Evert J. van Elk

Amyloid-β(1–42), Total Tau, and Phosphorylated Tau as Cerebrospinal Fluid Biomarkers for the Diagnosis of Alzheimer Disease

BACKGROUND To improve ante mortem diagnostic accuracy of Alzheimer disease (AD), measurement of the biomarkers amyloid-beta(1-42) (Abeta42), total tau (Tau), and tau phosphorylated at threonine(181) (pTau) in cerebrospinal fluid (CSF) has been proposed. We have used these markers and evaluated their performance. METHODS From January 2001 to January 2007, we assessed Abeta42, Tau, and pTau by commercial ELISAs in CSF from 248 consecutive AD patients and 131 patients with subjective memory complaints attending our outpatient memory clinic. Diagnoses were made blind to the results of the biomarker assays. We assessed sensitivity and specificity and analyzed trends over time. RESULTS Interassay CVs from analysis of pools of surplus CSF specimens were mean 11.3% (SD 4.9%) for Abeta42; 9.3% (1.5%) for Tau, and 9.4% (2.5%) for pTau, respectively (n = 7-18). To achieve 85% sensitivity, cutoff values were 550 (95% CI 531-570) ng/L for Abeta42; 375 (325-405) ng/L for Tau, and 52 (48-56) ng/L for pTau. Corresponding specificities were 83% (95% CI 76%-89%) for Abeta42, 78% (70%-85%) for Tau, and 68% (60%-77%) for pTau. Logistic regression to investigate the simultaneous impact of the 3 CSF biomarkers on the diagnosis yielded a sensitivity of 93.5% and specificity of 82.7%, at a discrimination line of Abeta42 = 373 + 0.82 x Tau. The area under the ROC curves of Tau and pTau showed significant fluctuation over time. CONCLUSIONS CSF biomarkers Abeta42 and Tau can be used as a diagnostic aid in AD. pTau did not have additional value over these 2 markers. Cutoff values, sensitivities, specificities, and discrimination lines depend on the patient groups studied and laboratory experience.

CSF biomarker levels in early and late onset Alzheimer's disease

OBJECTIVE To compare CSF levels of beta-amyloid 1-42 (Abeta(1-42)), total tau (tau) and tau phosphorylated at threonine 181 (ptau-181) between AD patients and controls according to age. METHODS 248 AD patients (48% men) and 127 controls (51% men, 22 volunteers and 105 subjective complainers) underwent lumbar puncture. Both patients and controls were divided into a young (<65 years) and old (>or=65 years) group. RESULTS All three biomarkers showed main effects of diagnosis (p<0.001). There was an interaction between diagnosis and age for all three biomarkers (p<0.05), as old controls had lower Abeta(1-42) and higher (p)tau than young controls (Abeta(1-42) 699+/-250 versus 866+/-191pg/ml, tau 408+/-245 versus 243+/-102pg/ml, ptau-181 60+/-28 versus 42+/-15pg/ml), but there was no difference according to age among AD patients (Abeta(1-42) 451+/-178 versus 425+/-146pg/ml, tau 741+/-460 versus 798+/-467pg/ml, ptau-181 91+/-42 versus 91+/-41pg/ml). CONCLUSION We found that the older control group had lower Abeta(1-42) and higher (p)tau compared to the younger control group. This suggests that older individuals may have AD pathology, even in the absence of objective cognitive impairment.

CSF Biomarkers in Alzheimer's Disease and Controls: Associations with APOE Genotype are Modified by Age

The object of this study was to elucidate the effect of age in the relationship between APOE genotype and CSF biomarkers amyloid-beta1-42 (Abeta42), total tau (tau) and tau phosphorylated at threonine 181 (ptau-181) in AD and controls. 302 AD patients and 174 controls were categorized into APOE epsilon4 carriers and non-carriers, and into younger and older (65years). In controls, older age and APOE epsilon4 were independently associated with lower Abeta42 and higher tau and ptau-181 levels (p < 0.05). For tau and ptau-181, there were also interactions (p < 0.10): older carriers had higher levels than older non-carriers, without effect for younger controls. In AD, APOE epsilon4 genotype had a main effect on Abeta42, but there was also an interaction: older carriers had lower Abeta42 than older non-carriers, without effect for younger AD patients (p < 0.05). For tau and ptau-181, there were only interactions: older carriers had higher levels than older non-carriers, while younger AD patients showed the opposite (p 0.05). Association between CSF biomarkers and APOE genotype were modified by age in both controls and AD patients. This suggests that cognitively healthy APOE epsilon4 carriers are more prone to develop AD pathology with aging. For AD patients, this provides support for the existence of subtypes within the disease.

Diagnostic impact of CSF biomarkers in a local hospital memory clinic.

Background: CSF biomarkers amyloid-β 1–42 (Aβ42), total tau (tau) and tau phosphorylated at threonine 181 (ptau-181) are useful diagnostic markers for Alzheimer’s disease (AD). We examined the impact of these biomarkers in the diagnostic process in a non-academic memory clinic. Methods: One hundred and nine patients with available CSF were included from the local hospital memory clinic. Initially, patients were clinically diagnosed, and the clinician indicated their confidence in the diagnosis. Next the CSF results were presented, and the clinician re-evaluated his initial diagnosis. The main outcomes were changes in initial diagnosis and diagnostic confidence. Results: Forty-seven patients were initially diagnosed with AD, 26 were diagnosed with another type of dementia, 18 were diagnosed with mild cognitive impairment, and 18 received a non-dementia diagnosis. All biomarkers distinguished between AD and non-dementia (p < 0.01); tau and ptau-181 also distinguished AD from other types of dementia (p < 0.001). After CSF biomarker levels were revealed, 11 diagnoses changed. In 31% of the diagnoses, the clinician gained confidence, while in 10% confidence decreased. Conclusion: We found that knowledge of CSF biomarker profiles changed the diagnosis in 10% of the cases, and confidence in the diagnosis increased for one third of the patients.

Progression from MCI to AD: predictive value of CSF Aβ42 is modified by APOE genotype.

OBJECTIVE To study CSF biomarkers amyloid-beta 1-42 (Aβ42) and total tau (tau) in relation to APOE genotype in their ability to predict progression from mild cognitive impairment (MCI) to Alzheimers disease (AD). METHODS In 100 MCI patients CSF Aβ42, tau and APOE genotype were determined. At follow-up of 18 (13-24) months 58 patients remained non-progressive and 42 progressed to AD. RESULTS Cox proportional hazards models showed an interaction between Aβ42 and APOE genotype (p<0.05). Stratification for APOE revealed HR (95% CI) for abnormal Aβ42 of 8.2 (2.1-31.9) for ε4 non-carriers, 3.9 (0.8-18.5) for heterozygotes and 0.3 (0.0-1.7) for homozygotes. Inversely, stratification for Aβ42 revealed that in patients with normal levels of Aβ42, ε4 homozygotes had a strongly increased risk of progression to AD with HR (95% CI) 20.8 (2.4-182.8). Tau and APOE independently predicted progression to AD. CONCLUSIONS Aβ42 was a stronger predictor of progression to AD in APOE ε4 non-carriers than in carriers. Furthermore, the risk of progression for ε4 homozygotes was very high, also in patients with normal levels of Aβ42.

CSF biomarkers predict cognitive decline in Alzheimer's disease

in Alzheimer’s disease (AD) and may play an important role in the physiopathology of this neurodegenerative disorder. Nevertheless few studies addressed whether its levels are already reduced in the prodromal stages of the disease, i.e. mild cognitive impairment. Objective: To assess BDNF serum levels in subjects with mild cognitive impairment and Alzheimer’s disease as compared to controls. Methods: One-hundred sixty-seven elderly subjects (31 AD, 72 MCI, and 64 controls) were enrolled to this study. BDNF plasma levels were determined by ELISA. Results: BDNF levels were decreased in Alzheimer’s disease 617.45 6 113.44 pg/mL and MCI (518.78 674.43 pg/mL) as compared to controls (1000.76 6 78.95 pg/ mL) (p<0.001). After grouping MCI subjects in amnestic, non-amnestic and multiple-domain MCI, we found that BDNF levels were significantly reduced in amnestic (p1⁄40.035) and multiple-domain MCI (p1⁄40.002) as compared to controls. No significant differences in BDNF levels were found between mild cognitive impairment subtypes and Alzheimer’s disease. These results remained significant after controlling for confounding effects of age, years of education and APOE4 genotyping. Conclusions: MCI subtypes (amnestic and multiple-domain), commonly regarded as a prodromal stage of AD, showed the lowest BDNF levels, similar to those observed in AD patients. Our results suggest that decreased neurotrophic support is already present in the prodromal stages of AD and may play role in the physiopathology of this disorder.

P3-079: CSF biomarker levels, APOE genotype and the effect of aging

Background: We examined the influence of apoE genotype on CSF biomarkers amyloid beta-42 (A 42), total tau (tau) and tau phopshorylated at threonine 181 (ptau-181) in Alzheimer’s disease (AD) and controls. In addition we assessed if this association was modified by age. Methods: We included 250 AD patients and 154 controls. CSF levels of A 42, tau and ptau-181 were measured and apoE genotype was determined. Patients and controls were categorized in apoE4 negative and apoE4 positive groups. Results: Controls and AD patients did not differ in sex, but there was a difference in age (61 11 years vs 67 9, p 0.001). In controls, two-way ANOVA with apoE genotype and age (dichotomized at 65 years) as independent variables revealed main effects of apoE genotype and age for A 42 (p 0.001), but there was no interaction (p 0.78). By contrast, for tau and ptau-181 there were main effects for apoE genotype and age (p 0.001) and interactions between these factors (p 0.001). Old controls with the apoE4 genotype had higher levels of tau and ptau-181 than old controls lacking the apoE4 allele, without an effect of apoE genotype in young controls. In the group of AD patients, there were no main effects of apoE genotype or age, but there were interactions. Older apoE4 carriers had lower levels of A 42 than apoE4 non-carriers, without an effect for the young AD (interaction p 0.03). For tau and ptau-181 old apoE4 carriers had higher values than apoE4 non-carriers, while among young AD patients, we observed the opposite (interaction p 0.09 and p 0.08). Conclusions: We found that CSF biomarker levels were associated with apoE genotype and age in both AD patients and controls. This could imply that the cognitively healthy with the apoE4 genotype are more prone to develop AD pathology in aging. The opposite associations between apoE and CSF biomarkers in young and old AD patients might imply a different role of this gene in the pathophysiology of the disease.