Cerebrospinal Fluid Amyloid-β Research Articles

Cerebrospinal fluid β-amyloid 1–42 and tau in control subjects at risk for Alzheimer’s disease: The effect of APOE ε4 allele

Cerebrospinal fluid (CSF) measures of beta-amyloid(1-42) and tau are linked with the known neuropathology of Alzheimer's disease (AD). Numerous lines of evidence have also suggested that individuals with at least one APOE epsilon4 allele on chromosome 19 are at increased risk of developing AD. We tested these CSF markers in groups of subjects with AD and healthy older control subjects, using the absence or presence of the APOE epsilon4 allele as a predictive variable in the search for possible prognostic biomarkers of AD. We assessed the levels of beta-amyloid(1-42) and total tau in the CSF of 292 subjects (142 control subjects and 150 subjects with mild-to-moderate AD), who were research participants at the National Institute of Mental Health. The group of control subjects was enriched with a high percentage of subjects with a positive family history of AD. All subjects underwent extensive global cognitive testing. When divided according to the absence or presence of the APOE epsilon4 allele, the control subjects with at least one epsilon4 allele had significantly lower CSF beta-amyloid(1-42) but not tau levels than control subjects without an APOE epsilon4 allele (p < .01). As expected, the AD patients had lower levels of CSF beta-amyloid(1-42) and higher CSF tau levels than the normal control group (p < .01). The association of APOE epsilon4 allele and lower, more AD-like levels of CSF beta-amyloid(1-42) in older control subjects is consistent with previous studies showing possible neuroimaging and cognitive abnormalities with epsilon4 carriers and suggests that CSF beta-amyloid(1-42) decreases might represent an early biomarker of AD. Longitudinal follow-up is of course required to verify whether this biomarker is indeed predictive of clinical conversion to AD.

Cerebrospinal fluid amyloid beta peptide patterns in Alzheimer's disease patients and nondemented controls depend on sample pretreatment: indication of carrier-mediated epitope masking of amyloid beta peptides.

A quantitative urea-based amyloid beta (Abeta)-sodium dodecyl sulfate-polyacrylamide gel electrophoresis with Western immunoblot (Abeta-SDS-PAGE/immunoblot) reveals highly conserved and disease-specific Abeta peptide patterns (Abeta 1-37, 1-38, 1-39, 1-40, 1-42) in Alzheimer's disease (AD) patients and nondemented controls. For further standardization of this method, we analyzed cerebrospinal fluid (CSF) of eight probable AD patients and seven nondemented controls using different preanalytical procedures for Abeta-SDS-PAGE/immunoblot and Abeta1-42-enzyme linked immunosorbent assay (ELISA). Both diagnostic groups were discriminated significantly by absolute levels of Abeta1-42 and ratios of Abeta1-42/40, 1-42/38, 1-42/39. Preanalytical freezing of CSF led to a highly significant loss of all Abeta peptide species. This effect was most pronounced for Abeta1-42 and completely prevented by SDS-heat denaturation prior to freezing. Prolonged storage of SDS-heat denatured CSF led to a selective loss of Abeta1-42 and impaired the discrimination of diagnostic groups as measured by Abeta-SDS-PAGE/immunoblot. Neither freezing nor storage significantly affected absolute Abeta1-42 levels as determined by Abeta1-42-ELISA, but both impaired the discrimination of diagnostic groups. Hence, we suggest immediate analysis of samples for Abeta1-42-ELISA, analysis after a short freezing interval for Abeta-SDS-PAGE/immunoblot, and avoidance of prolonged storage intervals. Remarkably, Abeta-SDS-PAGE/immunoblot measured threefold higher levels of Abeta1-42 in CSF than Abeta1-42-ELISA. In summary, our results indicate carrier-mediated epitope masking of Abeta1-42.

Lack of association of the cholesterol 24-hydroxylase (CYP46) intron 2 polymorphism with Alzheimer’s disease

An association was recently reported between an increased risk of Alzheimer’s disease and an intron 2 AA genotype of CYP46, the enzyme hydroxylating cholesterol to 24S-hydroxycholesterol. Moreover, CYP46 AA-carriers were found to have increased levels of amyloid-β and tau in brain and cerebrospinal fluid. We determined the CYP46 intron 2 genotype in a cohort of 178 AD and 105 non-demented control subjects, but found no significant association with AD for any of the individual genotypes or alleles. Further, in an autopsy confirmed subset of this cohort, the proposed CYP46 risk genotype was not associated with any increase in the brain levels of amyloid-β40, amyloid-β42 or in the levels of amyloid plaques and neurofibrillary tangles. Despite growing evidence implicating cholesterol metabolism in AD risk and Aβ generation, our data does not support a robust genetic relationship between the CYP46 intron 2 polymorphism and AD risk or neuropathology.

Relationship between apoE genotype and CSF β-amyloid (1–42) and tau in patients with probable and definite Alzheimer’s disease

We investigated the usefulness of cerebrospinal fluid (CSF) β-amyloid42 (Aβ42), β-amyloid40 (Aβ40) and tau analyses in the diagnosis of Alzheimer’s disease (AD). The study included 41 definite AD cases, 80 patients with probable AD, 27 with other dementias and 39 neurological controls. Aβ42, Aβ40 and tau protein concentrations in CSF were measured of using ELISA assays. Aβ42 levels were decreased and tau increased in AD. Combination of Aβ42 and tau resulted a sensitivity of 50.4% for AD and specificities of 94.8% for controls and 85.2% for other dementias. Ninety-one percent of the patients with Aβ42 below the cutoff value (340 pg/ml) and tau above the cutoff value (380 pg/ml) had AD. AD patients carrying apoE ϵ4 allele had lower Aβ42 ( P < 0.005) and higher tau ( P < 0.05) levels than those without an ϵ4 allele, and 18 (81.8%) of the 22 AD patients who had normal Aβ42 and tau levels were apoE ϵ4 allele non-carriers. Low Aβ42 and high tau concentration in CSF strongly support the diagnosis of AD. Measurement of Aβ42 may help the early diagnosis of cases at risk for AD such as apoE ϵ4 allele carriers.