Cerebrospinal fluid phospho-tau,total tau and beta-amyloid(1-42) in the differentiation between Alzheimer's disease and vascular dementia

The two most frequently examined biomarkers in the diagnosis of dementia are cerebrospinal fluid (CSF) tau and beta-amyloid(1-42) (Abeta(1-42)). An assay for tau phosphorylated at threonine 181 (phospho-tau) has recently been developed. We studied these three markers in patients with possible Alzheimer's disease (AD; n = 23), probable AD (n = 50), AD with relevant cerebrovascular disease (AD with CVD; n = 14), possible vascular dementia (VaD; n = 39), probable VaD (n = 36), cognitively impaired (n = 13) and 27 neurologically healthy controls. Compared with the controls, tau levels were significantly increased in possible AD, probable AD, AD with CVD and probable VaD. Abeta(1-42) was decreased in all dementia groups compared with the controls. In contrast, phospho-tau levels were increased only in probable AD compared with the controls. From the results of the present study, it is concluded that neither measurement of phospho-tau, tau nor Abeta(1-42) in CSF can discriminate entirely between dementia and cognitively non-disturbed controls or between dementia of different aetiologies in the clinical diagnostic procedure.     

The cerebrospinal fluid levels of tau, growth-associated protein-43 and soluble amyloid precursor protein correlate in Alzheimer's disease, reflecting a common pathophysiological process

Cerebrospinal fluid (CSF) levels of tau (total tau), growth-associated protein-43 (GAP-43), soluble amyloid precursor protein (sAPP; i.e. total sAPP), and beta-amyloid(42) (Abeta(42)) were studied in patients with frontotemporal dementia (FTD; n = 14), Alzheimer's disease (AD; n = 47) and vascular dementia (VAD; n = 16), and in age-matched controls (n = 12). CSF-tau was increased in AD compared to controls and FTD (p < 0.001 for both). CSF-GAP-43 was increased in AD compared to controls (p < 0.05), and both CSF-GAP-43 and CSF-sAPP were increased in AD compared to FTD (p < 0.01). Positive and highly significant correlations were found between CSF-tau and CSF-GAP-43 in all groups and between CSF-tau, CSF-GAP-43 and CSF-sAPP in AD. The correlations found may reflect a common pathophysiologic process such as axonal degeneration.     

CSF tau protein and β-amyloid (1–42) in Alzheimer''s disease diagnosis: discrimination from normal ageing and other dementias in the Greek population

Cerebrospinal fluid (CSF) levels of tau protein and amyloid beta(1-42) peptide (Abeta42) have been suggested as possible diagnostic markers of Alzheimer's disease (AD). In order to evaluate their diagnostic potential in clinical practice, we measured tau and Abeta42 levels in the CSF of 49 AD patients, 15 patients with non-AD neurodegenerative dementias (NAND), six patients with vascular dementia (VD) and 49 elderly controls. All the subjects were of Greek origin. A marked increase in tau, a decrease in Abeta42 and a marked increase in the tau/Abeta42 ratio was noted in AD. Abeta42 alone had a specificity of 80% and a sensitivity of 82% in differentiating AD from normal ageing, whilst the corresponding values for differentiating AD from NAND or VD were 80 and 71, or 67 and 82%, respectively. Tau was better in differentiating AD, from normal ageing (specificity 96%, sensitivity 88%), NAND (specificity 93%, sensitivity 71%) and VD (specificity 83%, sensitivity 94%). The tau/Abeta42 ratio achieved values comparable or even better than tau for differentiating AD from normal ageing (specificity 86%, sensitivity 96%) and VD (specificity 83%, sensitivity 90%) and definitely better than any of the candidate markers alone, for differentiating AD from NAND (specificity 100%, sensitivity 71%). Thus, the combined use of CSF tau and Abeta42 in the form of the tau/Abeta42 ratio is a simple, safe and useful adjuvant to clinical criteria for dementia diagnosis.     

Glycosylation of acetylcholinesterase and butyrylcholinesterase changes as a function of the duration of Alzheimer's disease

The identification of biochemical markers of Alzheimer's disease (AD) may help in the diagnosis of the disease. Previous studies have shown that Abeta(1-42) is decreased, and tau and phospho-tau are increased in AD cerebrospinal fluid (CSF). Our own studies have identified glycosylated isoforms of acetylcholinesterase (Glyc-AChE) and butyrylcholinesterase (Glyc-BuChE) that are increased in AD CSF. Glyc-AChE is increased in APP (SW) Tg2576 transgenic mice prior to amyloid plaque deposition, which suggests that Glyc-AChE may be an early marker of AD. The aim of this study was to determine whether Glyc-AChE or Glyc-BuChE is increased in CSF at early stages of AD and to compare the levels of these markers with those of Abeta(1-42), tau and phospho-tau. Lumbar CSF was obtained ante mortem from 106 non-AD patients, including 15 patients with mild cognitive impairment (MCI), and 102 patients with probable AD. Glyc-AChE, tau and phospho-tau were significantly increased in the CSF of AD patients compared to non-neurological disease (NND) controls. Abeta(1-42) was lower in the AD patients than in NND controls. A positive correlation was found between the levels of Glyc-AChE or Glyc-BuChE and disease duration. However, there was no clear correlation between the levels of tau, phospho-tau or Abeta(1-42) and disease duration. The results suggest that Glyc-AChE and Glyc-BuChE are unlikely to be early markers of AD, although they may have value as markers of disease progression.     

AD with subcortical white matter lesions and vascular dementia: CSF markers for differential diagnosis

We investigated whether the cerebrospinal fluid (CSF) biomarkers beta-amyloid 1-42 (Abeta1-42), total tau (t-tau) protein and tau protein phosphorylated at threonine 181 (p-tau181) could discriminate Alzheimer's disease (AD) from vascular dementia (VD) patients. CSF samples of Abeta1-42, t-tau, and p-tau181 were collected from probable AD (n=35), probable AD with white matter changes (WMC) indicative of concomitant cerebrovascular disorder (CVD, n=31), VD (n=20), and an age-matched subgroup of patients with other neurological disorders (OND) without cognitive impairment (n=24). AD patients showed very low Abeta1-42 levels (median=393 pg/ml). Abeta1-42, but not t-tau, differentiated AD from VD patients. However, the markers did not discriminate AD vs. AD plus WMC. In particular, both subgroups showed similar CSF biomarkers but they were significantly different from VD. ROC analysis showed that Abeta1-42 could discriminate AD from VD (AUC=0.85). The cutoff of 493 pg/ml gave sensitivity and specificity values of 77% and 80%, respectively. Similar results were obtained when Abeta1-42 was employed to discriminate AD with WMC from VD (95% specificity and 60% sensitivity, but with cutoff of 750 pg/ml). T-tau increased aspecifically in all cognitively impaired patients. P-tau181 performed better than t-tau in discriminating AD (with or without WMC) vs. VD. In conclusion, Abeta1-42 proved to be a valuable tool to discriminate AD vs. VD patients and possibly to improve diagnostic accuracy in clinical forms, improperly classified as "mixed dementia" based on radiological vascular lesions.     

Prediction of Alzheimer's disease using the CSF Abeta42/Abeta40 ratio in patients with mild cognitive impairment

Evidence supports an important role for beta-amyloid (Abeta) in the pathogenesis of Alzheimer's disease (AD). Here, we investigate baseline levels of the 40- and 42-amino-acid-long Abeta peptides (Abeta40 and Abeta42) in cerebrospinal fluid (CSF) from a cohort of patients with mild cognitive impairment (MCI, n = 137) in relation to the final diagnosis after 4-6 years of follow-up time. CSF Abeta42 concentration at baseline and the Abeta42/Abeta40 ratio were significantly decreased in the MCI patients who developed AD as compared to cognitively stable MCI patients and MCI patients who developed other forms of dementia (p < 0.001). The baseline levels of Abeta40 were similar in all MCI groups but correlated with change in Mini Mental State Examination scores in converters to AD. The Abeta42/Abeta40 ratio was superior to Abeta42 concentration with regard to identifying incipient AD in MCI (p < 0.05). In conclusion, the data provide further support for the view that amyloid precursor protein metabolism is disturbed in early sporadic AD and points to the usefulness of the Abeta42/Abeta40 ratio as a predictive biomarker for AD.     

Cerebrospinal fluid neuron-specific enolase: a further marker of Alzheimer's disease?

To investigate whether neuron-specific enolase (NSE) plays a role in dementia, we measured cerebrospinal fluid (CSF) concentrations of NSE, Abeta42 and total protein tau (h-tau) in different dementia patients. We studied 159 patients: 76 with Alzheimer's disease (AD), 35 with mild cognitive impairment (MCI), 28 with frontotemporal dementia (FTD), and 20 with Lewy body disease (LBD). Thirty healthy age-matched subjects were studied as controls. NSE was measured by immunoradiometric assay, Abeta42 and h-tau were dosed by ELISA assay. Mean CSF NSE was significantly higher in AD (15.1+/-9.9 ng/ml) than in controls (8.3+/-3.5 ng/ml, p<0.01), FTD (9.1+/-6.1 ng/ml, p<0.05) and MCI (9.7+/-7.8 ng/ml, p<0.05). Ab42 was significantly lower in AD (413.8+/-163.7 pg/ml) than in MCI (708.4+/-422.1 pg/ml, p<0.001) and controls (914.4+/-277.1 pg/ml, p<0.05); it was also significantly reduced in FTD (497.1+/-221.9 pg/ml) versus MCI (p<0.05) and controls (p<0.001); and in LBD patients (477.1+/-225.7 pg/ml) compared with MCI (p<0.05) and controls (p<0.001). H-tau concentration was significantly higher in AD (607.9+/-372.3 pg/ml, p<0.001) than in MCI (383.8+/-277.9 pg/ml, p<0.05), controls (176.6+/-43.9 pg/ml, p<0.001) and LBD (472.3+/-357.7 pg/ml, p<0.05); it was also increased in FTD (541.76+/-362.8 pg/ml) versus contro s (176.6+/-43.9 pg/ml, p<0.001). Furthermore, NSE was inversely correlated with Ab42 (r=-0.333, p=0<0001) and directly correlated with h-tau (r=0.370, p=0<0001). In conclusion, CSF NSE emerged as a specific indicator of AD and showed the same behaviour as the other accepted markers of AD, being correlated with both biomarkers.     

Cerebrospinal fluid tau/beta-amyloid(42) ratio as a prediction of cognitive decline in nondemented older adults

OBJECTIVES: To investigate the ability of cerebrospinal fluid (CSF) and plasma measures to discriminate early-stage Alzheimer disease (AD) (defined by clinical criteria and presence/absence of brain amyloid) from nondemented aging and to assess whether these biomarkers can predict future dementia in cognitively normal individuals. DESIGN: Evaluation of CSF beta-amyloid(40) (Abeta(40)), Abeta(42), tau, phosphorylated tau(181), and plasma Abeta(40) and Abeta(42) and longitudinal clinical follow-up (from 1 to 8 years). SETTING: Longitudinal studies of healthy aging and dementia through an AD research center. PARTICIPANTS: Community-dwelling volunteers (n = 139) aged 60 to 91 years and clinically judged as cognitively normal (Clinical Dementia Rating [CDR], 0) or having very mild (CDR, 0.5) or mild (CDR, 1) AD dementia. RESULTS: Individuals with very mild or mild AD have reduced mean levels of CSF Abeta(42) and increased levels of CSF tau and phosphorylated tau(181). Cerebrospinal fluid Abeta(42) level completely corresponds with the presence or absence of brain amyloid (imaged with Pittsburgh Compound B) in demented and nondemented individuals. The CSF tau/Abeta(42) ratio (adjusted hazard ratio, 5.21; 95% confidence interval, 1.58-17.22) and phosphorylated tau(181)/Abeta(42) ratio (adjusted hazard ratio, 4.39; 95% confidence interval, 1.62-11.86) predict conversion from a CDR of 0 to a CDR greater than 0. CONCLUSIONS: The very mildest symptomatic stage of AD exhibits the same CSF biomarker phenotype as more advanced AD. In addition, levels of CSF Abeta(42), when combined with amyloid imaging, augment clinical methods for identifying in individuals with brain amyloid deposits whether dementia is present or not. Importantly, CSF tau/Abeta(42) ratios show strong promise as antecedent (preclinical) biomarkers that predict future dementia in cognitively normal older adults.     

Neurofilament heavy-chain NfH(SMI35) in cerebrospinal fluid supports the differential diagnosis of Parkinsonian syndromes.

We aimed to evaluate the potential of the cerebrospinal fluid (CSF) axonal damage biomarker NfH(SMI35) in the laboratory-supported differential diagnosis of parkinsonian syndromes. Patients with idiopathic Parkinson's disease (PD; n = 22), multiple-system atrophy (MSA; n = 21), progressive supranuclear palsy (PSP; n = 21), corticobasal degeneration (CBD; n = 6), and age-matched controls (n = 45) were included. CSF levels of NfH(SMI35) were measured using ELISA. Levels of CSF NfH(SMI35) were elevated in PSP compared to PD and controls (P < 0.05 each). They were also significantly higher in MSA than in PD and controls (P < 0.05 each). NfH(SMI35) differentiated PD from PSP with a sensitivity of 76.5% and a specificity of 94.4%. Axonal damage as measured by CSF NfH(SMI35) is most prominent in the more rapidly progressive syndromes PSP and MSA as compared to PD or CBD. CSF NfH(SMI35) may therefore be of some value for the laboratory-supported differential diagnosis of atypical parkinsonian syndromes.     

Decreased CSF-beta-amyloid 42 in Alzheimer's disease and amyotrophic lateral sclerosis may reflect mismetabolism of beta-amyloid induced by disparate mechanisms

Both tau and beta-amyloid 42 (Abeta42) have been implicated in Alzheimer's disease (AD) and tau alone in frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). These proteins can be measured in the cerebrospinal fluid (CSF); differences from normal CSF levels may reflect pathophysiological mechanisms. Using ELISAs, we investigated the levels of total CSF-tau (here referred to as tau), phosphorylated CSF-tau (phosphotau), and Abeta42 in patients with AD (n = 19), FTD (n = 14), ALS (n = 11) and Parkinson's disease (PD; n = 15) and in age-matched controls (n = 17). Both CSF-tau and CSF-phosphotau were increased in AD compared with FTD (p < 0.001), ALS (p < 0.001), PD (p < 0.001) and controls (p < 0.001). CSF-Abeta42 was markedly decreased in AD and ALS (both p < 0.001) and slightly decreased in FTD (p < 0.01) and PD (p < 0.05) compared with controls. Using CSF-phosphotau may improve the differentiation of AD from FTD and ALS in clinical praxis. Furthermore, decreased CSF-Abeta42 levels may be common in neurodegenerative disorders possibly reflecting changes in the metabolism of beta-amyloid or axonal degeneration.     

Inverse relation between in vivo amyloid imaging load and cerebrospinal fluid Abeta42 in humans

OBJECTIVES: Amyloid-beta(42) (Abeta(42)) appears central to Alzheimer's disease (AD) pathogenesis and is a major component of amyloid plaques. Mean cerebrospinal fluid (CSF) Abeta(42) is decreased in dementia of the Alzheimer's type. This decrease may reflect plaques acting as an Abeta(42) "sink," hindering transport of soluble Abeta(42) between brain and CSF. We investigated this hypothesis. METHODS: We compared the in vivo brain amyloid load (via positron emission tomography imaging of the amyloid-binding agent, Pittsburgh Compound-B [PIB]) with CSF Abeta(42) and other measures (via enzyme-linked immunosorbent assay) in clinically characterized research subjects. RESULTS: Subjects fell into two nonoverlapping groups: those with positive PIB binding had the lowest CSF Abeta(42) level, and those with negative PIB binding had the highest CSF Abeta(42) level. No relation was observed between PIB binding and CSF Abeta(40), tau, phospho-tau(181), plasma Abeta(40), or plasma Abeta(42). Importantly, PIB binding and CSF Abeta(42) did not consistently correspond with clinical diagnosis; three cognitively normal subjects were PIB-positive with low CSF Abeta(42), suggesting the presence of amyloid in the absence of cognitive impairment (ie, preclinical AD). INTERPRETATION: These observations suggest that brain amyloid deposition results in low CSF Abeta(42), and that amyloid imaging and CSF Abeta(42) may potentially serve as antecedent biomarkers of (preclinical) AD.     

Intrathecal inflammation precedes development of Alzheimer's disease

OBJECTIVES: To analyse the cerebrospinal fluid (CSF) values of the proinflammatory cytokines, interleukin 1beta (IL1beta), tumour necrosis factor alpha (TNFalpha), GM-CSF, of the anti-inflammatory cytokine TGFbeta, of tau protein, a marker for neurodegeneration, and of beta amyloid (Abeta), a protein involved in the formation of senile plaques, in prospectively followed up patients with mild cognitive impairment (MCI). METHODS: Analyses of CSF levels of TNFalpha, IL1beta, GM-CSF, TGFbeta, betaa, and tau protein were performed using ELISA in 56 patients with MCI who were followed up prospectively and in 25 age matched, healthy controls. RESULTS: Patients with MCI displayed significantly higher levels of TNFalpha and tau protein and significantly lower levels of TGFbeta and Abeta compared with the healthy controls. After nine months of follow up, 25 patients still displayed MCI while the remaining 31 patients had progressed to Alzheimer's disease (AD). Only MCI patients who progressed to AD at follow up, showed significantly higher CSF levels of TNFalpha than controls. In addition, reduced CSF-Abeta42 levels were only found in MCI patients that progressed to AD, further supporting the notion that disturbed metabolism of Abeta is an early finding in AD. CONCLUSIONS: These results demonstrate increased production of the proinflammatory cytokine, TNFalpha and decreased production of the anti-inflammatory cytokine TGFbeta in patients with MCI at risk to develop AD, suggesting a propensity towards inflammation in this patient group and indicating that CNS inflammation is a early hallmark in the pathogenesis of AD.     

Evaluation of CSF-Chlamydia pneumoniae,CSF-tau,and CSF-Abeta42 in Alzheimer’s disease and vascular dementia

The potential role of microbiological factors such as Chlamydia pneumoniae (ChP) in the pathogenesis of neurodegenerative disorders, including Alzheimer's disease (AD) and vascular dementia (VD), has been suggested, but the correctness of this hypothesis still needs to be tested. In this study the appearance of ChP in the cerebrospinal fluid (CSF) of 57 AD and 21 VD patients and in 47 controls (CG) as well as the influence of ChP on the levels of tau protein and Abeta42 were investigated. The frequency of ChP occurrence in the AD patient group (43.9%) was significantly higher (p < 0.001) than in the control group (10.6%). In the case of VD patients, 9.5% of this group was positive for ChP. The presence of ChP DNA in the CSF of patients with AD significantly increases the occurrence of this disease (odds ratio = 7.21). Cerebrospinal fluid Abeta42 levels were significantly lower in patients with AD than in the CG (p < 0.001). Cerebrospinal tau protein was significantly higher in AD vs. CG (p = 0.007). However, no relationships between the presence of the bacterium in CSF and the level of either tau or Abeta42 protein were observed. In conclusion, we may suspect that testing for the presence of ChP in CSF, along with the tau and Abeta42 markers, may be used in the clinic diagnosis of AD.     

CSF Abeta42 and tau or phosphorylated tau and prediction of progressive mild cognitive impairment

Baseline CSF amyloid beta-peptide-42 (Abeta42), tau, and phosphorylated tau (P-tau) levels from 46 control subjects and 78 patients with mild cognitive impairment (MCI) were measured. Twenty-three patients with MCI developed dementia during the study. Abnormal biomarkers were found early in the course of Alzheimer disease (AD). The most predictive assay for AD among the patients with MCI was the combination of Abeta42 and P-tau.     

Biochemical diagnosis of Alzheimer disease by measuring the cerebrospinal fluid ratio of phosphorylated tau protein to beta-amyloid peptide42

BACKGROUND: The antemortem diagnosis of Alzheimer disease (AD) requires time-consuming and costly procedures. Therefore, biochemical tests that can direct the physician rapidly to the correct diagnosis are highly desirable. Measurement of single biochemical markers in cerebrospinal fluid (CSF), such as total tau protein and beta-amyloid peptide42 (Abeta42), shows robust alterations that highly correlate with the clinical diagnosis of AD but generally lack sufficient diagnostic accuracy. OBJECTIVE: To study the combination of CSF phosphorylated tau protein (phospho-tau) and Abeta42 as biochemical markers for AD. METHODS: We combined CSF measurements of phospho-tau and Abeta42 in 100 consecutive patients who under-went diagnostic workup for dementia and in 31 healthy control subjects. RESULTS: We found that the calculated ratio of phospho-tau to Abeta42 was significantly increased in patients with AD and provided high diagnostic accuracy in distinguishing patients with AD from healthy control subjects (sensitivity, 86%; specificity, 97%), subjects with non-AD dementias (sensitivity, 80%; specificity, 73%), and subjects with other neurological disorders (sensitivity, 80%; specificity, 89%). CONCLUSION: The diagnostic usefulness of the CSF ratio of phospho-tau to Abeta42 is superior to either measure alone and can be recommended as an aid to evaluating individuals suspected of having dementia.     

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.     

Decreased cerebrospinal fluid amyloid beta (1-40) levels in frontotemporal lobar degeneration

The role of amyloid metabolism in the pathophysiology of frontotemporal lobar degeneration (FTLD) has yet to be elucidated. We compared CSF levels of amyloid beta 1-40 (Abeta40) and amyloid beta 1-42 (Abeta42) in patients with FTLD (n = 21) versus patients with Alzheimer's disease (AD, n = 39) and in control subjects (n = 30). While in AD cases Abeta42 levels were lower and CSF Abeta40 levels equal to those in controls, a significant decrease in Abeta40 and increase in the CSF Abeta42/Abeta40 ratio was observed in FTLD compared with AD and control subjects. These findings favour a differential involvement of amyloid beta peptides in FTLD compared with AD.     

Value of CSF beta-amyloid1-42 and tau as predictors of Alzheimer's disease in patients with mild cognitive impairment

Subjects with mild cognitive impairment (MCI) are at a high risk of developing clinical Alzheimer's disease (AD). We asked to what extent the core biomarker candidates cerebro-spinal fluid (CSF) beta-amyloid(1-42) (Abeta(1-42)) and CSF tau protein concentrations predict conversion from MCI to AD. We studied 52 patients with MCI, 93 AD patients, and 10 healthy controls (HC). The MCI group was composed of 29 patients who had converted to AD during follow-up, and of 23 patients who showed no cognitive decline. CSF Abeta(1-42) and tau protein levels were assessed at baseline in all subjects, using enzyme-linked immunosorbent assays. For assessment of sensitivity and specificity, we used independently established reference values for CSF Abeta(1-42) and CSF tau. The levels of CSF tau were increased, whereas levels of Abeta(1-42) were decreased in MCI subjects. Abeta(1-42) predicted AD in converted MCI with a sensitivity of 59% and a specificity of 100% compared to HC. Tau yielded a greater sensitivity of 83% and a specificity of 90%. In a multiple Cox regression analysis within the MCI group, low baseline levels of Abeta(1-42), but not other predictor variables (tau protein, gender, age, apolipoprotein E epsilon4 carrier status, Mini Mental Status Examination score, observation time, antidementia therapy), correlated with conversion status (P<0.05). Our findings support the notion that CSF tau and Abeta(1-42) may be useful biomarkers in the early identification of AD in MCI subjects.     

Relationships among cerebrospinal fluid biomarkers in dementia of the Alzheimer type

Cerebrospinal fluid (CSF) contains proteins known to be involved in the pathogenesis of Alzheimer disease (AD), including amyloid-related proteins, tau protein and apolipoprotein E. While the CSF concentrations of these proteins have been compared in subjects with and without dementia of the Alzheimer type (DAT), they have not been simultaneously assessed in carefully staged DAT subjects and control subjects to examine correlations among them. In this study, CSF concentrations of soluble amyloid precursor protein (sAPP), two forms of beta-amyloid protein (Abeta and Abeta ), tau, and apolipoprotein E were assessed in subjects with (n = 33) and without (n = 11) DAT. Direct correlations were found between CSF concentrations of sAPP and tau and Abeta, and between apolipoprotein E and Abeta within the DAT subjects and within the combined group of DAT and control subjects. A weak inverse correlation was also found between CSF concentrations of tau and Abeta within the combined group of DAT and control subjects. Moreover, increased severity of dementia was correlated with increased CSF tau concentrations and decreased sAPP and Abeta concentrations. Increased CSF concentrations of tau significantly discriminated DAT and control subjects, as did the ratios of tau to Abeta and tau to Abeta(1-42).     

Treatment with simvastatin in patients with Alzheimer's disease lowers both alpha- and beta-cleaved amyloid precursor protein

We investigated the clinical and biological effects of cholesterol-lowering treatment with a statin in 19 patients with Alzheimer's disease. They received simvastatin 20 mg/day for 12 weeks in an open trial. Primary efficacy parameters were the changes after 12 weeks in the cerebrospinal fluid (CSF) levels of beta-amyloid(42) (Abeta(42)), alpha-secretase-cleaved amyloid precursor protein (alpha-sAPP), beta-secretase-cleaved APP (beta-sAPP), tau, phospho-tau and the plasma levels of Abeta(42). A secondary efficacy parameter was the change in the Alzheimer's Disease Assessment Scale-Cognition (ADAS-cog) score. After 12 weeks, CSF alpha-sAPP and CSF beta-sAPP were significantly reduced (p < 0.001), but the CSF levels of tau, phospho-tau, Abeta(42) and the plasma levels of Abeta(42) were unchanged. The ADAS-cog score was slightly increased (p < 0.05). The results suggest that simvastatin acts directly on the processing of APP by inhibiting both the alpha- and the beta-secretase pathways.