Progression from MCI to AD: predictive value of CSF Aß42 is modified by APOE genotype.

OBJECTIVE: To study CSF biomarkers amyloid-beta 1-42 (Aß42) and total tau (tau) in relation to APOE genotype in their ability to predict progression from mild cognitive impairment (MCI) to Alzheimer's disease (AD). METHODS: In 100 MCI patients CSF Aß42, 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 Aß42 and APOE genotype (p<0.05). Stratification for APOE revealed HR (95% CI) for abnormal Aß42 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 Aß42 revealed that in patients with normal levels of Aß42, 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: Aß42 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 Aß42.

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

BACKGROUND: CSF biomarkers amyloid-beta 1-42 (Abeta42), 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.

Amyloid-beta(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 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.

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.