Fluid biomarker agreement and interrelation in dementia due to Alzheimer's disease.

The cerebrospinal fluid (CSF) levels of ß-amyloid 42, total tau, and phosphorylated tau 181 are supposed to be all continuously abnormal in dementia due to Alzheimer's disease (AD), being the most advanced disease stage. The aim of the present study, which included a monocentric and a multicentric sample (N = 119 and 178, respectively), was to investigate the degree of CSF biomarker agreement and interrelation in AD dementia. Based on previously published cut-off values, biomarker values were categorized as positive or negative for AD (dichotomization strategy) and as either positive, negative, or borderline (trichotomization strategy). The statistical analyses relied on distance correlation analysis and kappa (k) statistics. Poor agreement (k < 0.4) and low interrelations between the studied biomarkers were detected in all cases with the exception of the interrelation between the markers total tau and phosphorylated tau 181, especially in the monocentric sample. Interestingly, lower interrelation and agreement degrees were observed in carriers of the Apolipoprotein E ε4 allele compared to non-carriers. The clinical phenotype currently referred to as "AD dementia" is characterized by an inhomogeneous CSF biomarker profile, possibly mirroring the complex genesis of AD-typical dementia symptoms and pointing to the necessity of shedding more light on the hypothesis of biomarker stability over time in symptomatic AD.

Cerebrospinal Fluid BACE1 Activity and sAßPPß as Biomarker Candidates of Alzheimer's Disease.

BACKGROUND/AIMS: The utility of ß-site amyloid-ß precursor protein (AßPP) cleaving enzyme 1 (BACE1) activity and soluble AßPP ß (sAßPPß) levels in cerebrospinal fluid (CSF) in detecting Alzheimer's disease (AD) is still elusive. METHODS: BACE1 activity and sAßPPß concentration were measured in patients with AD dementia (n = 56) and mild cognitive impairment (MCI) due to AD (n = 76) with abnormal routine AD CSF markers, in patients with MCI with normal CSF markers (n = 39), and in controls without preclinical AD (n = 48). In a subsample with available 18F-fluorodeoxyglucose positron emission tomography (FDG PET) data, ordinal regression models were employed to compare the contribution of BACE1 and sAßPPß to correct diagnostic classification to that of FDG PET. RESULTS: BACE1 activity was significantly higher in patients with MCI due to AD compared to both controls and patients with MCI with normal CSF markers. sAßPPß did not differ between any of the studied groups. Interestingly, BACE1 activity was not found to be inferior to FDG PET as predictive covariate in differentiating between the diagnostic groups. CONCLUSIONS: Further studies using biomarker-underpinned diagnoses are warranted to shed more light on the potential diagnostic utility of BACE1 activity as AD biomarker candidate in MCI.

Plasma levels of soluble amyloid precursor protein ß in symptomatic Alzheimer's disease.

The established biomarkers of Alzheimer's disease (AD) require invasive endeavours or presuppose sophisticated technical equipment. Consequently, new biomarkers are needed. Here, we report that plasma levels of soluble amyloid precursor protein ß (sAPPß), a protein of the initial phase of the amyloid cascade, were significantly lower in patients with symptomatic AD (21 with mild cognitive impairment due to AD and 44 with AD dementia) with AD-typical cerebral hypometabolic pattern compared with 27 cognitively healthy elderly individuals without preclinical AD. These findings yield further evidence for the potential of sAPPß in plasma as an AD biomarker candidate.

Mapping CSF biomarker profiles onto NIA-AA guidelines for Alzheimer's disease.

The National Institute on Aging-Alzheimer's Association (NIA-AA) guidelines for Alzheimer's disease (AD) propose the categorization of individuals according to their biomarker constellation. Though the NIA-AA criteria for preclinical AD and AD dementia have already been applied in conjunction with imaging AD biomarkers, the application of the criteria using comprehensive cerebrospinal fluid (CSF) biomarker information has not been thoroughly studied yet. The study included a monocentric cohort with healthy (N = 41) and disease (N = 22) controls and patients with AD dementia (N = 119), and a multicentric sample with healthy controls (N = 116) and patients with AD dementia (N = 102). The CSF biomarkers ß-amyloid 1-42, total tau, and phosphorylated tau at threonine 181 were measured with commercially available assays. Biomarker values were trichotomized into positive for AD, negative, or borderline. In controls the presence of normal CSF profiles varied between 13.6 and 25.4 % across the studied groups, while up to 8.6 % of them had abnormal CSF biomarkers. In 40.3-52.9 % of patients with AD dementia, a typical CSF profile for AD was detected. Approximately 40 % of the potential biomarker constellations are not considered in the NIA-AA guidelines, and more than 40 % of participants could not be classified into the NIA-AA categories with distinct biomarker constellations. Here, a refined scheme covering all potential biomarker constellations is proposed. These results enrich the discussion on the NIA-AA guidelines and point to a discordance between clinical symptomatology and CSF biomarkers even in patients with full-blown AD dementia, who are supposed to have a clearly positive for AD neurochemical profile.

Plasma Levels of Soluble AßPPß as a Biomarker for Alzheimer's Disease with Dementia.

Cost- and time-effective markers of Alzheimer's disease (AD), reliable and feasible at the population level are urgently needed. Soluble amyloid-ß protein precursor ß (sAßPPß) in plasma has attracted scientific attention as a potential AD biomarker candidate. Here we report that plasma sAßPPß levels in patients with AD dementia and typical for AD cerebrospinal fluid (CSF) biomarker profiles (N = 33) are significantly lower (p < 0.01) than those of cognitively healthy elderly individuals without AD (N = 39), while CSF sAßPPß levels did not differ between the studied groups. This provides further evidence for the potential of sAßPPß in plasma as an AD biomarker candidate.

Conflicting cerebrospinal fluid biomarkers and progression to dementia due to Alzheimer's disease.

BACKGROUND: According to new diagnostic guidelines for Alzheimer's disease (AD), biomarkers enable estimation of the individual likelihood of underlying AD pathophysiology and the associated risk of progression to AD dementia for patients with mild cognitive impairment (MCI). Nonetheless, how conflicting biomarker constellations affect the progression risk is still elusive. The present study explored the impact of different cerebrospinal fluid (CSF) biomarker constellations on the progression risk of MCI patients. METHODS: A multicentre cohort of 469 patients with MCI and available CSF biomarker results and clinical follow-up data was considered. Biomarker values were categorized as positive for AD, negative or borderline. Progression risk differences between patients with different constellations of total Tau (t-Tau), phosphorylated Tau at threonine 181 (p-Tau) and amyloid-beta 1-42 (Aß42) were studied. Group comparison analyses and Cox regression models were employed. RESULTS: Patients with all biomarkers positive for AD (N = 145) had the highest hazard for progression to dementia due to AD, whilst patients with no positive biomarkers (N = 111) had the lowest. The risk of patients with only abnormal p-Tau and/or t-Tau (N = 49) or with positive Aß42 in combination with positive t-Tau or p-Tau (N = 119) is significantly lower than that of patients with all biomarkers positive. CONCLUSIONS: The risk of progression to dementia due to AD differs between patients with different CSF biomarker constellations.