Cognitive test results are associated with mortality and rehospitalization in heart failure: Swedish prospective cohort study.

AIMS: We aimed to search for associations between cognitive test results with mortality and rehospitalization in a Swedish prospective heart failure (HF) patient cohort. METHODS AND RESULTS: Two hundred and eighty-one patients hospitalized for HF (mean age, 74 years; 32% women) were assessed using cognitive tests: Montreal Cognitive Assessment (MoCA), A Quick Test of Cognitive speed, Trail Making Test A, and Symbol Digit Modalities Test. The mean follow-up time censored at rehospitalization or death was 13 months (interquartile range, 14) and 28 months (interquartile range, 29), respectively. Relations between cognitive test results, mortality, and rehospitalization risk were analysed using multivariable Cox regression model adjusted for age, sex, body mass index, systolic blood pressure, atrial fibrillation, diabetes, smoking, educational level, New York Heart Association class, and prior cardiovascular disease. A total of 80 patients (29%) had signs of cognitive impairment (MoCA score < 23 points). In the fully adjusted Cox regression model using standardized values per 1 SD change of each cognitive test, lower score on MoCA [hazard ratio (HR), 0.75; confidence interval (CI), 0.60-0.95; P = 0.016] and Symbol Digit Modalities Test (HR, 0.66; CI, 0.48-0.90; P = 0.008) yielded significant associations with increased mortality. Rehospitalization risk (n = 173; 62%) was significantly associated with lower MoCA score (HR, 0.84; CI, 0.71-0.99; P = 0.033). CONCLUSIONS: Two included cognitive tests were associated with mortality in hospitalized HF patients, independently of traditional risk factors. In addition, worse cognitive test scores on MoCA heralded increased risk of rehospitalization.

Levels of islet amyloid polypeptide in cerebrospinal fluid and plasma from patients with Alzheimer's disease.

The biologically active pancreatic hormone peptide islet amyloid polypeptide (IAPP) regulates brain functions such as appetite and cognition. It also plays a role in clearance of amyloid beta (Aß), a peptide implicated in the dementia disorder Alzheimer's disease (AD). If IAPP becomes modified, it loses its biological activity and starts to aggregate. Such aggregations have been found in the AD brain and decreased plasma levels of the unmodified IAPP (uIAPP) have been shown in the same patients. In the current study, we analyze levels of uIAPP and total IAPP (unmodified and modified) in cerebrospinal fluid (CSF) to investigate its potential as a biomarker for AD. We found no differences in neither CSF nor plasma levels of uIAPP or total IAPP in AD patients compared to cognitive healthy individuals (NC). The levels of uIAPP in CSF of NC were positively correlated with uIAPP in plasma, Q-albumin and albumin levels in CSF, but negatively correlated with CSF levels of t-tau and p-tau. These findings were not seen in AD patients. Levels of total CSF IAPP correlated positively with total Q-albumin and albumin levels in CSF in both AD and NC. In addition, total plasma IAPP correlated positively with CSF t-tau and p-tau in NC and negatively with CSF Aß42 in AD patients. To conclude, our studies did not find evidence supporting the use of CSF IAPP as an AD biomarker. However, our findings, indicating a compromised translocation of uIAPP in and out of the brain in AD patients as well as the correlations between total plasma IAPP and AD biomarkers, encourage further research on the role for IAPP in AD.

Sex-specific genetic predictors of Alzheimer's disease biomarkers.

Cerebrospinal fluid (CSF) levels of amyloid-ß 42 (Aß42) and tau have been evaluated as endophenotypes in Alzheimer's disease (AD) genetic studies. Although there are sex differences in AD risk, sex differences have not been evaluated in genetic studies of AD endophenotypes. We performed sex-stratified and sex interaction genetic analyses of CSF biomarkers to identify sex-specific associations. Data came from a previous genome-wide association study (GWAS) of CSF Aß42 and tau (1527 males, 1509 females). We evaluated sex interactions at previous loci, performed sex-stratified GWAS to identify sex-specific associations, and evaluated sex interactions at sex-specific GWAS loci. We then evaluated sex-specific associations between prefrontal cortex (PFC) gene expression at relevant loci and autopsy measures of plaques and tangles using data from the Religious Orders Study and Rush Memory and Aging Project. In Aß42, we observed sex interactions at one previous and one novel locus: rs316341 within SERPINB1 (p = 0.04) and rs13115400 near LINC00290 (p = 0.002). These loci showed stronger associations among females (ß = - 0.03, p = 4.25 × 10-8; ß = 0.03, p = 3.97 × 10-8) than males (ß = - 0.02, p = 0.009; ß = 0.01, p = 0.20). Higher levels of expression of SERPINB1, SERPINB6, and SERPINB9 in PFC was associated with higher levels of amyloidosis among females (corrected p values < 0.02) but not males (p > 0.38). In total tau, we observed a sex interaction at a previous locus, rs1393060 proximal to GMNC (p = 0.004), driven by a stronger association among females (ß = 0.05, p = 4.57 × 10-10) compared to males (ß = 0.02, p = 0.03). There was also a sex-specific association between rs1393060 and tangle density at autopsy (pfemale = 0.047; pmale = 0.96), and higher levels of expression of two genes within this locus were associated with lower tangle density among females (OSTN p = 0.006; CLDN16 p = 0.002) but not males (p ≥ 0.32). Results suggest a female-specific role for SERPINB1 in amyloidosis and for OSTN and CLDN16 in tau pathology. Sex-specific genetic analyses may improve understanding of AD's genetic architecture.

Dementia behaviour management programme at home: impact of a palliative care approach on care managers and professional caregivers of home care services.

OBJECTIVES: Care managers and professional caregivers of home care services are sometimes unaware of the psychosocial approaches to the challenging behaviour of dementia. Therefore, we developed a Behaviour Analytics & Support Enhancement (BASE) programme. We investigated the effects of the programme on the attitudes towards dementia care among professionals. METHOD: Forty-six participants in Japan received training in August 2016. The ongoing monitoring and assessment system was introduced to the participants for repeated measures of challenging behaviour. A 1-day follow-up meeting for debriefing was also performed after two months. A baseline and follow-up questionnaire survey was administered to the participating caregivers using a Japanese version of the Approaches to Dementia Questionnaire (ADQ) and the Zarit Burden Interview (ZBI). RESULTS: A significant improvement was observed in the total ADQ score among the participating caregivers from baseline to follow-up assessment. There was no significant difference between the baseline and follow-up assessment in the ZBI scores. In the follow-up meeting, several participants reported challenges and suggested solutions in facilitating a discussion on an action plan among professionals from various organizations. CONCLUSION: The implementation of the programme resulted in enhanced attitudes towards dementia care among the participants without an increased burden of care. Future studies should examine the programme's effectiveness on the challenging behaviour of persons with dementia.

No independent association between pulse wave velocity and dementia: a population-based, prospective study.

OBJECTIVE: Carotid-femoral pulse wave velocity (CFPWV), a marker of aortic stiffness, has been associated with cognitive test results and markers of cerebral small vessel disease, but its association with dementia has not been studied in detail. Our aim was to assess the association of CFPWV with prevalent and incident dementia in a large population-based study. METHODS: In total, CFPWV was measured in 3056 participants of the Malmö Diet and Cancer study 2007-2012 (age range 61-85 years). Individuals scoring below preset cut-offs on cognitive screening tests were thoroughly evaluated for prevalent dementia. Also, dementia diagnoses were retrieved from the Swedish National Patient Register up until 31 December 2014, and then validated through medical records and neuroimaging findings. RESULTS: We identified 159 cases of dementia, of which 57 were classified as prevalent, and 102 as incident during a median follow-up of 4.6 years. In fully adjusted logistic regressions, CFPWV was not associated with prevalent all-cause dementia (odds ratio 0.95 per 1 m/s increase in CFPWV, 95% confidence interval 0.83-1.08), and it did not predict incident all-cause dementia (odds ratio 1.00, 95% confidence interval 0.91-1.09). Neither was CFPWV associated with subtypes of dementia (Alzheimer's disease, vascular dementia, mixed dementia), although the number of cases in subgroups were low. CONCLUSION: No independent association was found between CFPWV and dementia. It remains a matter of debate why CFPWV repeatedly has been associated with cognitive test results and markers of cerebral small vessel disease, but not with dementia.

Genome-wide, high-content siRNA screening identifies the Alzheimer's genetic risk factor FERMT2 as a major modulator of APP metabolism.

Genome-wide association studies (GWASs) have identified 19 susceptibility loci for Alzheimer's disease (AD). However, understanding how these genes are involved in the pathophysiology of AD is one of the main challenges of the "post-GWAS" era. At least 123 genes are located within the 19 susceptibility loci; hence, a conventional approach (studying the genes one by one) would not be time- and cost-effective. We therefore developed a genome-wide, high-content siRNA screening approach and used it to assess the functional impact of gene under-expression on APP metabolism. We found that 832 genes modulated APP metabolism. Eight of these genes were located within AD susceptibility loci. Only FERMT2 (a ß3-integrin co-activator) was also significantly associated with a variation in cerebrospinal fluid Aß peptide levels in 2886 AD cases. Lastly, we showed that the under-expression of FERMT2 increases Aß peptide production by raising levels of mature APP at the cell surface and facilitating its recycling. Taken as a whole, our data suggest that FERMT2 modulates the AD risk by regulating APP metabolism and Aß peptide production.

Increased amyloidogenic APP processing in APOE ɛ4-negative individuals with cerebral ß-amyloidosis.

Increased APP (amyloid precursor protein) processing causes ß-amyloid (Aß) accumulation in autosomal dominant Alzheimer's disease (AD), but it is unclear if it also affects sporadic Aß accumulation. We tested healthy controls and patients with mild cognitive symptoms (N=331) in the BioFINDER study, using cerebrospinal fluid (CSF) Aß40 as a surrogate for amyloidogenic APP processing. We find that levels of brain Aß fibrils (measured by 18F-flutemetamol PET) are independently associated with high CSF Aß40 (P<0.001) and APOE ɛ4 (P<0.001). The association between CSF Aß40 and brain Aß is stronger in APOE ɛ4-negative than in positive people (P=0.0080). The results are similar for CSF Aß38 and for a combination of CSF Aß38 and CSF Aß40. In conclusion, sporadic Aß accumulation may be partly associated with increased amyloidogenic APP production, especially in APOE ɛ4-negative subjects. The risk for sporadic AD may consequently depend on increased Aß production, in addition to decreased Aß clearance.

Cerebrospinal fluid levels of IL-6 are decreased and correlate with cognitive status in DLB patients.

INTRODUCTION: Inflammatory processes have previously been shown to influence cognition and progression of dementia. An involvement of interleukin (IL)-6 has in particular been suggested as altered levels of IL-6 in cerebrospinal fluid (CSF) have been found in patients with Alzheimer's disease (AD). Also, an association between cognitive decline and levels of IL-6 in CSF have been reported. The aim of the present study was to investigate whether patients clinically diagnosed with dementia with Lewy bodies (DLB) display altered CSF IL-6 levels in comparison with patients with AD and control subjects without dementia and whether the IL-6 levels are correlated with cognitive status and biomarkers for AD and synucleinopathy. METHODS: To analyse CSF of patients with AD (n = 45), patients with DLB (n = 29) and control subjects without dementia (n = 36), we used immunoassays to measure levels of IL-6 (multiplex electrochemiluminescence); AD markers phosphorylated tau, total tau and amyloid-ß1-42 (enzyme-linked immunosorbent assay [ELISA]); and α-synuclein (ELISA). Cognitive status was evaluated using the Mini Mental State Examination (MMSE). RESULTS: Our analysis showed significantly lower levels of IL-6 in CSF from patients with DLB than in CSF from patients with AD and control subjects without dementia. The IL-6 levels were also negatively correlated with MMSE and positively correlated with α-synuclein CSF levels. CONCLUSIONS: Our findings support previous studies by demonstrating a link between inflammatory processes and dementia progression and further strengthen the hypothesis that IL-6 is involved in dementia pathology and cognitive decline.

An integrated workflow for multiplex CSF proteomics and peptidomics-identification of candidate cerebrospinal fluid biomarkers of Alzheimer's disease.

Many disease processes in the brain are reflected in the protein composition of the cerebrospinal fluid (CSF). In addition to proteins, CSF also contains a large number of endogenous peptides whose potential as disease biomarkers largely remains to be explored. We have developed a novel workflow in which multiplex isobaric labeling is used for simultaneous quantification of endogenous CSF peptides and proteins by liquid chromatography coupled with mass spectrometry. After the labeling of CSF samples, endogenous peptides are separated from proteins by ultrafiltration. The proteins retained on the filters are trypsinized, and the tryptic peptides are collected separately. We evaluated this technique in a comparative pilot study of CSF peptide and protein profiles in eight patients with Alzheimer's disease (AD) and eight nondemented controls. We identified several differences between the AD and control group among endogenous peptides derived from proteins known to be associated with AD, including neurosecretory protein VGF (ratios AD/controls 0.45-0.81), integral membrane protein 2B (ratios AD/controls 0.72-0.84), and metallothionein-3 (ratios AD/controls 0.51-0.61). Analysis of tryptic peptides identified several proteins that were altered in the AD group, some of which have previously been reported as changed in AD, for example, VGF (ratio AD/controls 0.70).

Solitary living in Alzheimer's disease over 3 years: association between cognitive and functional impairment and community-based services.

INTRODUCTION: Many individuals with Alzheimer's disease (AD) live alone, and this figure is expected to increase. This study aimed to describe the cognitive and functional abilities of solitary-living AD patients, and the potential predictors of their usage of community-based services. METHODS: This 3-year, prospective, multicenter study included 1,021 participants with mild-to-moderate AD (Mini-Mental State Examination score, 10-26) treated with a cholinesterase inhibitor in a routine clinical setting. At baseline and every 6 months, patients were assessed using cognitive, instrumental, and basic activities of daily living (ADL) scales, and service utilization was recorded. Logistic regression models were used to predict the usage of community-based services. RESULTS: At the start of cholinesterase inhibitor therapy (time of AD diagnosis), 355 individuals (35%) were living alone. They were mainly female, older, had more impaired basic ADL capacity, and had a larger number of concomitant medications when compared with those living with family. Regarding the solitary-living patients, lower instrumental ADL (IADL) ability and more medications were independent predictors of usage of home-help services, whereas more impaired IADL at baseline and faster IADL deterioration were predictors of nursing home admission. For those living with family, older age, lower basic ADL, and a greater number of medications predicted home-help services, whereas a larger amount of home help predicted nursing home placement. In addition, female sex was a risk factor for both the utilization of home-help services and nursing home placement. Cognitive ability was not significantly associated with the usage of community-based services. CONCLUSION: A large number of AD patients, predominantly females, live alone with severe cognitive and functional impairment. The amount of home-help services used did not reflect cognitive severity, suggesting that home help did not meet the needs related to cognitive deterioration. Increased knowledge of how community-based services can better accommodate the care needs of solitary-living individuals with AD is essential.

Nonlinear association between pulse wave velocity and cognitive function: a population-based study.

BACKGROUND: Arterial stiffness has been hypothesized to contribute to cognitive decline. However, previous studies have reported inconsistent results. The aim of this cross-sectional study was to investigate the association between carotid-femoral pulse wave velocity (cfPWV), a marker of arterial stiffness, and cognitive function. METHODS: The study population comprised 2637 individuals from the population-based Malmö Diet and Cancer Study (mean age 72.1 years, 60.8% women). During the follow-up examinations between 2007 and 2012, cfPWV and results on the a quick test of cognitive speed (AQT) and Mini Mental State Examination (MMSE) cognitive tests were measured. RESULTS: After adjustments for demographics and traditional cardiovascular risk factors, a linear association was found between cfPWV and AQT (B = 0.37; P = 0.039). On the basis of hypothesis that individuals with high cfPWV values have worse cognitive function than can be inferred from a linear association, cfPWV was dichotomized at the 90th percentile (the binary variable denoted cfPWV >13.8). When cfPWV >13.8 was added to the model, the linear association between continuous cfPWV and AQT disappeared (B = -0.08; P = 0.72), but cfPWV >13.8 was highly significant (B = 4.81; P = 0.004). In the adjusted model with MMSE as outcome variable, cfPWV >13.8 also reached a statistically significant effect. CONCLUSION: Arterial stiffness was inversely associated with cognitive function in a nonlinear fashion, with individuals in the top decentile of cfPWV explaining the association. Results from linear regressions should thus be interpreted with caution because, even when statistical significance is reached, they can be explained by pronounced nonlinearity.

Assessment of peptide chemical modifications on the development of an accurate and precise multiplex selected reaction monitoring assay for apolipoprotein e isoforms.

Apolipoprotein E (ApoE) is a polymorphic protein that plays a major role in lipid metabolism in the central nervous system and periphery. It has three common allelic isoforms, ApoE2, ApoE3, and ApoE4, that differ in only one or two amino acids. ApoE isoforms have been associated with the occurrence and progression of several pathological conditions, such as coronary atherosclerosis and Alzheimer's disease. The aim of this study was to develop a mass spectrometry (MS)-based assay for absolute quantification of ApoE isoforms in cerebrospinal fluid and plasma samples using isotope-labeled peptides. The assay included five tryptic peptides: CLAVYQAGAR (ApoE2), LGADMEDVCGR (ApoE2 and 3), LAVYQAGAR (ApoE3 and 4), LGADMEDVR (ApoE4), and LGPLVEQGR (total ApoE). Both cerebrospinal fluid and plasma samples were assayed to validate the method. The digestion yield and the extension of chemical modifications in selected amino acid residues (methionine oxidation, glutamine deamidation, and cyclization of N-terminus carbamidomethylcysteine) were also studied. The ApoE phenotype was successfully assigned to all samples analyzed in a blinded manner. The method showed good linearity (R(2) > 0.99) and reproducibility (within laboratory imprecision <13%). The comparison of the MS-based assay with an ELISA for total ApoE concentration showed a moderate correlation (R(2) = 0.59). This MS-based assay can serve as an important tool in clinical studies aiming to elucidate the association between ApoE genotype, total ApoE, and ApoE isoform concentrations in various disorders related to ApoE polymorphisms.

Diabetes mellitus and elevated copeptin levels in middle age predict low cognitive speed after long-term follow-up.

BACKGROUND/AIMS: We examined the potential impact of vascular risk factors including copeptin - a robust surrogate marker of arginine vasopressin associated with the metabolic syndrome and diabetes risk - on future cognitive abilities in a population-based cohort. METHODS: Participants (n = 933) were investigated using baseline data, including copeptin levels, and data collected 16 years later using the Mini-Mental State Examination (MMSE) and A Quick Test of Cognitive Speed (AQT). RESULTS: Logistic regression showed that diabetes (OR, 1.86; p < 0.05) and higher copeptin levels (OR, 1.19; p < 0.05) were independently associated with an increased risk of low AQT performance. CONCLUSION: Prevalence of diabetes mellitus and elevated copeptin levels in middle age predict lower cognitive speed after long-term follow-up.

Comparison of brief cognitive tests and CSF biomarkers in predicting Alzheimer's disease in mild cognitive impairment: six-year follow-up study.

INTRODUCTION: Early identification of Alzheimer's disease (AD) is needed both for clinical trials and in clinical practice. In this study, we compared brief cognitive tests and cerebrospinal fluid (CSF) biomarkers in predicting conversion from mild cognitive impairment (MCI) to AD. METHODS: At a memory clinic, 133 patients with MCI were followed until development of dementia or until they had been stable over a mean period of 5.9 years (range 3.2-8.8 years). The Mini-Mental State Examination (MMSE), the clock drawing test, total tau, tau phosphorylated at Thr(181) (P-tau) and amyloid-ß(1-42) (Aß(42)) were assessed at baseline. RESULTS: During clinical follow-up, 47% remained cognitively stable and 53% developed dementia, with an incidence of 13.8%/year. In the group that developed dementia the prevalence of AD was 73.2%, vascular dementia 14.1%, dementia with Lewy bodies (DLB) 5.6%, progressive supranuclear palsy (PSP) 4.2%, semantic dementia 1.4% and dementia due to brain tumour 1.4%. When predicting subsequent development of AD among patients with MCI, the cognitive tests classified 81% of the cases correctly (AUC, 0.85; 95% CI, 0.77-0.90) and CSF biomarkers 83% (AUC, 0.89; 95% CI, 0.82-0.94). The combination of cognitive tests and CSF (AUC, 0.93; 95% CI 0.87 to 0.96) was significantly better than the cognitive tests (p = 0.01) and the CSF biomarkers (p = 0.04) alone when predicting AD. CONCLUSIONS: The MMSE and the clock drawing test were as accurate as CSF biomarkers in predicting future development of AD in patients with MCI. Combining both instruments provided significantly greater accuracy than cognitive tests or CSF biomarkers alone in predicting AD.

Evaluation of a previously suggested plasma biomarker panel to identify Alzheimer's disease.

There is an urgent need for biomarkers in plasma to identify Alzheimer's disease (AD). It has previously been shown that a signature of 18 plasma proteins can identify AD during pre-dementia and dementia stages (Ray et al, Nature Medicine, 2007). We quantified the same 18 proteins in plasma from 174 controls, 142 patients with AD, and 88 patients with other dementias. Only three of these proteins (EGF, PDGF-BB and MIP-1δ) differed significantly in plasma between controls and AD. The 18 proteins could classify patients with AD from controls with low diagnostic precision (area under the ROC curve was 63%). Moreover, they could not distinguish AD from other dementias. In conclusion, independent validation of results is important in explorative biomarker studies.

Ubiquitin carboxyl-terminal esterase L1 (UCHL1) S18Y polymorphism in patients with cataracts.

BACKGROUND: Cataract is characterized by light-scattering protein aggregates. The ubiquitin-proteasome system has been proposed a role in proteolytic removal of these protein aggregates. Ubiquitin carboxyl-terminal esterase L1 (UCHL1) is a de-ubiquitinating enzyme with important functions in recycling of ubiquitin. A protective role of the p.S18Y polymorphism of the UCHL1 gene has been shown in Parkinson`s disease. The current study aimed to examine possible effects on cataract formation. METHODS: Patients with cataract (n = 493) and controls (n = 142) were analyzed for the UCHL1 p.S18Y polymorphism using dynamic allele-specific hybridization. RESULTS: Significant differences were observed in allele and genotype frequencies of the p.S18Y polymorphism between controls and cataract patients, where a positive UCHL1 allele A carrier status was associated with the cataract diagnosis (adjusted OR 1.7 [95% CI = 1.1-2.6] p = 0.02). No significant differences were seen in genotype distribution when stratifying for type of cataract. Nor did the mean age at cataract surgery differ between genotypes. CONCLUSION: The current study does not support a protective role for the UCHL1 S18Y polymorphism in cataract development, but may instead suggest a disease-promoting effect.

Differences in survival between patients with dementia with Lewy bodies and patients with Alzheimer's disease--measured from a fixed cognitive level.

INTRODUCTION: The aim of this study was to compare survival in patients with Alzheimer's disease (AD) and patients with dementia with Lewy bodies (DLB). Since anamnestic and retrospective information about disease duration are unreliable variables, we measured survival from a fixed cognitive level. METHODS: Survival time was measured from the reported disease onset, from the time of diagnosis, from Mini-Mental State Examination (MMSE) 20 ± 1, and from MMSE 17 ± 1. RESULTS: Survival time was significantly shorter in the DLB group compared to the AD group both from the time of diagnosis and from the cognitive levels of 20 and 17 on the MMSE. There was no difference in survival when measured from the reported disease onset. DISCUSSION: Our findings indicate that DLB patients have a more malignant clinical course. Our method of investigating survival in a cognitively homogenous population may gain scientific power. Reliable methods to predict survival and the clinical course are of great value for patients, caregivers, doctors, and society.

Higher cathepsin B levels in plasma in Alzheimer's disease compared to healthy controls.

Cathepsin B is suggested to be involved in amyloid-ß (Aß) processing and Alzheimer's disease (AD). Studies of cathepsin B levels in plasma and cerebrospinal fluid (CSF) have not been previously performed. We examined cathepsin B levels in plasma and CSF samples in persons with AD, mild cognitive impairment (MCI), and healthy controls in order to test the hypothesis that cathepsin B levels can discriminate persons with AD or MCI from healthy controls. Cathepsin B, Cystatin C, Aß1-40 and Aß1-42, total tau, phosphorylated tau, and albumin levels in plasma and CSF were analyzed by ELISA (Cathepsin B) turbidimetry (cystatin C), xMAP Luminex technology (Aß1-40 and Aß1-42 and tau), and Cobas C501 analyzer (albumin) in persons with AD (n=101), MCI (n=84), and healthy control subjects (n=28). Plasma cathepsin B levels were higher in persons with AD compared to healthy controls, both in unadjusted models and in multivariable models adjusting for age, gender, APOE genotype, cystatin C, and albumin levels: Odds ratio (OR) for AD per 1 SD of plasma cathepsin B; 2.04, 95% confidence interval (CI); 1.01-4.14, p= 0.05. There was no difference between diagnostic groups in cathepsin B levels in CSF: OR for AD per 1 SD of CSF cathepsin B; 0.93, 95% CI; 0.37-2.30, p= 0.87. Plasma cathepsin B levels were higher in persons with AD compared to healthy controls whereas there was no difference between diagnostic groups in cathepsin B levels in CSF. Further investigation of cathepsin B as a predictor of AD is warranted.

Cystatin C levels are positively correlated with both Abeta42 and tau levels in cerebrospinal fluid in persons with Alzheimer's disease, mild cognitive impairment, and healthy controls.

Cystatin C is suggested to be involved in neurodegeneration and the development of Alzheimer's disease (AD) by binding to soluble amyloid-beta (Abeta) peptides. Studies of cystatin C levels in cerebrospinal fluid (CSF) in relation to risk of AD are conflicting and relations between cystatin C, Abeta42, and tau levels in CSF in AD, mild cognitive impairment (MCI), and healthy controls are unknown. The objective of this study was to investigate cystatin C, Abeta42, and tau levels in CSF in AD, MCI, and controls. As a secondary aim, the relationships between cystatin C, Abeta42, and tau levels across disease groups were investigated. Cystatin C, Abeta42, total tau, and phosphorylated tau levels in CSF were analyzed by turbidimetry (cystatin C) and xMAP Luminex technology (Abeta and tau) in persons with AD (n=101), MCI (n=84), and healthy control subjects (n=28). Mean cystatin C levels were similar in cases of AD (5.6 micromol/L +/- 1.7), MCI (5.4 micromol/L +/- 1.48), and controls (5.6 micromol/L +/- 1.6). However, CSF cystatin C levels were strongly and positively correlated with total tau and phosphorylated tau levels (r=0.61-0.81, p< 0.0001) and Abeta42 (r=0.35-0.65, p< 0.001) independent of age, gender, and APOE genotype. Mean CSF cystatin C levels did not differ between patients with AD and MCI and healthy controls. Interestingly, cystatin C levels were positively correlated with both tau and Abeta42 levels in CSF independent of age, gender, and APOE genotype.

Nrf2-encoding NFE2L2 haplotypes influence disease progression but not risk in Alzheimer's disease and age-related cataract.

Alzheimer's disease (AD) and age-related cataract, disorders characterized by protein aggregation causing late-onset disease, both involve oxidative stress. We hypothesize that common variants of NFE2L2 and KEAP1, the genes encoding the main regulators of the Nrf2 system, an important defence system against oxidative stress, may influence risk of AD and/or age-related cataract. This case-control study combines an AD material (725 cases and 845 controls), and a cataract material (489 cases and 182 controls). Genetic variation in NFE2L2 and KEAP1 was tagged by eight and three tag single nucleotide polymorphisms (SNPs), respectively. Single SNPs and haplotypes were analyzed for associations with disease risk, age parameters, MMSE and AD cerebrospinal fluid biomarkers. NFE2L2 and KEAP1 were not associated with risk of AD or cataract. However, one haplotype allele of NFE2L2 was associated with 2 years earlier age at AD onset (p(c)=0.013) and 4 years earlier age at surgery for posterior subcapsular cataract (p(c)=0.019). Another haplotype of NFE2L2 was associated with 4 years later age at surgery for cortical cataract (p(c)=0.009). Our findings do not support NFE2L2 or KEAP1 as susceptibility genes for AD or cataract. However, common variants of the NFE2L2 gene may affect disease progression, potentially altering clinically recognized disease onset.