA) in serum (S) and cerebrospinal fluid (CSF) samples from 45 patients with "probable Alzheimer's disease (AD)", 19 patients with vascular dementia (VAD) and 33 age-matched healthy individuals. There was no significant correlation between S-NSE and CSF-NSE, or between CSF/S albumin ratio and CSF-NSE, findings suggesting that the major portion of CSF-NSE is intrathecally produced and that analysis of CSF-NSE alone (without accompanying analysis of serum) is sufficient. CSF-NSE was significantly higher in the AD group (4.7 +/- 2.7 ng/mL; p < 0.0001) and in VAD group (4.5 +/- 2.5 ng/mL; p < 0.001) as compared with the control group (2.2 +/- 1.0 ng/mL), while it did not differ significantly between the AD and the VAD group. These findings suggest that CSF-NSE have a potential as a non-disease specific marker for the neuronal degeneration in dementia disorders.

Beta-Amyloid protein immunoreactivity in skin is not a reliable marker of Alzheimer's disease. An autopsy-controlled study.

As a possible diagnostic marker for Alzheimer's disease (AD), we investigated beta-amyloid protein (beta/A4) immunoreactivity in skin. Furthermore, we studied the presence of beta-amyloid precursor protein 695 immunoreactivity in skin. Lifetime skin biopsy specimens were stained for beta/A4 and beta-amyloid precursor protein 695. The follow-up period was 12 months. We determined the correlation between beta/A4 immunoreactivity in skin and brain in patients with a neuropathologic diagnosis. All patients with dementia were hospitalized; most of them had moderate to severe dementia. Aged nondemented controls were residents of a nursing home. The Down's syndrome (DS) group included both hospitalized and ambulatory patients. Young nondemented controls were medical students or staff members who volunteered for the study. The study included a total of 111 subjects. Thirty-five patients had probable AD, nine had possible AD, 15 had multi-infarct dementia, one had idiopathic Parkinson's disease, and one had Parkinson's disease and possible AD. There were also 19 elderly nondemented controls, 23 patients with DS, and eight young nondemented controls. Immunohistochemical detection of beta/A4 in skin and correlation to the diagnosis of AD. Immunopositivity for beta/A4 antibody was present in and around the endothelium of dermal blood vessels in a proportion of patients with AD and multi-infarct dementia as well as elderly controls. The patients with sporadic AD displayed beta/A4 immunoreactivity significantly more frequently than did patients with familial AD, patients with multi-infarct dementia, and controls. The beta/A4 immunopositivity in skin was rare in the patients with DS and not present in young controls. Instead, 48% of patients with DS but none of other groups had beta-amyloid precursor protein 695 immunoreactivity in skin. Only four (31%) of 13 patients with neuropathologically confirmed AD had shown endothelial beta/A4 immunopositivity in skin biopsy specimens while alive. Our results do not support beta/A4 as a diagnostic marker for AD.

Intact primary memory in mild to moderate Alzheimer disease: Indices from the California Verbal Learning Test

The California Verbal Learning Test (CVLT; Delis, Kramer, Kaplan, & Ober, 1987) was administered to patients with mild to moderate Alzheimer disease (AD) (Group AD; n = 13) and to a control group of normal older adults (Group NC; n = 13) matched on age and education. Two measures were used to determine whether primary memory (PM) is impaired in early AD. One measure, considered a relatively "pure" measure of PM, is based on the procedure developed by Tulving and Colotla (1970) which considers an item to be recalled from PM if no more than six items intervene between its presentation and recall. The other measure is the more commonly used recall from recency. No significant difference between the AD and NC Groups was found, both on the Tulving and Colotla measure, as well as on the recall from recency measure of PM. A significant difference was obtained on two measures of secondary memory (SM), namely, Tulving and Colotla's measure and recall from the primacy and middle regions of the list of words. In comparison to NC, and AD patients showed little evidence of learning over the five trials, and poor retention even over short delays. In addition, the patients with AD showed deficits in clustering words by taxonomic category at recall. We conclude that impairment in PM cannot be used as a diagnostic marker of AD in the early stages of the disease process.

Relationship between serum α1-antichymotrypsin and Alzheimer's disease

We obtained serum samples and measured α1-antichymotrypsin (ACT) levels in 36 pairs of consecutive probable Alzheimer's disease (AD) patients and age- and sex-matched, cognitively intact control subjects. Serum ACT was measured by radial immunodiffusion. Unique to this study, we found that ACT levels rose significantly with age within controls (but not within AD cases), thus ACT may be related to the aging process. Consistent with other reports, we found that AD cases had greater serum ACT in 27 of 36 pairs [mean difference = 135.5 (SE = 50.8) mg/l ( p < 0.05)]. Severity and duration of AD were not significantly associated with the observed difference. The ACT increase observed in AD is not sufficient to recommend ACT's use as a diagnostic marker for AD. Because adult Down's syndrome (DS) persons are known to have pathologic features of AD, we also measured serum ACT levels in 11 adult, noninstitutionalized, DS persons paired with 11 age- and sex-matched, volunteer control subjects; we found no statistically significant difference. The unexpected age-associated increase in ACT among normal controls could be an indicator of early amyloid plaque formation. Future studies comparing ACT levels in both serum and cerebrospinal fluid should help to clarify the origin of ACT found in amyloid plaques and its value as a diagnostic marker for AD.

Longitudinal sensitivity of the Fuld cholinergic profile to Alzheimer's disease.

The diagnostic sensitivity of a profile (Fuld, 1984) thought to mark cholinergic changes in Alzheimer's Disease (AD) was examined in a sample of 53 patients meeting criteria for AD on two occasions and in 19 patients for three occasions. The low obtained sensitivities of the Fuld profile (17%-26%) across testings is consistent with previous studies that used a single time point. The findings also revealed unstable positive and negative profiles over time. There were no performance differences on intellectual or memory measures when comparing subjects identified as positive or negative by the Fuld index. The results demonstrate that the index is insensitive to the dementing process and is a poor diagnostic marker for AD.

Analysis and Quantitation of the β‐Amyloid Precursor Protein in the Cerebrospinal Fluid of Alzheimer's Disease Patients with a Monoclonal Antibody‐Based Immunoassay

One of the major clinical findings in Alzheimer's disease (AD) is the formation of deposits of beta-amyloid protein in amyloid plaques, derived from the beta-amyloid precursor protein (beta-APP). To determine the possible use of beta-APP as a diagnostic marker for AD in CSF, a monoclonal antibody-based immunoassay specific for this protein was developed. The assay does not differentiate between beta-APP695 and beta-APP751 forms but does preferentially recognize beta-APP751 complexed with a protease. Of the two sets of CSF samples tested, one set, obtained from living patients, gave a slightly lower level of beta-APP in AD and Parkinson's disease patients relative to controls, whereas the other set, composed of postmortem samples, showed no significant differences between the AD and control groups.

Cholinesterases in cerebrospinal fluid. A longitudinal study in Alzheimer disease.

We measured acetylcholinesterase (AChE) and butyrylcholinesterase activities in the lumbar cerebrospinal fluid (CSF) of 39 patients with dementia of Alzheimer type and 21 age-matched controls. The mean lumbar CSF AChE activity in our patients did not differ significantly from that of controls. The 7S and 11S molecular forms were also unchanged. When CSF was analyzed at six-month intervals, there was no significant decline in AChE activity over a span of 12 months. Our results and those of previous studies demonstrate that CSF AChE is not a useful diagnostic marker of Alzheimer disease.