CSF Alzheimer's Disease Biomarkers Research Articles

Plasma multianalyte profiling in mild cognitive impairment and Alzheimer disease

While plasma biomarkers have been proposed to aid in the clinical diagnosis of Alzheimer disease (AD), few biomarkers have been validated in independent patient cohorts. Here we aim to determine plasma biomarkers associated with AD in 2 independent cohorts and validate the findings in the multicenter Alzheimer's Disease Neuroimaging Initiative (ADNI). Using a targeted proteomic approach, we measured levels of 190 plasma proteins and peptides in 600 participants from 2 independent centers (University of Pennsylvania, Philadelphia; Washington University, St. Louis, MO), and identified 17 analytes associated with the diagnosis of very mild dementia/mild cognitive impairment (MCI) or AD. Four analytes (apoE, B-type natriuretic peptide, C-reactive protein, pancreatic polypeptide) were also found to be altered in clinical MCI/AD in the ADNI cohort (n = 566). Regression analysis showed CSF Aβ42 levels and t-tau/Aβ42 ratios to correlate with the number of APOE4 alleles and plasma levels of B-type natriuretic peptide and pancreatic polypeptide. Four plasma analytes were consistently associated with the diagnosis of very mild dementia/MCI/AD in 3 independent clinical cohorts. These plasma biomarkers may predict underlying AD through their association with CSF AD biomarkers, and the association between plasma and CSF amyloid biomarkers needs to be confirmed in a prospective study.

P4‐304: Effects of elevated plasma cholesterol on CSF lipids and Alzheimer's disease CSF biomarkers in African green monkeys

P4‐304: Effects of elevated plasma cholesterol on CSF lipids and Alzheimer's disease CSF biomarkers in African green monkeys

P4‐075: Cholesterol ester transfer protein–deficient polymorphisms alter cerebrospinal fluid biomarkers and reduce Alzheimer's disease–related cognitive impairment in apolipoprotein E‐ε4 carriers

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by accumulation amyloid-β (Aβ) and tau deposits within the brain. The most significant genetic risk factor for late-onset AD is the e4 allele of apolipoprotein E (apoE), a major lipid and Aβ binding protein. While only 15% of the normal population carries apoE4, up to 60% of AD patients have one or two copies of apoE4. Recent genetic studies suggest that cholesterol ester transfer protein (CETP) deficient polymorphisms may reduce AD incidence in apoE4 carriers. While CETP deficient polymorphisms and CETP inhibitors treatment have been shown to produce larger plasma HDL with increased apoE content, the effect of CETP loss-of-function on CSF apoE and AD biomarkers is unknown. Here we evaluated the impact of CETP deficient polymorphisms and apoE genotype on CSF disease markers and AD status. CSF from 80 probable AD patients and 50 normal controls were characterized for apoE, apoJ, apoAI and cholesterol content in addition to AD biomarkers Aβ 40, Aβ 42, tau and p-tau. Corresponding plasma samples were evaluated for triglycerides, total cholesterol, HDL and LDL cholesterol, CETP, apoE, apoJ and apoAI content. Genotyping for apoE (APOE e 2/e 3/e 4) and the three most common CETP deficient polymorphisms (CETp I405V, TaqIB and -629C>A) was carried out by restriction fragment length polymorphism analysis. We found that 40 of the 80 probable AD patients presented a biochemically confirmed AD CSF profile established by cut-offs for Aβ 42/tau and Aβ 42/40 ratio. Within this AD population, patients carrying both apoE4 and CETP deficient polymorphisms had a less deteriorated CSF tau to Aβ 42 ratio disease profile when compared to patients carrying the non-deficient CETP alleles. CETP deficient polymorphisms also impacted the level of apolipoproteins and cholesterol in the CSF. Furthermore, while CETP deficient polymorphisms did not appear to affect AD incidence, AD patients carrying apoE4 and CETP deficient polymorphisms showed reduced cognitive impairment when compared to the non-deficient CETP alleles. Our results suggest that CETP deficient polymorphisms slow disease progression in apoE4 carriers and reveal the potential for CETP inhibitors to be a therapeutic approach for the prevention and possibly the treatment of AD.

CSF biomarkers for Alzheimer disease correlate with cortical brain biopsy findings

To assess the relationship between Alzheimer disease (AD)-related pathologic changes in frontal cortical brain biopsy and AD biomarkers in ventricular vs lumbar CSF, and to evaluate the relationships of AD biomarkers in CSF and cortical biopsy with the final clinical diagnosis of AD. In 182 patients with presumed normal pressure hydrocephalus (152 with known APOE carrier status), Aβ plaques and tau in the cortical brain biopsies were correlated with the ventricular and lumbar CSF Aβ42, total tau, and p-tau levels measured by ELISA. In a median follow-up of 2.0 years, 51 patients developed AD dementia. The patients with Aβ plaques in the cortical biopsy had lower (p = 0.009) CSF Aβ42 levels than those with no Aβ plaques. The patients with tau in the cortical biopsy had lower (p = 0.014) Aβ42 but higher (p = 0.015) p-tau 181 in CSF as compared to those with no tau in the cortical biopsy. The patients with amyloid + tau + biopsies had the lowest Aβ42 and highest tau and p-tau 181 levels in CSF. The Aβ42 levels were lower and the tau and p-tau 181 higher in the ventricular vs corresponding lumbar CSF samples. In multivariate analysis, the presence of cortical Aβ was independently predicted by the APOE ε4 carrier status and age but not by CSF Aβ42 or tau levels. Amyloid plaques and hyperphosphorylated tau in cortical brain biopsies are reflected by low CSF Aβ42 and high CSF tau and p-tau levels, respectively.

Age and diagnostic performance of Alzheimer disease CSF biomarkers

Core CSF changes in Alzheimer disease (AD) are decreased amyloid β(1-42), increased total tau, and increased phospho-tau, probably indicating amyloid plaque accumulation, axonal degeneration, and tangle pathology, respectively. These biomarkers identify AD already at the predementia stage, but their diagnostic performance might be affected by age-dependent increase of AD-type brain pathology in cognitively unaffected elderly. We investigated effects of age on the diagnostic performance of CSF biomarkers in a uniquely large multicenter study population, including a cross-sectional cohort of 529 patients with AD dementia (median age 71, range 43-89 years) and 304 controls (67, 44-91 years), and a longitudinal cohort of 750 subjects without dementia with mild cognitive impairment (69, 43-89 years) followed for at least 2 years, or until dementia diagnosis. The specificities for subjects without AD and the areas under the receiver operating characteristics curves decreased with age. However, the positive predictive value for a combination of biomarkers remained stable, while the negative predictive value decreased only slightly in old subjects, as an effect of the high AD prevalence in older ages. Although the diagnostic accuracies for AD decreased with age, the predictive values for a combination of biomarkers remained essentially stable. The findings highlight biomarker variability across ages, but support the use of CSF biomarkers for AD even in older populations.

Cerebrospinal fluid markers for differential dementia diagnosis in a large memory clinic cohort

To determine how amyloid β 42 (Aβ42), total tau (t-tau), and phosphorylated tau (p-tau) levels in CSF behave in a large cohort of patients with different types of dementia. Baseline CSF was collected from 512 patients with Alzheimer disease (AD) and 272 patients with other types of dementia (OD), 135 patients with a psychiatric disorder (PSY), and 275 patients with subjective memory complaints (SMC). Aβ42, t-tau, and p-tau (at amino acid 181) were measured in CSF by ELISA. Autopsy was obtained in a subgroup of 17 patients. A correct classification of patients with AD (92%) and patients with OD (66%) was accomplished when CSF Aβ42 and p-tau were combined. Patients with progressive supranuclear palsy had normal CSF biomarker values in 90%. Patients with Creutzfeldt-Jakob disease demonstrated an extremely high CSF t-tau at a relatively normal CSF p-tau. CSF AD biomarker profile was seen in 47% of patients with dementia with Lewy bodies (DLB), 38% in corticobasal degeneration (CBD), and almost 30% in frontotemporal lobar degeneration (FTLD) and vascular dementia (VaD). PSY and SMC patients had normal CSF biomarkers in 91% and 88%. Older patients are more likely to have a CSF AD profile. Concordance between clinical and neuropathologic diagnosis was 85%. CSF markers reflected neuropathology in 94%. CSF Aβ42, t-tau, and p-tau are useful in differential dementia diagnosis. However, in DLB, FTLD, VaD, and CBD, a substantial group exhibit a CSF AD biomarker profile, which requires more autopsy confirmation in the future.

P4‐417: The effects of statin use on Alzheimer's disease CSF biomarkers in cognitively healthy elderly

P4‐417: The effects of statin use on Alzheimer's disease CSF biomarkers in cognitively healthy elderly

Longitudinal change in CSF biomarkers in a presymptomatic carrier of an APP mutation

Persons inheriting fully penetrant autosomal dominant mutations causing familial Alzheimer disease (AD) provide the opportunity to characterize presymptomatic biomarker changes in a population where studies might be performed to efficiently identify preventative interventions. Decreased Aβ42 and increased total tau (t-tau) and phosphorylated tau (p-tau) in CSF are associated with incident1 and established AD.2 These markers have been increasingly incorporated as outcome measures for clinical trials, but further characterization of their natural course is necessary to interpret such studies. Though longitudinal changes in these markers are expected for individuals developing AD, such changes have yet to be thoroughly documented prospectively. Here we report changes in AD CSF biomarkers over time in a presymptomatic carrier of the V717I mutation in the amyloid precursor protein ( APP ) gene.3 ### Methods. Due to confidentiality issues, the gender and chronological age of this individual are not disclosed. As the age of disease onset can be consistent within families harboring this APP mutation,3 we report the individual's age relative to the median age of dementia diagnosis within their family. The subject was enrolled in a UCLA institutional review board– approved study of persons at risk for …

A novel PSEN1 gene mutation (L235R) associated with familial early-onset Alzheimer's disease

Mutations in the presenilin 1 ( PSEN1) gene are the most frequent cause of familial Alzheimer's disease (AD), with at least 182 different mutations published to date. We report a 48-year-old woman (age at onset 47 years) who presented a progressive alteration of episodic memory, spatial disorientation, apathy, language disturbances and neglect of personal care. Her MMSE score was 20/30. The patient presented an unusually rapid deterioration and at 6 months follow-up her cognitive and functional status had worsened considerably (MMSE score of 11). Cranial MRI showed a bilateral atrophy with temporal and parietal predominance and the quantification of AD CSF biomarkers showed the typical AD signature. Family history evidenced an autosomal dominant pattern of inheritance. Mutational screening was performed by direct sequencing of exons 3–12 of PSEN1. The patient presented the 3/3 APOE genotype. Genetic analysis revealed a nucleotide substitution in exon 7 of PSEN1 gene, producing a missense mutation in codon 235 from leucine amino acid to arginine (L235R). This amino acid is conserved between presenilin-1 and presenilin-2 proteins. The L235R mutation had not been previously reported, although other mutations in the same residue have also been associated with familial early-onset AD, providing support for the importance of this residue for the presenilin-1 function.

Blood‐based neurochemical diagnosis of vascular dementia: a pilot study

Blood-based tests for the differential diagnosis of Alzheimer's disease (AD) are under intensive investigation and have shown promising results with regard to Abeta40 and Abeta42 peptide species in incipient AD. Moreover, plasma Abeta40 was suggested as an independent cerebrovascular risk factor candidate. These considerations prompted us to analyse a total of 72 plasma samples in vascular dementias (VAD, n = 15), AD with cerebrovascular disease (AD with CVD, n = 7), AD (n = 15), Parkinson's disease and Parkinson's disease dementia (PD/PDD, n = 20) and 15 patients with depression that served as controls (DC) for distinct plasma amyloid-beta (Abeta) peptide patterns. For the analysis of plasma we used immunoprecipitation followed by the quantitative Abeta-SDS-PAGE/immunoblot. For comparison, CSF tau and Abeta1-42 analyses were performed. The major outcome was an increase in Abeta1-40 in plasma of VAD paralleled by a decrease in the ratio of Abeta1-38/Abeta1-40. The ratio Abeta1-38/Abeta1-40 in plasma enabled contrasts of beyond 85% and 80% for discriminating VAD from DC and all other patients, respectively. In CSF, we confirmed the typical CSF biomarker constellation of increased tau and diminished Abeta1-42 levels for AD. The diagnostic accuracy of plasma Abeta1-38/Abeta1-40 for VAD resembled the accuracy of CSF biomarkers for AD. From the presented results, we consider the ratio of plasma Abeta1-38/Abeta1-40 peptides to be a blood-based biomarker candidate for VAD.