Aβ1-40 Ratio Research Articles

Clinical utility of cerebrospinal fluid biomarkers measured by LUMIPULSE® system.

Cerebrospinal fluid (CSF) biomarkers of Alzheimer's disease (AD) are well-established in research settings, but their use in routine clinical practice remains a largely unexploited potential. Here, we examined the relationship between CSF biomarkers, measured by a fully automated immunoassay platform, and brain β-amyloid (Aβ) deposition status confirmed by amyloid positron emission tomography (PET). One hundred ninety-nine CSF samples from clinically diagnosed AD patients enrolled in a clinical study and who underwent amyloid PET were used for the measurement of CSF biomarkers Aβ 1-40 (Aβ40), Aβ 1-42 (Aβ42), total tau (t-Tau), and phosphorylated tau-181 (p-Tau181) using the LUMIPULSE system. These biomarkers and their combinations were compared to amyloid PET classification (negative or positive) using visual read assessments. Several combinations were also analyzed with a multivariable logistic regression model. Aβ42, t-Tau, and p-Tau181, and the ratios of Aβ42 with other biomarkers had a good diagnostic agreement with amyloid PET imaging. The multivariable logistic regression analysis showed that amyloid PET status was associated with Aβ40 and Aβ42, but other factors, such as MMSE, sex, t-Tau, and p-Tau181, did not significantly add information to the model. CSF biomarkers measured with the LUMIPULSE system showed good agreement with amyloid PET imaging. The ratio of Aβ42 with the other analyzed biomarkers showed a higher correlation with amyloid PET than Aβ42 alone, suggesting that the combinations of biomarkers could be useful in the diagnostic assessment in clinical research and potentially in routine clinical practice.

The Role of Amyloid-β, Tau, and α-Synuclein Proteins as Putative Blood Biomarkers in Patients with Cerebral Amyloid Angiopathy.

Cerebral amyloid angiopathy (CAA) is a cerebrovascular disorder characterized by the deposition of amyloid-β protein (Aβ) within brain blood vessels that develops in elderly people and Alzheimer's disease (AD) patients. Therefore, the investigation of biomarkers able to differentiate CAA patients from AD patients and healthy controls (HC) is of great interest, in particular in peripheral fluids. The current study aimed to detect the neurodegenerative disease (ND)-related protein (i.e., Aβ1-40, Aβ1-42, tau, and α-synuclein) levels in both red blood cells (RBCs) and plasma of CAA patients and HC, evaluating their role as putative peripheral biomarkers for CAA. For this purpose, the proteins' concentration was quantified in RBCs and plasma by homemade immunoenzymatic assays in an exploratory cohort of 20 CAA patients and 20 HC. The results highlighted a significant increase of Aβ1-40 and α-synuclein concentrations in both RBCs and plasma of CAA patients, while higher Aβ1-42 and t-tau levels were detected only in RBCs of CAA individuals compared to HC. Moreover, Aβ1-42/Aβ1-40 ratio increased in RBCs and decreased in plasma of CAA patients. The role of these proteins as candidate peripheral biomarkers easily measurable with a blood sample in CAA needs to be confirmed in larger studies. In conclusion, we provide evidence concerning the possible use of blood biomarkers for contributing to CAA diagnosis and differentiation from other NDs.

Association between ambient air pollution exposure and plasma β-amyloid levels in the French Three-City study : preliminary results

Background: Existing research suggests an association between air pollution exposure and Alzheimer’s Disease (AD). However, underlying biological mechanisms are still unknown. We aimed to evaluate if air pollution exposure was associated with plasma β-amyloid (Aβ) levels. Methods: We selected 287 participants of the Three-City study who were cognitively unimpaired at 12-year follow-up. Aβ levels were measured on plasma samples stored at baseline and at 10 years (INNO-BIA plasma Aβ forms kits (Innogenetics)). Land-use regression models were used to estimate fine particulate matter (PM2.5), nitrogen dioxide (NO2) and black carbon (BC) exposure at participants’ residential address over the 5-year preceding the baseline visit. Linear regression was performed to assess the association of each pollutant with plasma Aβ levels at baseline and with their evolution over time. Results: Participants’ median age at baseline was 68.8 (IQR: 5.1), and 56.1% were women. Median levels (IQR) of plasma Aβ at baseline were 158.8 (37.5) pg/mL for Aβ1-40 and 41.4 (11.9) pg/mL for Aβ1-42. Median Aβ1-42/Aβ1-40 ratio was 0.255 (IQR: 0.065). We found that exposure to the three air pollutants was associated with decreased Aβ1-42/Aβ1-40 ratio at baseline. For instance, an IQR increase in PM2.5 (1.8 µg/m3) was associated with a 0.0119 decrease in the Aβ ratio (95% CI: -0.0209; -0.0029). There were no significant associations between air pollutants and Aβ evolution over time. Conclusion: In our cognitively unimpaired population, exposure to air pollution was associated with decreased plasma Aβ ratio at baseline. These results seem to corroborate previous ones on air pollution detrimental effect on cognition, as a decreased plasma Aβ ratio may predict AD. Further longitudinal studies using cutting edge methods to quantify plasmatic Aβ levels and brain Aβ deposits are still needed to better understand the influence of air pollution on the neuropathological process in AD. Keywords: Air pollution, Alzheimer’s Disease, Biomarkers

A task-specific cognitive domain decline is correlated with plasma and neuroimaging markers in patients with Parkinson's disease.

Cognitive impairment is a disabling non-motor symptom of Parkinson's disease (PD). It remains uncertain whether declines in specific cognitive domains relate to imaging or plasma biomarkers across the disease continuum. We investigated whether neuroimaging and plasma biomarkers correlate with individual task-specific cognitive domain declines evidenced by computerized neuropsychological tests in PD patients. A total of 107 participants, including 87 PD patients (30 with normal cognition [PD-NC], 30 with mild cognitive impairment [PD-MCI], 27 with dementia [PDD]), and 20 healthy controls, were recruited. All received the Cambridge Neuropsychological Test Automatic Battery (CANTAB) test, brain MRI, and assays of plasma biomarkers, including α-synuclein, tau, Aβ42, and Aβ40. PD patients had generally poorer cognitive performance than controls. Patients with PD-MCI and PDD had worse performance in visual, verbal, and working memory and executive function than those with PD-NC. After adjusting for covariates, PDD patients had global cortical thinning, especially in the temporal and parietal lobes, and higher plasma α-synuclein levels and tau:Aβ42 ratios than PD-NC group. Plasma α-synuclein level was associated with frontal lobe-mediated tasks, while the tau:Aβ42 ratio was associated with posterior cortical-mediated tasks. Facial emotion recognition tasks and visual pattern recognition associated with frontotemporal cortical thinning. The accuracy of predicting PDD using age alone (area under the curve [AUC] 0.756) increased by incorporating plasma biomarkers (AUC = 0.851, p = 0.025). Cognitive decline in PD patients has a task-specific correlation with neuroimaging and plasma biomarkers, which may implicate the underlying neuropathological process of PDD.

Astrocyte calcium dysfunction causes early network hyperactivity in Alzheimer's disease.

SummaryDysfunctions of network activity and functional connectivity (FC) represent early events in Alzheimer’s disease (AD), but the underlying mechanisms remain unclear. Astrocytes regulate local neuronal activity in the healthy brain, but their involvement in early network hyperactivity in AD is unknown. We show increased FC in the human cingulate cortex several years before amyloid deposition. We find the same early cingulate FC disruption and neuronal hyperactivity in AppNL-F mice. Crucially, these network disruptions are accompanied by decreased astrocyte calcium signaling. Recovery of astrocytic calcium activity normalizes neuronal hyperactivity and FC, as well as seizure susceptibility and day/night behavioral disruptions. In conclusion, we show that astrocytes mediate initial features of AD and drive clinically relevant phenotypes.

Plasma Aβ42/40 ratio, p-tau181, GFAP, and NfL across the Alzheimer's disease continuum: A cross-sectional and longitudinal study in the AIBL cohort.

Plasma amyloid beta (Aβ)1-42/Aβ1-40 ratio, phosphorylated-tau181 (p-tau181), glial fibrillary acidic protein (GFAP), and neurofilament light (NfL) are putative blood biomarkers for Alzheimer's disease (AD). However, head-to-head cross-sectional and longitudinal comparisons of the aforementioned biomarkers across the AD continuum are lacking. Plasma Aβ1-42, Aβ1-40, p-tau181, GFAP, and NfL were measured utilizing the Single Molecule Array (Simoa) platform and compared cross-sectionally across the AD continuum, wherein Aβ-PET (positron emission tomography)-negative cognitively unimpaired (CU Aβ-, n = 81) and mild cognitive impairment (MCI Aβ-, n = 26) participants were compared with Aβ-PET-positive participants across the AD continuum (CU Aβ+, n = 39; MCI Aβ+, n = 33; AD Aβ+, n = 46) from the Australian Imaging, Biomarker & Lifestyle Flagship Study of Ageing (AIBL) cohort. Longitudinal plasma biomarker changes were also assessed in MCI (n = 27) and AD (n = 29) participants compared with CU (n = 120) participants. In addition, associations between baseline plasma biomarker levels and prospective cognitive decline and Aβ-PET load were assessed over a 7 to 10-year duration. Lower plasma Aβ1-42/Aβ1-40 ratio and elevated p-tau181 and GFAP were observed in CU Aβ+, MCI Aβ+, and AD Aβ+, whereas elevated plasma NfL was observed in MCI Aβ+ and AD Aβ+, compared with CU Aβ- and MCI Aβ-. Among the aforementioned plasma biomarkers, for models with and without AD risk factors (age, sex, and apolipoprotein E (APOE) ε4 carrier status), p-tau181 performed equivalent to or better than other biomarkers in predicting a brain Aβ-/+ status across the AD continuum. However, for models with and without the AD risk factors, a biomarker panel of Aβ1-42/Aβ1-40, p-tau181, and GFAP performed equivalent to or better than any of the biomarkers alone in predicting brain Aβ-/+ status across the AD continuum. Longitudinally, plasma Aβ1-42/Aβ1-40, p-tau181, and GFAP were altered in MCI compared with CU, and plasma GFAP and NfL were altered in AD compared with CU. In addition, lower plasma Aβ1-42/Aβ1-40 and higher p-tau181, GFAP, and NfL were associated with prospective cognitive decline and lower plasma Aβ1-42/Aβ1-40, and higher p-tau181 and GFAP were associated with increased Aβ-PET load prospectively. These findings suggest that plasma biomarkers are altered cross-sectionally and longitudinally, along the AD continuum, and are prospectively associated with cognitive decline and brain Aβ-PET load. In addition, although p-tau181 performed equivalent to or better than other biomarkers in predicting an Aβ-/+ status across the AD continuum, a panel of biomarkers may have superior Aβ-/+ status predictive capability across the AD continuum. Area under the curve (AUC) of p-tau181 ≥ AUC of Aβ42/40, GFAP, NfL in predicting PET Aβ-/+ status (Aβ-/+). AUC of Aβ42/40+p-tau181+GFAP panel ≥ AUC of Aβ42/40/p-tau181/GFAP/NfL for Aβ-/+. Longitudinally, Aβ42/40, p-tau181, and GFAP were altered in MCI versus CU. Longitudinally, GFAP and NfL were altered in AD versus CU. Aβ42/40, p-tau181, GFAP, and NfL are associated with prospective cognitive decline. Aβ42/40, p-tau181, and GFAP are associated with increased PET Aβ load prospectively.

A Profile of Nanoparticle-Based Plasma Neurodegenerative Biomarkers for Cognitive Function Among Patients Undergoing Hemodialysis.

PurposeThis study aimed to compare the plasma levels of nanoparticle-based neurodegenerative biomarkers between hemodialysis (HD) participants with grossly normal cognitive function and healthy controls.Patients and MethodsA cohort of participants undergoing maintenance HD and healthy controls were enrolled for comparison between July and October 2021. The immunomagnetic reduction method was used to measure plasma neurodegenerative biomarkers Aβ1-40, Aβ1-42, tau protein, and neurofilament light chain (NfL). The clinical dementia rating (CDR) was used to evaluate cognitive function. A receiver operating characteristic curve was used to discriminate between HD participants and healthy controls.ResultsThere were 52 and 18 participants in the HD and healthy control groups, respectively. The mean age of the HD participants was 62 years, and that of the healthy controls was 57 years. The mean HD vintage in the HD cohort was 11.8 years. HD participants demonstrated significantly higher plasma levels of Aβ1-42, tau protein, Aβ1-42 × tau, and NfL and Aβ1-42/Aβ1-40 ratio and significantly lower plasma Aβ1-40 levels than healthy controls. The measured plasma biomarkers could not discriminate between CDR0 and CDR0.5 HD participants. The area under the curve of the study biomarkers to discriminate HD participants from healthy controls ranged from 0.987 (Aβ1-42 × tau) to 0.889 (NfL).ConclusionThe plasma levels of nanoparticle-based neurodegenerative biomarkers were higher in HD participants with grossly normal cognitive function than in healthy controls. These findings imply that neurodegenerative changes appear in HD participants. A profile of plasma neurodegenerative biomarkers could be considered a potential surrogate for evaluating long-term cognitive function in HD participants.

Establishing In-House Cutoffs of CSF Alzheimer's Disease Biomarkers for the AT(N) Stratification of the Alzheimer Center Barcelona Cohort.

Background: Clinical diagnosis of Alzheimer’s disease (AD) increasingly incorporates CSF biomarkers. However, due to the intrinsic variability of the immunodetection techniques used to measure these biomarkers, establishing in-house cutoffs defining the positivity/negativity of CSF biomarkers is recommended. However, the cutoffs currently published are usually reported by using cross-sectional datasets, not providing evidence about its intrinsic prognostic value when applied to real-world memory clinic cases. Methods: We quantified CSF Aβ1-42, Aβ1-40, t-Tau, and p181Tau with standard INNOTEST® ELISA and Lumipulse G® chemiluminescence enzyme immunoassay (CLEIA) performed on the automated Lumipulse G600II. Determination of cutoffs included patients clinically diagnosed with probable Alzheimer’s disease (AD, n = 37) and subjective cognitive decline subjects (SCD, n = 45), cognitively stable for 3 years and with no evidence of brain amyloidosis in 18F-Florbetaben-labeled positron emission tomography (FBB-PET). To compare both methods, a subset of samples for Aβ1-42 (n = 519), t-Tau (n = 399), p181Tau (n = 77), and Aβ1-40 (n = 44) was analyzed. Kappa agreement of single biomarkers and Aβ1-42/Aβ1-40 was evaluated in an independent group of mild cognitive impairment (MCI) and dementia patients (n = 68). Next, established cutoffs were applied to a large real-world cohort of MCI subjects with follow-up data available (n = 647). Results: Cutoff values of Aβ1-42 and t-Tau were higher for CLEIA than for ELISA and similar for p181Tau. Spearman coefficients ranged between 0.81 for Aβ1-40 and 0.96 for p181TAU. Passing–Bablok analysis showed a systematic and proportional difference for all biomarkers but only systematic for Aβ1-40. Bland–Altman analysis showed an average difference between methods in favor of CLEIA. Kappa agreement for single biomarkers was good but lower for the Aβ1-42/Aβ1-40 ratio. Using the calculated cutoffs, we were able to stratify MCI subjects into four AT(N) categories. Kaplan–Meier analyses of AT(N) categories demonstrated gradual and differential dementia conversion rates (p = 9.815−27). Multivariate Cox proportional hazard models corroborated these findings, demonstrating that the proposed AT(N) classifier has prognostic value. AT(N) categories are only modestly influenced by other known factors associated with disease progression. Conclusions: We established CLEIA and ELISA internal cutoffs to discriminate AD patients from amyloid-negative SCD individuals. The results obtained by both methods are not interchangeable but show good agreement. CLEIA is a good and faster alternative to manual ELISA for providing AT(N) classification of our patients. AT(N) categories have an impact on disease progression. AT(N) classifiers increase the certainty of the MCI prognosis, which can be instrumental in managing real-world MCI subjects.

Importance of cerebrospinal fluid storage conditions for the Alzheimer's disease diagnostics on an automated platform.

Alzheimer's disease (AD) is considered the most common cause of dementia in older people. Cerebrospinal fluid (CSF) Aβ1-42, Aβ1-40, total Tau (t-Tau), and phospho Tau (p-Tau) are important biomarkers for the diagnosis, however, they are highly dependent on the pre-analytical conditions. Our aim was to investigate the potential influence of different storage conditions on the simultaneous quantification of these biomarkers in a fully-automated platform to accommodate easier pre-analytical conditions for laboratories. CSF samples were obtained from 11 consecutive patients. Aβ1-42, Aβ1-40, p-Tau, and t-Tau were quantified using the LUMIPULSE G600II automated platform. Temperature and storage days significantly influenced Aβ1-42 and Aβ1-40 with concentrations decreasing with days spent at 4°C. The use of the Aβ1-42/Aβ1-40 ratio could partly compensate it. P-Tau and t-Tau were not affected by any of the tested storage conditions. For conditions involving storage at 4°C, a correction factor of 1.081 can be applied. Diagnostic agreement was almost perfect in all conditions. Cutoffs calculated in samples stored at-80°C can be safely used in samples stored at-20°C for 15-16days or up to two days at RT and subsequent freezing at-80°C. For samples stored at 4°C, cutoffs would require applying a correction factor, allowing to work with the certainty of reaching the same clinical diagnosis.

Quantitative analysis of PACAP-38 and amyloid beta composition using a dual reaction in reduced graphene oxide biosensor to verify the neuroprotective role of PACAP-38

Here, we developed a sophisticated reduced graphene oxide (rGO) sensor capable of monitoring the progress of Alzheimer’s disease by quantifying the concentration of amyloid beta (Aβ) and pituitary adenylate cyclase activating polypeptide 38 (PACAP-38). Western blot analysis following induction of apoptosis in mouse hippocampal neurons with TNF-α demonstrated that PACAP-38/Aβ binding inhibited neural cell apoptosis. To verify the direct binding of PACAP-38 to Aβ, a simulated docking model was generated, and binding affinities were quantified using surface plasmon resonance (SPR). After PACAP-38-Aβ binding was confirmed, the properties of each protein were evaluated by the rGO sensor based on differences in their charge to determine the PACAP-38: Aβ ratio. Based on the observed changes in resistance obtained by measuring each protein monomer, expected resistance change values were derived for each binding reaction and subsequent accumulation of PACAP-38 and Aβ. Subsequently, rGO sensor measured changes in resistance following binding and accumulation of each protein. The resistance change values were compared with the expected values to verify the accuracy of the sensor for quantifying accumulated proteins. The accuracy of the sensor was determined based on deviation of the sensor output within its dynamic range. The significance was expressed based on the equation for significance values and was confirmed to be as high as 96% between expected and measured values. Collectively, our results verify the neuroprotective role of PACAP-38 and proposes rGO sensor as a potential tool for early diagnosis of as well as monitoring the progression of Alzheimer’s disease.

Whole-genome sequencing reveals novel ethnicity-specific rare variants associated with Alzheimer’s disease

Alzheimer’s disease (AD) is the most common multifactorial neurodegenerative disease among elderly people. Genome-wide association studies (GWAS) have been highly successful in identifying genetic risk factors. However, GWAS investigate common variants, which tend to have small effect sizes, and rare variants with potentially larger phenotypic effects have not been sufficiently investigated. Whole-genome sequencing (WGS) enables us to detect those rare variants. Here, we performed rare-variant association studies by using WGS data from 140 individuals with probable AD and 798 cognitively normal elder controls (CN), as well as single-nucleotide polymorphism genotyping data from an independent large Japanese AD cohort of 1604 AD and 1235 CN subjects. We identified two rare variants as candidates for AD association: a missense variant in OR51G1 (rs146006146, c.815 G > A, p.R272H) and a stop-gain variant in MLKL (rs763812068, c.142 C > T, p.Q48X). Subsequent in vitro functional analysis revealed that the MLKL stop-gain variant can contribute to increases not only in abnormal cells that should die by programmed cell death but do not, but also in the ratio of Aβ42 to Aβ40. We further detected AD candidate genes through gene-based association tests of rare variants; a network-based meta-analysis using these candidates identified four functionally important hub genes (NCOR2, PLEC, DMD, and NEDD4). Our findings will contribute to the understanding of AD and provide novel insights into its pathogenic mechanisms that can be used in future studies.

Plasma amyloid beta predicts conversion to dementia in subjects with mild cognitive impairment: The BALTAZAR study.

Blood-based biomarkers are the next challenge for Alzheimer's disease (AD) diagnosis and prognosis. Mild cognitive impairment (MCI) participants (N=485) of the BALTAZAR study, a large-scale longitudinal multicenter cohort, were followed-up for 3 years. A total of 165 of them converted to dementia (95% AD). Associations of conversion and plasma amyloid beta (Aβ)1-42 , Aβ1-40 , Aβ1-42 /Aβ1-40 ratio were analyzed with logistic and Cox models. Converters to dementia had lower level of plasma Aβ1-42 (37.1 pg/mL [12.5] vs. 39.2 [11.1] , P value=.03) and lower Aβ1-42 /Aβ1-40 ratio than non-converters (0.148 [0.125] vs. 0.154 [0.076], P value=.02). MCI participants in the highest quartile of Aβ1-42 /Aβ1-40 ratio (>0.169) had a significant lower risk of conversion (hazard ratio adjusted for age, sex, education, apolipoprotein E ε4, hippocampus atrophy=0.52 (95% confidence interval [0.31-0.86], P value=.01). In this large cohort of MCI subjects we identified a threshold for plasma Aβ1-42 /Aβ1-40 ratio that may detect patients with a low risk of conversion to dementia within 3 years.

Cerebrospinal Fluid EV Concentration and Size Are Altered in Alzheimer's Disease and Dementia with Lewy Bodies.

Alzheimer’s disease (AD), dementia with Lewy bodies (DLB) and frontotemporal dementia (FTD) represent the three major neurodegenerative dementias characterized by abnormal brain protein accumulation. In this study, we investigated extracellular vesicles (EVs) and neurotrophic factors in the cerebrospinal fluid (CSF) of 120 subjects: 36 with AD, 30 with DLB, 34 with FTD and 20 controls. Specifically, CSF EVs were analyzed by Nanoparticle Tracking Analysis and neurotrophic factors were measured with ELISA. We found higher EV concentration and lower EV size in AD and DLB groups compared to the controls. Classification tree analysis demonstrated EV size as the best parameter able to discriminate the patients from the controls (96.7% vs. 3.3%, respectively). The diagnostic performance of the EV concentration/size ratio resulted in a fair discrimination level with an area under the curve of 0.74. Moreover, the EV concentration/size ratio was associated with the p-Tau181/Aβ42 ratio in AD patients. In addition, we described altered levels of cystatin C and progranulin in the DLB and AD groups. We did not find any correlation between neurotrophic factors and EV parameters. In conclusion, the results of this study suggest a common involvement of the endosomal pathway in neurodegenerative dementias, giving important insight into the molecular mechanisms underlying these pathologies.

Detection and quantification of Aβ-3-40 (APP669-711) in cerebrospinal fluid.

Neurochemical biomarkers can support the diagnosis of Alzheimer's disease and may facilitate clinical trials. In blood plasma, the ratio of the amyloid-β (Aβ) peptides Aβ-3-40/Aβ1-42 can predict cerebral amyloid-β pathology with high accuracy (Nakamura et al., 2018). Whether or not Aβ-3-40 (aka. amyloid precursor protein (APP) 669-711) is also present in cerebrospinal fluid (CSF) is not clear. Here, we investigated whether Aβ-3-40 can be detected in CSF and to what extent the CSF Aβ-3-40/Aβ42 ratio is able to differentiate between individuals with or without amyloid-β positron emission tomography (PET) evidence of brain amyloid. The occurrence of Aβ-3-40 in human CSF was assessed by immunoprecipitation followed by mass spectrometry. For quantifying the CSF concentrations of Aβ-3-40 in 23 amyloid PET-negative and 17 amyloid PET-positive subjects, we applied a sandwich-type immunoassay. Our findings provide clear evidence of the presence of Aβ-3-40 and Aβ-3-38 in human CSF. While there was no statistically significant difference in the CSF concentration of Aβ-3-40 between the two diagnostic groups, the CSF Aβ-3-40/Aβ42 ratio was increased in the amyloid PET-positive individuals. We conclude that Aβ-3-40 appears to be a regular constituent of CSF and may potentially serve to accentuate the selective decrease in CSF Aβ42 in Alzheimer's disease.

Clinical usefulness of the CSF β-amyloid Aβ1-42/Aβ1-40 ratio for Alzheimer’s disease diagnosis: a retrospective study in a Belgian academic hospital

Clinical usefulness of the CSF β-amyloid Aβ1-42/Aβ1-40 ratio for Alzheimer’s disease diagnosis: a retrospective study in a Belgian academic hospital

Presenilin Is Essential for ApoE Secretion, a Novel Role of Presenilin Involved in Alzheimer's Disease Pathogenesis.

Alzheimer's disease (AD) is a debilitating dementia characterized by progressive memory loss and aggregation of amyloid-β (Aβ) protein into amyloid plaques in patient brains. Mutations in presenilin (PS) lead to abnormal generation of Aβ, which is the major cause of familial AD (FAD), and apolipoprotein E4 (ApoE4) is the major genetic risk factor for sporadic AD (SAD) onset. However, whether dysfunction of PS is involved in the pathogenesis of SAD is largely unknown. We found that ApoE secretion was completely abolished in PS-deficient cells and markedly decreased by inhibition of γ-secretase activity. Blockade of γ-secretase activity by a γ-secretase inhibitor, DAPT, decreased ApoE secretion, suggesting an important role of γ-secretase activity in ApoE secretion. Reduced ApoE secretion is also observed in nicastrin-deficient cells with reduced γ-secretase activity. PS deficiency enhanced nuclear translocation of ApoE and binding of ApoE to importin α4, a nuclear transport receptor. Moreover, the expression of PS mutants in PS-deficient cells suppressed the restoration effects on ApoE secretion compared with the expression of wild-type PS. Plasma ApoE levels were lower in FAD patients carrying PS1 mutations compared with normal control subjects. Our findings suggest a novel role of PS contributing to the pathogenesis of SAD by regulating ApoE secretion.SIGNIFICANCE STATEMENT Familial AD (FAD) typically results from mutations in the genes encoding amyloid precursor protein, presenilin 1 (PS1), or PS2. Many PS mutants have been found to exert impaired γ-secretase activity and increased amyloid-β 42 (Aβ42)/Aβ40 ratio, which induce early amyloid deposition and FAD. On the other hand, apolipoprotein E4 (ApoE4) is the major genetic risk factor for sporadic AD (SAD) and contributes to AD pathogenesis because it has reduced Aβ clearance capability compared with ApoE3 and ApoE2. FAD and SAD have long been considered to be caused by these two independent mechanisms; however, for the first time, we demonstrated that PS is essential for ApoE secretion and PS mutants affected ApoE secretion in vitro and in human samples, suggesting a novel mechanism by which PS is also involved in SAD pathogenesis.

Plasma p-tau181/Aβ1-42 ratio predicts Aβ-PET status and correlates with CSF-p-tau181/Aβ1-42 and future cognitive decline.

In Alzheimer's disease (AD), plasma amyloid beta (Aβ)1-42 and phosphorylated tau (p-tau) predict high amyloid status from Aβ positron emission tomography (PET); however, the extent to which combination of these plasma assays can predict remains unknown. Prototype Simoa assays were used to measure plasma samples from participants who were either cognitively normal (CN) or had mild cognitive impairment (MCI)/AD in the Australian Imaging, Biomarkers and Lifestyle (AIBL) study. The p-tau181/Aβ1-42 ratio showed the best prediction of Aβ-PET across all participants (area under the curve [AUC] = 0.905, 95% confidence interval [CI]: 0.86-0.95) and in CN (AUC = 0.873; 0.80-0.94), and symptomatic (AUC = 0.908; 0.82-1.00) adults. Plasma p-tau181/Aβ1-42 ratio correlated with cerebrospinal fluid (CSF) p-tau181 (Elecsys, Spearman's ρ = 0.74, P < 0.0001) and predicted abnormal CSF Aβ (AUC = 0.816; 0.74-0.89). The p-tau181/Aβ1-42 ratio also predicted future rates of cognitive decline assessed by AIBL Preclinical Alzheimer Cognitive Composite or Clinical Dementia Rating Sum of Boxes (P < 0.0001). Plasma p-tau181/Aβ1-42 ratio predicted both Aβ-PET status and cognitive decline, demonstrating potential as both a diagnostic aid and as a screening and prognostic assay for preclinical AD trials.

Transcriptional profiles in olfactory pathway-associated brain regions of African green monkeys: Associations with age and Alzheimer's disease neuropathology.

IntroductionOlfactory impairment in older individuals is associated with an increased risk of Alzheimer's disease (AD). Characterization of age versus neuropathology‐associated changes in the brain olfactory pathway may elucidate processes underlying early AD pathogenesis. Here, we report age versus AD neuropathology–associated differential transcription in four brain regions in the olfactory pathway of 10 female African green monkeys (vervet, Chlorocebus aethiops sabaeus), a well‐described model of early AD‐like neuropathology.MethodsTranscriptional profiles were determined by microarray in the olfactory bulb (OB), piriform cortex (PC), temporal lobe white matter (WM), and inferior temporal cortex (ITC). Amyloid beta (Aβ) plaque load in parietal and temporal cortex was determined by immunohistochemistry, and concentrations of Aβ42, Aβ40, and norepinephrine in ITC were determined by enzyme‐linked immuosorbent assay (ELISA). Transcriptional profiles were compared between middle‐aged and old animals, and associations with AD‐relevant neuropathological measures were determined.ResultsTranscriptional profiles varied by brain region and age group. Expression levels of TRO and RNU4‐1 were significantly lower in all four regions in the older group. An additional 29 genes were differentially expressed by age in three of four regions. Analyses of a combined expression data set of all four regions identified 77 differentially expressed genes (DEGs) by age group. Among these DEGs, older subjects had elevated levels of CTSB , EBAG9, LAMTOR3, and MRPL17, and lower levels of COMMD10 and TYW1B. A subset of these DEGs was associated with neuropathology biomarkers. Notably, CTSB was positively correlated with Aβ plaque counts, Aβ42:Aβ40 ratios, and norepinephrine levels in all brain regions.DiscussionThese data demonstrate age differences in gene expression in olfaction‐associated brain regions. Biological processes exhibiting age‐related enrichment included the regulation of cell death, vascular function, mitochondrial function, and proteostasis. A subset of DEGs was specifically associated with AD phenotypes. These may represent promising targets for future mechanistic investigations and perhaps therapeutic intervention.

Clinical application of CSF biomarkers for Alzheimer's disease: From rationale to ratios.

Biomarker testing is recommended for the accurate and timely diagnosis of Alzheimer's disease (AD). Using illustrative case narratives we consider how cerebrospinal fluid (CSF) biomarker tests may be used in different presentations of cognitive impairment to facilitate timely and differential diagnosis, improving diagnostic accuracy, providing prognostic information, and guiding personalized management in diverse scenarios. Evidence shows that (1) CSF ratios are superior to amyloid beta (Aβ)1‐42 alone; (2) concordance of CSF ratios to amyloid positron emission tomography (PET) is better than Aβ1‐42 alone; and (3) phosphorylated tau (p‐tau)/Aβ1‐42 ratio is superior to p‐tau alone. CSF biomarkers are recommended for the exclusion of AD as the underlying cause of cognitive impairment, diagnosis of AD at an early stage, differential diagnosis of AD in individuals presenting with other neuropsychiatric symptoms, accurate diagnosis of AD in an atypical presentation, and for clinical trial enrichment.Highlights Cerebrospinal fluid (CSF) Alzheimer's disease (AD) biomarker testing may be underused outside specialist centers.CSF biomarkers improve diagnostic accuracy, guiding personalized management of AD.CSF ratios (amyloid beta [Aβ]1‐42/Aβ1‐40 and phosphorylated tau/Aβ1‐42) perform better than single markers.CSF ratios produce fewer false‐negative and false‐positive results than individual markers.CSF biomarkers should be included in diagnostic work‐up of AD and mild cognitive impairment due to AD.

Limited Longitudinal Change in Self-reported Spatial Navigation Ability in Preclinical Alzheimer Disease.

Subtle changes in objective spatial navigation ability have been observed in the preclinical stage of Alzheimer disease (AD) cross-sectionally and have been found to predict clinical progression. However, longitudinal change in self-reported spatial navigation ability in preclinical AD has yet to be examined. The current study examined whether AD biomarkers suggestive of preclinical AD at baseline spatial navigation assessment and APOE genotype predicted decline in self-reported spatial navigation ability and whether APOE genotype moderated the association of AD biomarkers with change in self-reported spatial navigation. Clinically normal (Clinical Dementia Rating Scale=0) adults aged 56 to 90 completed the Santa Barbara Sense of Direction Scale (SBSOD) annually for an average of 2.73 years. Biomarker data was collected within +/-2 years of baseline (ie, cerebrospinal fluid Aβ42, p-tau181, p-tau181/Aβ42 ratio, positron emission tomography imaging with Florbetapir or Pittsburgh Compound-B, and hippocampal volume). APOE genotyping was obtained for all participants. SBSOD demonstrated a nonsignificant trend toward a decline over time (P=0.082). AD biomarkers did not predict change in self-reported spatial navigation (all Ps>0.163). APOE genotype did not moderate the relationship between AD biomarkers and self-reported spatial navigation in planned analyses (all Ps>0.222). Results suggest that self-reported spatial navigation ability, as estimated with the SBSOD, may be limited as a measure of subtle cognitive change in the preclinical stage of AD.