Cerebrospinal fluid biomarkers for Alzheimer’s disease: diagnostic performance in a homogeneous mono-center population

The cerebrospinal fluid (CSF) biomarkers amyloid-β (Aβ)(1-42), T-tau, and P-tau have good diagnostic accuracy for clinically diagnosed Alzheimer’s disease (AD). However, in multi-center studies, the predictive values of the CSF biomarkers have been lower, possibly due to differences in procedures for lumbar puncture and CSF handling and storage, and to differences in patient populations, clinical evaluations, and diagnostic procedures. Here we investigate the diagnostic accuracy of CSF biomarkers in a well defined homogeneous mono-center population. We also evaluate an extended panel of amyloid related biomarkers. Sixty consecutive patients admitted for cognitive impairment to a memory clinic were recruited. The participants included patients with AD or mild cognitive impairment (MCI) diagnosed with AD upon follow-up (n = 32), patients with stable MCI (n = 13), patients with other dementias diagnosed at primary evaluation or upon follow-up (n = 15), and healthy controls(n = 20). CSF was analyzed for Aβ(1-42), T-tau, and P-tau, and PA(X-38), Aβ(X-40), Aβ(X-42), sAβPPα, and sAβPPβ. In multivariate analysis, thecore biomarkers Aβ(1-42), T-tau, and P-tau demonstrated a high ability to diagnose AD versus the combined groups of controls and stable MCI, with an area under the receiver operating characteristic curve (AUROC) of 0.97 (95% CI 0.93–1.00, p < 0.0001). The additional biomarkers only marginally increased AUROC to 0.98 (95% CI 0.95–1.00, p < 0.0001), this increase mainly mediated by Aβ(X-42). In conclusion, CSF biomarkers Aβ(1-42), T-tau, and P-tau have very high diagnostic accuracy in a well defined cohort of untreated patients, demonstrating the excellent potency of CSF biomarkers to identify pathological processes in AD when astringent analytical protocol is used.     

Cerebrospinal fluid soluble amyloid-β protein precursor as a potential novel biomarkers of Alzheimer's disease

In this report, we confirm our previous findings of increased concentrations of soluble amyloid-β protein precursor (sAβPP) in cerebrospinal fluid (CSF) of patients with Alzheimer's disease (AD) and mild cognitive impairment (MCI) in a large cohort of patients (n = 314), not overlapping with those of our previous study, and we extend our observations by including a control group of participants with normal cognition. In addition, we investigate the effects of age, the APOEε4 genotype, and the blood-CSF barrier function on the concentrations of sAβPPα and sAβPPβ. The study participants were categorized according to clinical-neuropsychological criteria, supported by CSF neurochemical dementia diagnostics (NDD) analyses. sAβPPα concentrations in the AD group (132.0 ± 44.8) were significantly higher than in the control group (105.3 ± 37.3, p < 0.0005) but did not differ from the MCI-AD group (138.5 ± 39.5, p = 0.91). The MCI-AD group differed significantly from the MCI-O (97.3 ± 34.3, p < 0.05) group. There was no difference between the control and the MCI-O groups (p = 0.94). Similarly, sAβPPβ concentrations in the AD group (160.2 ± 54.3) were significantly higher than in the control group (129.9 ± 44.6, p < 0.005) but did not differ from the MCI-AD group (184.0 ± 56.4, p = 0.20). The MCI-AD group differed significantly from the MCI-O (127.8 ± 46.2, p < 0.05) group. There was no difference between the control and the MCI-O groups (p > 0.99). We observed highly significant correlation of the two sAβPP forms. Age and the CSF-serum albumin ratio were significant albeit weak predictors of the sAβPPα and sAβPPβ concentrations, while carrying the APOEε4 allele did not influenced the levels of the sAβPP forms. Taken together, the results strongly suggest that CSF sAβPP concentrations may be considered as an extension of already available NDD tools.     

Interrelations between CSF soluble AβPPβ, amyloid-β 1-42, SORL1, and tau levels in Alzheimer's disease

Recently, light has been shed on possible interrelations between the two most important pathological hallmarks of Alzheimer's disease (AD): the amyloid cascade and axonal degeneration. In this study, we investigated associations between sβAPPβ, a product of the cleavage of the amyloid-β protein precursor (AβPP) by β-secretase, amyloid-β 1-42 (Aβ42), soluble SORL1 (also called LR11 or SORLA), a receptor that is involved in AβPP processing, and the marker of axonal degeneration tau in the cerebrospinal fluid (CSF) of 76 patients with mild cognitive impairment (MCI), 61 patients with AD, and 17 patients with frontotemporal dementia, which neuropathologically is not related to the amyloid pathology. In the AD group, significant associations between sAβPPβ, tau (p < 0.001), and soluble SORL1 (p < 0.001) were detected according to linear regression models. In patients with MCI, sAβPPβ correlated significantly with tau (p < 0.001) and soluble SORL1 (p = 0.003). In the FTD group, only SORL1 (p = 0.011) was associated with sAβPPβ and not tau. Aβ42 was found to be significantly related to tau levels in CSF in the MCI group (p < 0.001) and they tended to be associated in the AD group (p = 0.05). Our results provide further evidence for a link between the two facets of AD pathology, which is likely to be mediated by the binding of Aβ oligomers to specifically targeted neurons, resulting in stimulating tau hyperphosphorylation and neurodegeneration.     

Cerebrospinal fluid levels of complement proteins C3, C4 and CR1 in Alzheimer’s disease

Alzheimer's disease (AD) is strongly associated with loss of synapses. The complement system has been shown to be involved in synaptic elimination. Several studies point to an association between AD and the complement system. The purpose of this study was to examine the association of cerebrospinal fluid (CSF) levels of complement components 3 and 4 (C3 and C4, respectively), and complement receptor 1 (CR1) with AD in 43 patients with AD plus dementia, 42 patients with mild cognitive impairment (MCI) who progressed to AD during follow-up (MCI-AD), 42 patients with stable MCI and 44 controls. Complement levels were also applied in a multivariate model to determine if they provided any added value to the core AD biomarkers Aβ42, T-tau and P-tau. We found elevated CSF levels of C3 and C4 in AD compared with MCI without progression to AD, and elevated CSF levels of CR1 in MCI-AD and AD when these groups were merged. These results provide support for aberrant complement regulation as a part in the AD process, but the changes are not diagnostically useful.     

Performance of aβ1-40, aβ1-42, total tau, and phosphorylated tau as predictors of dementia in a cohort of patients with mild cognitive impairment

Mild cognitive impairment (MCI) is a common condition in the elderly which may remain stable along time (MCI-MCI) or evolve into Alzheimer's disease (MCI-AD) or other dementias. Cerebrospinal fluid (CSF) classical biomarkers, i.e., amyloid-β 1-42 (Aβ1-42), total tau (t-tau), and phosphorylated tau (p-tau) reflect the neuropathological changes taking place in AD brains, thus disclosing the disease in its prodromal phase. With the aim to evaluate the power of each biomarker and/or their combination in predicting AD progression, we have measured CSF Aβ1-40, Aβ1-42, t-tau, and p-tau in patients with AD, MCI-MCI, MCI-AD, and other neurological diseases without dementia (OND) followed up for four years. Aβ1-42 levels were significantly lower in AD and MCI-AD than in MCI-MCI. T-tau and p-tau levels were significantly increased in AD and MCI-AD versus OND and MCI-MCI. The Aβ1-42/Aβ1-40 ratio showed a significant decrease in AD and MCI-AD as compared to MCI-MCI. Both Aβ1-42/t-tau and Aβ1-42/p-tau ratios showed significantly decreased values in AD and MCI-AD with respect to OND and MCI-MCI. Aβ1-42/p-tau ratio was the best parameter for discriminating MCI-AD from MCI-MCI (sensitivity 81%, specificity 95%), being also correlated with the annual change rate in the Mini Mental State Examination annual change rate score (MMSE-ACR, rS = -0.71, p < 0.0001). Survival analysis showed that 81% of MCI with a low Aβ1-42/p-tau ratio (<1372) progressed to AD. The best model of logistic regression analysis retained Aβ1-42 and p-tau (sensitivity 75%, 95%CI: 70-80%; specificity 96%, 95%CI: 94-98%). We can conclude that Aβ1-42 and p-tau reliably predict conversion to AD in MCI patients.     

Impaired lipoprotein receptor-mediated peripheral binding of plasma amyloid-β is an early biomarker for mild cognitive impairment preceding Alzheimer's disease

Soluble circulating low density lipoprotein receptor-related protein-1 (sLRP) provides key plasma binding activity for Alzheimer's disease (AD) amyloid-β peptide (Aβ). sLRP normally binds 70-90% of plasma Aβ preventing free Aβ access to the brain. In AD, Aβ binding to sLRP is compromised by increased levels of oxidized sLRP which does not bind Aβ. Here, we determined plasma oxidized sLRP and Aβ40/42 sLRP-bound, other proteins-bound and free plasma fractions, cerebrospinal fluid (CSF) tau/Aβ42 ratios, and mini-mental state examination (MMSE) scores in patients with mild cognitive impairment (MCI) who progressed to AD (MCI-AD, n = 14), AD (n = 14) and neurologically healthy controls (n = 14) recruited from the G?teborg MCI study. In MCI-AD patients prior to conversion to AD and AD patients, the respective increases in oxidized sLRP and free plasma Aβ40 and Aβ42 levels were 4.9 and 3.7-fold, 1.8, and 1.7-fold and 4.3 and 3.3-fold (p < 0.05, ANOVA with Tuckey post-hoc test). In MCI-AD and AD patients increases in oxidized sLRP and free plasma Aβ40 and Aβ42 correlated with increases in CSF tau/Aβ42 ratios and reductions in MMSE scores (p < 0.05, Pearson analysis). A heterogeneous group of 'stable' MCI patients that was followed over 2-4 years (n = 24) had normal CSF tau/Aβ42 ratios but increased oxidized sLRP levels (p < 0.05, Student's t test). Data suggests that a deficient sLRP-Aβ binding might precede and correlate later in disease with an increase in the tau/Aβ42 CSF ratio and global cognitive decline in MCI individuals converting into AD, and therefore is an early biomarker for AD-type dementia.     

Intra-individual stability of CSF biomarkers for Alzheimer's disease over two years

This study examines the intra-individual stability of cerebrospinal fluid (CSF) biomarkers for Alzheimer's disease (AD) over 2 years in 83 patients with mild cognitive impairment (MCI) and 17 cognitively healthy control individuals. All participants underwent clinical and neuropsychological evaluation and lumbar puncture at baseline and after 2 years at a university hospital memory clinic. CSF was analyzed for total tau (T-tau), phospho-tau(181) (P-tau(181)) and amyloid-beta(1-42) (Abeta(1-42)). During the 2-year observational time, 12 MCI patients progressed to AD and 3 progressed to vascular dementia, while 68 remained stable. Baseline T-tau and P-tau(181) levels were elevated in the MCI-AD group as compared to the stable MCI patients and the control group (p<0.01), while baseline Abeta(1-42) levels were lower (p<0.001). Stable MCI patients were biochemically indistinguishable from controls. The biomarker levels at baseline and after 2 years showed Pearson R values between 0.81 and 0.91 (p<0.001) and coefficients of variation of 7.2 to 8.7%. In conclusion, intra-individual biomarker levels are remarkably stable over 2 years. Thus, even minor biochemical changes induced by treatment against AD should be detectable using these biomarkers, which bodes well for their usefulness as surrogate markers for drug efficacy in clinical trials.     

Evaluation of CSF biomarkers as predictors of Alzheimer's disease: a clinical follow-up study of 4.7 years

In this study, we determined the diagnostic accuracy of cerebrospinal fluid (CSF) biomarkers to predict development of Alzheimer's disease (AD) within five years in patients with mild cognitive impairment (MCI). To do so, the levels of tau, phosphorylated tau, Aβ42, Aβ40, Aβ38, sAβPPα, and sAβPPβ were analyzed in 327 CSF samples obtained at baseline from patients with AD (n = 94), MCI (n = 166), depressive disorder (n = 29), and cognitively healthy controls (n = 38). In the cohort with MCI at baseline, 33% subsequently developed AD and 16% developed other types of dementia; however, 51% were still cognitively stable after a followup of 4.7 years (range 3.0-7.2). Optimal cutoffs for each biomarker or combinations of biomarkers were defined in the AD, control, and depressive disorder groups. Several combinations resulted in sensitivity and specificity levels > 85% for differentiation of AD from controls and depressive disorder. Using the previously established cutoffs, a combination of Aβ42 and tau could predict future development of AD in MCI patients with a sensitivity of 88%, specificity 82%, positive predictive value 71%, and negative predictive value 94%. MCI patients with both low Aβ42 and high tau levels had a substantially increased risk of developing AD (OR 20; 95% CI 6-58), even after adjustment for confounding factors. Ultimately, CSF biomarkers can stratify MCI patients into those with very low or high risk for future development of AD. However, the specificities and positive predictive values are still too low to be able to diagnose AD before the patients fulfill the clinical criteria.     

CSF levels of heart fatty acid binding protein are altered during early phases of Alzheimer's disease

Heart fatty acid binding protein (HFABP) has been proposed as a putative marker for dementia disorders. To evaluate the value of this protein as an early marker of Alzheimer's disease (AD), we analyzed HFABP level and the classical biomarkers amyloid-β (Aβ)1-42, total tau (t-tau), and phosphorylated tau (p-tau) in cerebrospinal fluid (CSF) of patients with mild cognitive impairment (MCI) followed up for four years (n=41), AD (n=32), and subjects with other neurological diseases without dementia (OND, n=25). HFABP levels were higher in AD patients and in MCI converting to AD (MCI-AD) with respect to OND and to cognitively stable MCI patients (MCI-MCI). The receiver operator characteristics analysis for HFABP alone showed a sensitivity of 87% and a specificity of 81% for AD versus OND (area under the curve, AUC=0.83); sensitivity and specificity were 46% and 94%, respectively, when comparing MCI-MCI versus MCI-AD. CSF HFABP levels showed a strong positive correlation with both t-tau and p-tau. Interestingly, the ratio between HFABP and Aβ1-42 improved the performance in distinguishing AD from OND (sensitivity: 90%; specificity 82%, AUC=0.89), and gave the best accuracy in discriminating MCI-AD from MCI-MCI (sensitivity: 80%; specificity 100%, AUC=0.90). Survival analysis by means of Kaplan-Meier curve showed a significantly higher proportion of MCI patients converting to AD in the group with higher values of HFABP/Aβ1-42 ratio (cut-off=0.7). A significant correlation between HFABP/Aβ1-42 ratio and MMSE annual decrease rate was also documented (p<0.0001). HFABP /Aβ1-42 ratio might be a useful predictor of conversion in MCI patients.     

Cerebrospinal fluid matrix metalloproteinases and tissue inhibitor of metalloproteinases in combination with subcortical and cortical biomarkers in vascular dementia and Alzheimer's disease

Alzheimer's disease (AD) and vascular dementia (VaD) are intertwined by mixed dementia (MD) harboring varying degrees of AD pathology in combination with cerebrovascular disease. The aim was to assess whether there is a difference in the cerebrospinal fluid (CSF) profile, of selected proteins, between patients with VaD and MD with subcortical vascular disease (SVD), AD, and healthy controls that could contribute in the separation of the groups. The study included 30 controls, 26 SVD patients (9 VaD and 17 MD) and 30 AD patients. The protein panel included total tau (T-tau), hyperphosphorylated tau 181 (P-tau(181)), amyloid β 1-42 (Aβ(1-42)), neurofilament light (NF-L), myelin basic protein (MBP), heart fatty acid binding protein (H-FABP), matrix metalloproteinases (MMP-1, -2, -3, -9, and -10), and tissue inhibitors of metalloproteinases (TIMP-1 and -2). Immunochemical methods were utilized for quantification of the proteins in CSF and data analysis was performed with a multivariate discriminant algorithm. The concentrations of MBP, TIMP-1, P-tau(181), NF-L, T-tau, MMP-9, Aβ(1-42), and MMP-2 contributed the most to the separation between SVD and AD, with a sensitivity of 89% and a specificity of 90% (AUC = 0.92). MBP and NF-L performed the best in discriminating SVD from controls, while T-tau and Aβ(1-42) contributed the most in segregating AD from controls. The CSF biomarkers reflecting AD pathology (T-tau, P-tau(181), and Aβ(1-42)), white matter lesions (NF-L and MBP) and matrix remodeling (MMP-9 and TIMP-1) perform well in differentiating between SVD and AD patients.     

Association between CSF biomarkers and incipient Alzheimer's disease in patients with mild cognitive impairment: a follow-up study

BACKGROUND: Disease-modifying treatment strategies for Alzheimer's disease have led to an urgent need for biomarkers to identify the disease at a very early stage. Here, we assess the association between CSF biomarkers and incipient Alzheimer's in patients with mild cognitive impairment (MCI). METHODS: From a series of 180 consecutive patients with MCI, we assessed 137 who underwent successful lumbar puncture at baseline. Patients at risk of developing dementia were followed clinically for 4-6 years. Additionally, 39 healthy individuals, cognitively stable over 3 years, served as controls. We analysed CSF concentrations of beta amyloid(1-42) (Abeta42), total tau (T-tau), and phosphorylated tau (P-tau181) using Luminex xMAP technology. FINDINGS: During follow-up, 57 (42%) patients with MCI developed Alzheimer's disease, 21 (15%) developed other forms of dementia, and 56 (41%) remained cognitively stable for 5.2 years (range 4.0-6.8). A combination of CSF T-tau and Abeta42 at baseline yielded a sensitivity of 95% and a specificity of 83% for detection of incipient AD in patients with MCI. The relative risk of progression to Alzheimer's disease was substantially increased in patients with MCI who had pathological concentrations of T-tau and Abeta42 at baseline (hazard ratio 17.7, p<0.0001). The association between pathological CSF and progression to Alzheimer's disease was much stronger than, and independent of, established risk factors including age, sex, education, APOE genotype, and plasma homocysteine. The combination of T-tau and Abeta42/P-tau181 ratio yielded closely similar results (sensitivity 95%, specificity 87%, hazard ratio 19.8). INTERPRETATION: Concentrations of T-tau, P-tau181, and Abeta42 in CSF are strongly associated with future development of Alzheimer's disease in patients with MCI.     

Cerebrospinal fluid levels of total-tau, phospho-tau and Aβ42 predicts development of Alzheimer's disease in patients with mild cognitive impairment

Cerebrospinal fluid (CSF) biochemical diagnostic markers may be valuable to help in the diagnosis early in the course of Alzheimer's disease (AD), especially in the phase before clinically overt dementia, i.e. in patients with mild cognitive impairment (MCI). We studied 44 patients with MCI who, at 1-year follow-up investigation, had progressed to AD with dementia, and 32 controls. Three CSF biomarkers related to the central pathogenic processes in AD were analysed, including CSF total-tau (T-tau) (as a marker for neuronal degeneration), CSF phospho-tau (P-tau) (as a marker for hyperphosphorylation of tau and possibly for the formation of neurofibrillary tangles), and CSF Aβ42 (as a marker for Aβ metabolism, and possibly for the formation of senile plaques). At baseline, 35/44 (79.5%) of the MCI patients had high CSF T-tau, 31/44 (70.4%) high CSF P-tau, while 34/44 (77.3%) had low CSF-Aβ42 levels. The positive likelihood ratio was 8.45 for CSF T-tau, 7.49 for CSF P-tau and 8.20 for CSF Aβ42. These findings suggest that these CSF-markers are abnormal before the onset of clinical dementia, and that they may help to identify MCI patients that will progress to AD. CSF diagnostic markers will be especially important when drugs with potential effects on the progression of AD (e.g. γ-secretase inhibitors) will reach the clinical phase.     

Gintonin, a ginseng-derived lysophosphatidic acid receptor ligand, attenuates Alzheimer's disease-related neuropathies: involvement of non-amyloidogenic processing

Ginseng extracts show cognition-enhancing effects in Alzheimer's disease (AD) patients. However, little is known about the active components and molecular mechanisms of how ginseng exerts its effects. Recently, we isolated a novel lysophosphatidic acid (LPA) receptor-activating ligand from ginseng, gintonin. AD is caused by amyloid-β protein (Aβ) accumulation. Aβ is derived from amyloid-β protein precursors (AβPPs) through the amyloidogenic pathway. In contrast, non-amyloidogenic pathways produce beneficial, soluble AβPPα (sAβPPα). Here, we describe our investigations of the effect of gintonin on sAβPPα release, Aβ formation, Swedish-AβPP transfection-mediated neurotoxicity in SH-SY5Y neuroblastoma cells, and Aβ-induced neuropathy in mice. Gintonin promoted sAβPPα release in a concentration- and time-dependent manner. Gintonin action was also blocked by the Ca2+ chelator BAPTA, α-secretase inhibitor TAPI-2, and protein-trafficking inhibitor brefeldin. Gintonin decreased Aβ1-42 release and attenuated Aβ1-40-induced cytotoxicity in SH-SY5Y cells. Gintonin also rescued Aβ1-40-induced cognitive dysfunction in mice. Moreover, in a transgenic mouse AD model, long-term oral administration of gintonin attenuated amyloid plaque deposition as well as short- and long-term memory impairment. In the present study, we demonstrated that gintonin mediated the promotion of non-amyloidogenic processing to stimulate sAβPPα release to restore brain function in mice with AD. Gintonin could be a useful agent for AD prevention or therapy.     

Amyloid-β₄₂ is associated with cognitive impairment in healthy elderly and subjective cognitive impairment

The aim of this study was to predict cognitive performance on the basis of the cerebrospinal fluid (CSF) biomarkers total tau (T-tau) and amyloid-β?? (Aβ??) in controls and patients at various impairment levels. Previous studies have found an association of CSF T-tau levels with cognitive symptoms, but it has been difficult to relate Aβ to cognition, and it has thus been hypothesized that Aβ reaches a plateau level prior to cognitive symptoms. A comprehensive battery of neuropsychological tests was subjected to factor analysis to yield aggregated cognitive domains. Linear regression models were performed for the total sample of the Gothenburg MCI study (n = 435) and for each level of impairment. Aβ?? and T-tau accounted for a significant proportion of performance in all cognitive domains in the total sample. In controls (n = 60) and patients with subjective cognitive impairment (n = 105), Aβ?? predicted a significant proportion of semantic and working memory performance. For patients with mild cognitive impairment (n = 170), T-tau had the most pronounced impact across cognitive domains, and more specifically on episodic memory, visuospatial, and speed/executive performance. For patients with dementia (n = 100), the most pronounced impacts of Aβ?? were found in episodic memory and visuospatial functioning, while T-tau was substantially associated with episodic memory. Our results suggest that cognition is related to CSF biomarkers regardless of impairment level. Aβ?? is associated with cognitive functions from a potentially early to a later disease phase, and T-tau is more indicative of performance in a later disease phase.     

CSF tau and β-amyloid as biomarkers for mild cognitive impairment

Early diagnosis of Alzheimer s disease (AD) is relevant in order to initiate symptomatic treatment with antidementia drugs. This will be of greater significance if the drugs aimed at slowing down the degenerative process (secondary prevention) prove to affect AD pathology and are clinically effective, such as γ-secretase inhibitors. However, there is currently no clinical assessment to differentiate the patients with mild cognitive impairment (MCI) who will progress to AD from those with a benign form of memory impairment that is part of the normal aging process. Thus, there is great clinical need for diagnostic and predictive biomarkers, as well as biomarkers for classification purposes, to identify incipient AD in MCI subjects. The most promising cerebrospinal fluid (CSF) biomarker candidates are total tau protein (T-tau), phosphorylated tau protein (P-tau), and the 42-andno acid form offi-amyloid (Aβ42), which may, if used in the right clinical context, prove to have sufficient diagnostic accuracy and predictive power to resolve this diagnostic challenge.     

Amyloid-β(1-15/16) as a marker for γ-secretase inhibition in Alzheimer's disease

Amyloid-β (Aβ) producing enzymes are key targets for disease-modifying Alzheimer's disease (AD) therapies since Aβ trafficking is at the core of AD pathogenesis. Development of such drugs might benefit from the identification of markers indicating in vivo drug effects in the central nervous system. We have previously shown that Aβ(1-15) is produced by concerted β-and α-secretase cleavage of amyloid-β protein precursor (AβPP). Here, we test the hypothesis that this pathway is more engaged upon γ-secretase inhibition in humans, and cerebrospinal fluid (CSF) levels of Aβ(1-15/16) represent a biomarker for this effect. Twenty healthy men were treated with placebo (n = 5) or the γ-secretase inhibitor semagacestat (100 mg [n = 5], 140 mg [n = 5], or 280 mg [n = 5]). CSF samples were collected hourly over 36 hours and 10 time points were analyzed by immunoassay for Aβ(1-15/16), Aβ(x-38), Aβ(x-40), Aβ(x-42), sAβPPα, and sAβPPβ. The CSF concentration of Aβ(1-15/16) showed a dose-dependent response over 36 hours. In the 280 mg treatment group, a transient increase was seen with a maximum of 180% relative to baseline at 9 hours post administration of semagacestat. The concentrations of Aβ(x-38), Aβ(x-40), and Aβ(x-42) decreased the first 9 hours followed by increased concentrations after 36 hours relative to baseline. No significant changes were detected for CSF sAβPPα and sAβPPβ. Our data shows that CSF levels of Aβ(1-15/16) increase during treatment with semagacestat supporting its feasibility as a pharmacodynamic biomarker for drug candidates aimed at inhibiting γ-secretase-mediated AβPP-processing.     

Clioquinol reduces zinc accumulation in neuritic plaques and inhibits the amyloidogenic pathway in AβPP/PS1 transgenic mouse brain

Metal dyshomeostasis in the brain helps promote amyloid-β (Aβ) deposition in Alzheimer's disease (AD). Therefore, targeting the interactions between metal and Aβ is a potential therapeutic approach for AD. The metal chelator, clioquinol (CQ), is thought to reduce Aβ deposits in the AD transgenic mouse brain, and attenuate the clinical symptoms of AD patients. However, whether oral administration of CQ reduces zinc accumulation in Aβ plaques and inhibits the amyloidogenic pathway have not been properly established in AD transgenic mice. By means of autometallographic analysis, we show for the first time that both the number and size of the zinc-containing plaques were significantly reduced in the brain of amyloid-β protein precursor (AβPP)/presenilin 1 (PS1) double transgenic mice treated with CQ (30 mg/kg/day) orally for 2 months. This was accompanied by a reduction in Aβ burden in the CQ-treated mouse brain. Furthermore, CQ treatment markedly reduced the expression levels of AβPP protein, the β-site of AβPP cleaving enzyme 1 (BACE1), PS1, and the secreted β-secretase-derived fragments of AβPP (sAβPPβ). The present data indicate that CQ is able to reduce zinc accumulation in the neuritic plaques and inhibit amyloidogenic AβPP processing in the AβPP/PS1 mouse brain.     

Increasing the predictive accuracy of amyloid-β blood-borne biomarkers in Alzheimer's disease

Diagnostic measures for Alzheimer's disease (AD) commonly rely on evaluating the levels of amyloid-β (Aβ) peptides within the cerebrospinal fluid (CSF) of affected individuals. These levels are often combined with levels of an additional non-Aβ marker to increase predictive accuracy. Recent efforts to overcome the invasive nature of CSF collection led to the observation of Aβ species within the blood cellular fraction, however, little is known of what additional biomarkers may be found in this membranous fraction. The current study aimed to undertake a discovery-based proteomic investigation of the blood cellular fraction from AD patients (n = 18) and healthy controls (HC; n = 15) using copper immobilized metal affinity capture and Surface Enhanced Laser Desorption/Ionisation Time-Of-Flight Mass Spectrometry. Three candidate biomarkers were observed which could differentiate AD patients from HC (ROC AUC > 0.8). Bivariate pairwise comparisons revealed significant correlations between these markers and measures of AD severity including; MMSE, composite memory, brain amyloid burden, and hippocampal volume. A partial least squares regression model was generated using the three candidate markers along with blood levels of Aβ. This model was able to distinguish AD from HC with high specificity (90%) and sensitivity (77%) and was able to separate individuals with mild cognitive impairment (MCI) who converted to AD from MCI non-converters. While requiring further characterization, these candidate biomarkers reaffirm the potential efficacy of blood-based investigations into neurodegenerative conditions. Furthermore, the findings indicate that the incorporation of non-amyloid markers into predictive models, function to increase the accuracy of the diagnostic potential of Aβ.     

Injury markers but not amyloid markers are associated with rapid progression from mild cognitive impairment to dementia in Alzheimer's disease

Alzheimer's disease (AD) is a common cause of mild cognitive impairment (MCI). However, the time between the diagnosis of MCI and the diagnosis of dementia is highly variable. In this study we investigated which known risk factors and biomarkers of AD pathology were associated with rapid progression from MCI to dementia. Of the 203 subjects with MCI, 91 progressed to AD-type dementia and were considered to have MCI-AD at baseline. Subjects with MCI-AD were older, more frequently female and carrier of the APOE-ε4 allele, had lower scores on the Mini-Mental State Examination (MMSE), more medial temporal lobe atrophy (MTA) and lower levels of Aβ1-42 and increased levels of t-tau and p-tau in the cerebrospinal fluid (CSF) compared to subjects without AD-type dementia at follow up. Of the 91 subjects with MCI-AD, we had data available of CSF (n = 56), MTA (n = 76), and APOE-genotype (n = 63). Among the subjects with MCI-AD, MTA (hazard ratio (HR) 2.2, p = 0.004) and low MMSE score (HR 2.0 p = 0.007) were associated with rapid progression to dementia. High CSF t-tau (HR 1.7, p = 0.07) and p-tau (1.7, p = 0.08) tended to be associated with rapid progression to dementia. CSF Aβ1-42, APOE status, age, gender, and educational level were not associated with time to dementia. Our findings implicate a different role for biomarkers in diagnosis and prognosis of MCI-AD. While amyloid markers can be used to identify MCI-AD, injury markers may predict rapid progression to dementia.     

Update on the biomarker core of the Alzheimer's Disease Neuroimaging Initiative subjects

Here, we review progress by the Penn Biomarker Core in the Alzheimer's Disease Neuroimaging Initiative (ADNI) toward developing a pathological cerebrospinal fluid (CSF) and plasma biomarker signature for mild Alzheimer's disease (AD) as well as a biomarker profile that predicts conversion of mild cognitive impairment (MCI) and/or normal control subjects to AD. The Penn Biomarker Core also collaborated with other ADNI Cores to integrate data across ADNI to temporally order changes in clinical measures, imaging data, and chemical biomarkers that serve as mileposts and predictors of the conversion of normal control to MCI as well as MCI to AD, and the progression of AD. Initial CSF studies by the ADNI Biomarker Core revealed a pathological CSF biomarker signature of AD defined by the combination of Aβ1-42 and total tau (T-tau) that effectively delineates mild AD in the large multisite prospective clinical investigation conducted in ADNI. This signature appears to predict conversion from MCI to AD. Data fusion efforts across ADNI Cores generated a model for the temporal ordering of AD biomarkers which suggests that Aβ amyloid biomarkers become abnormal first, followed by changes in neurodegenerative biomarkers (CSF tau, F-18 fluorodeoxyglucose-positron emission tomography, magnetic resonance imaging) with the onset of clinical symptoms. The timing of these changes varies in individual patients due to genetic and environmental factors that increase or decrease an individual's resilience in response to progressive accumulations of AD pathologies. Further studies in ADNI will refine this model and render the biomarkers studied in ADNI more applicable to routine diagnosis and to clinical trials of disease modifying therapies.