Search

Background and Objectives: CSF biomarkers have immense diagnostic and prognostic potential for Alzheimer disease (AD). However, AD is still diagnosed relatively late in the disease process, sometimes even years after the initial manifestation of cognitive symptoms. Thus, further identification of biomarkers is required to detect related pathology in the preclinical stage and predict cognitive decline. Our study aimed to assess the association of neurogranin and β-site amyloid precursor protein-cleaving enzyme 1 (BACE1) with cognitive decline in individuals with subjective cognitive decline (SCD)., Methods: We enrolled participants with available neurogranin and BACE1 measurements in CSF from the DELCODE (DZNE-Longitudinal Cognitive Impairment and Dementia, Germany) cohort. The longitudinal change of Preclinical Alzheimer's Cognitive Composite score was assessed as the primary outcome in participants with SCD and controls. The secondary outcome was defined as conversion of SCD to mild cognitive impairment (MCI) during follow-up. Levels of neurogranin, BACE1, and neurogranin/BACE1 ratio across groups were compared by analysis of covariance after adjustment for demographics. The linear mixed-effects model and Cox regression analysis were applied to evaluate their association with cognitive decline and progression of SCD to MCI, respectively., Results: A total of 530 participants (mean age: 70.76 ± 6.01 years, 48.7% female) were analyzed in the study. The rate of cognitive decline was faster in individuals with SCD with higher neurogranin and neurogranin/BACE1 ratio (β = -0.138, SE = 0.065, p = 0.037, and β = -0.293, SE = 0.115, p = 0.013). Higher baseline neurogranin and neurogranin/BACE1 ratio were associated with an increased rate of conversion from SCD to MCI (hazard ratio [HR] 1.35 per SD, 95% CI 1.03-1.77, p = 0.028, and HR 1.53 per SD, 95% CI 1.13-2.07, p = 0.007). In addition, the impact of higher neurogranin levels on accelerating the rate of cognitive decline was more pronounced in the SCD group than in cognitively unimpaired controls (β = -0.077, SE = 0.033, p = 0.020)., Discussion: Our findings suggest that CSF neurogranin and BACE1 begin to change in the preclinical stage of AD and they are associated with clinical progression in individuals with SCD.

Introduction: Recent advances in biomarker research have improved the diagnosis and monitoring of Alzheimer's disease (AD), but in vivo biomarker-based workflows to assess 4R-tauopathy (4RT) patients are currently missing. We suggest a novel biomarker-based algorithm to characterize AD and 4RTs., Methods: We cross-sectionally assessed combinations of cerebrospinal fluid measures (CSF p-tau 181 and t-tau) and 18 F-PI-2620 tau-positron emission tomography (PET) in patients with AD (n = 64), clinically suspected 4RTs (progressive supranuclear palsy or corticobasal syndrome, n = 82) and healthy controls (n = 19)., Results: Elevated CSF p-tau 181 and cortical 18 F-PI-2620 binding was characteristic for AD while normal CSF p-tau 181 with elevated subcortical 18 F-PI-2620 binding was characteristic for 4RTs. 18 F-PI-2620-assessed posterior cortical hypoperfusion could be used as an additional neuronal injury biomarker in AD., Discussion: The specific combination of CSF markers and 18 F-PI-2620 tau-PET in disease-specific regions facilitates the biomarker-guided stratification of AD and 4RTs. This has implications for biomarker-aided diagnostic workflows and the advancement in clinical trials., Highlights: Novel biomarker-based algorithm for differentiating AD and 4R-tauopathies. A combination of CSF p-tau 181 and 18 F-PI-2620 discriminates AD versus 4R tauopathies. Hypoperfusion serves as an additional neuronal injury biomarker in AD., (© 2024 The Author(s). Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Introduction: Subjective cognitive decline (SCD) in amyloid-positive (Aβ+) individuals was proposed as a clinical indicator of Stage 2 in the Alzheimer's disease (AD) continuum, but this requires further validation across cultures, measures, and recruitment strategies., Methods: Eight hundred twenty-one participants from SILCODE and DELCODE cohorts, including normal controls (NC) and individuals with SCD recruited from the community or from memory clinics, underwent neuropsychological assessments over up to 6 years. Amyloid positivity was derived from positron emission tomography or plasma biomarkers. Global cognitive change was analyzed using linear mixed-effects models., Results: In the combined and stratified cohorts, Aβ+ participants with SCD showed steeper cognitive decline or diminished practice effects compared with NC or Aβ- participants with SCD. These findings were confirmed using different operationalizations of SCD and amyloid positivity, and across different SCD recruitment settings., Discussion: Aβ+ individuals with SCD in German and Chinese populations showed greater global cognitive decline and could be targeted for interventional trials., Highlights: SCD in amyloid-positive (Aβ+) participants predicts a steeper cognitive decline. This finding does not rely on specific SCD or amyloid operationalization. This finding is not specific to SCD patients recruited from memory clinics. This finding is valid in both German and Chinese populations. Aβ+ older adults with SCD could be a target population for interventional trials., (© 2024 The Author(s). Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Introduction: Blood-based biomarkers are a cost-effective and minimally invasive method for diagnosing the early and preclinical stages of amyloid positivity (AP). Our study aims to investigate our novel immunoprecipitation-immunoassay (IP-IA) as a test for predicting cognitive decline., Methods: We measured levels of amyloid beta (Aβ)X-40 and AβX-42 in immunoprecipitated eluates from the DELCODE cohort. Receiver-operating characteristic (ROC) curves, regression analyses, and Cox proportional hazard regression models were constructed to predict AP by Aβ42/40 classification in cerebrospinal fluid (CSF) and conversion to mild cognitive impairment (MCI) or dementia., Results: We detected a significant correlation between AßX-42/X-40 in plasma and CSF (r = 0.473). Mixed-modeling analysis revealed a substantial prediction of AßX-42/X-40 with an area under the curve (AUC) of 0.81 for AP (sensitivity: 0.79, specificity: 0.74, positive predictive value [PPV]: 0.71, negative predictive value [NPV]: 0.81). In addition, lower AβX-42/X-40 ratios were associated with negative PACC5 slopes, suggesting cognitive decline., Discussion: Our results suggest that assessing the plasma AβX-42/X-40 ratio via our semiautomated IP-IA is a promising biomarker when examining patients with early or preclinical AD., Highlights: New plasma Aβ42/Aβ40 measurement using immunoprecipitation-immunoassay Plasma Aβ42/Aβ40 associated with longitudinal cognitive decline Promising biomarker to detect subjective cognitive decline at-risk for brain amyloid positivity., (© 2024 The Author(s). Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Minimally invasive biomarkers are urgently needed to detect molecular pathology in frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). Here, we show that plasma extracellular vesicles (EVs) contain quantifiable amounts of TDP-43 and full-length tau, which allow the quantification of 3-repeat (3R) and 4-repeat (4R) tau isoforms. Plasma EV TDP-43 levels and EV 3R/4R tau ratios were determined in a cohort of 704 patients, including 37 genetically and 31 neuropathologically proven cases. Diagnostic groups comprised patients with TDP-43 proteinopathy ALS, 4R tauopathy progressive supranuclear palsy, behavior variant FTD (bvFTD) as a group with either tau or TDP-43 pathology, and healthy controls. EV tau ratios were low in progressive supranuclear palsy and high in bvFTD with tau pathology. EV TDP-43 levels were high in ALS and in bvFTD with TDP-43 pathology. Both markers discriminated between the diagnostic groups with area under the curve values >0.9, and between TDP-43 and tau pathology in bvFTD. Both markers strongly correlated with neurodegeneration, and clinical and neuropsychological markers of disease severity. Findings were replicated in an independent validation cohort of 292 patients including 34 genetically confirmed cases. Taken together, the combination of EV TDP-43 levels and EV 3R/4R tau ratios may aid the molecular diagnosis of FTD, FTD spectrum disorders and ALS, providing a potential biomarker to monitor disease progression and target engagement in clinical trials., (© 2024. The Author(s).)

Neuroinflammation is a hallmark of Alzheimer's disease (AD) and both positive and negative associations of individual inflammation-related markers with brain structure and cognitive function have been described. We aimed to identify inflammatory signatures of CSF immune-related markers that relate to changes of brain structure and cognition across the clinical spectrum ranging from normal aging to AD. A panel of 16 inflammatory markers, Aβ42/40 and p-tau181 were measured in CSF at baseline in the DZNE DELCODE cohort (n = 295); a longitudinal observational study focusing on at-risk stages of AD. Volumetric maps of gray and white matter (GM/WM; n = 261) and white matter hyperintensities (WMHs, n = 249) were derived from baseline MRIs. Cognitive decline (n = 204) and the rate of change in GM volume was measured in subjects with at least 3 visits (n = 175). A principal component analysis on the CSF markers revealed four inflammatory components (PCs). Of these, the first component PC1 (highly loading on sTyro3, sAXL, sTREM2, YKL-40, and C1q) was associated with older age and higher p-tau levels, but with less pathological Aβ when controlling for p-tau. PC2 (highly loading on CRP, IL-18, complement factor F/H and C4) was related to male gender, higher body mass index and greater vascular risk. PC1 levels, adjusted for AD markers, were related to higher GM and WM volumes, less WMHs, better baseline memory, and to slower atrophy rates in AD-related areas and less cognitive decline. In contrast, PC2 related to less GM and WM volumes and worse memory at baseline. Similar inflammatory signatures and associations were identified in the independent F.ACE cohort. Our data suggest that there are beneficial and detrimental signatures of inflammatory CSF biomarkers. While higher levels of TAM receptors (sTyro/sAXL) or sTREM2 might reflect a protective glia response to degeneration related to phagocytic clearance, other markers might rather reflect proinflammatory states that have detrimental impact on brain integrity., (© 2024. The Author(s).)

Background: The NIA-AA Research Framework on Alzheimer's disease (AD) proposes a transitional stage (stage 2) characterized by subtle cognitive decline, subjective cognitive decline (SCD) and mild neurobehavioral symptoms (NPS)., Objective: To identify participant clusters based on stage 2 features and assess their association with amyloid positivity in cognitively unimpaired individuals., Methods: We included baseline data of N = 338 cognitively unimpaired participants from the DELCODE cohort with data on cerebrospinal fluid biomarkers for AD. Classification into the AD continuum (i.e., amyloid positivity, A+) was based on Aβ42/40 status. Neuropsychological test data were used to assess subtle objective cognitive dysfunction (OBJ), the subjective cognitive decline interview (SCD-I) was used to detect SCD, and the Neuropsychiatric Inventory Questionnaire (NPI-Q) was used to assess NPS. A two-step cluster analysis was carried out and differences in AD biomarkers between clusters were analyzed., Results: We identified three distinct participant clusters based on presented symptoms. The highest rate of A+ participants (47.6%) was found in a cluster characterized by both OBJ and SCD. A cluster of participants that presented with SCD and NPS (A+:26.6%) and a cluster of participants with overall few symptoms (A+:19.7%) showed amyloid positivity in a range that was not higher than the expected A+ rate for the age group. Across the full sample, participants with a combination of SCD and OBJ in the memory domain showed a lower Aβ42/ptau181 ratio compared to those with neither SCD nor OBJ., Conclusions: The cluster characterized by participants with OBJ and concomitant SCD was enriched for amyloid pathology.

Background: Inflammation has been described as a key pathogenic event in Alzheimer's disease (AD), downstream of amyloid and tau pathology. Preclinical and clinical data suggest that the cholinergic basal forebrain may moderate inflammatory response to different pathologies., Objective: To study the association of cholinergic basal forebrain volume and functional connectivity with measures of neuroinflammation in people from the AD spectrum., Methods: We studied 261 cases from the DELCODE cohort, including people with subjective cognitive decline, mild cognitive impairment, AD dementia, first degree relatives, and healthy controls. Using Bayesian ANCOVA, we tested associations of MRI indices of cholinergic basal forebrain volume and functional connectivity with cerebrospinal fluid (CSF) levels of sTREM2 as a marker of microglia activation, and serum levels of complement C3. Using Bayesian elastic net regression, we determined associations between basal forebrain measures and a large inflammation marker panel from CSF and serum., Results: We found anecdotal to moderate evidence in favor of the absence of an effect of basal forebrain volume and functional connectivity on CSF sTREM2 and serum C3 levels both in Aβ42/ptau-positive and negative cases. Bayesian elastic net regression identified several CSF and serum markers of inflammation that were associated with basal forebrain volume and functional connectivity. The effect sizes were moderate to small., Conclusion: Our data-driven analyses generate the hypothesis that cholinergic basal forebrain may be involved in the neuroinflammation response to Aβ42 and phospho-tau pathology in people from the AD spectrum. This hypothesis needs to be tested in independent samples.