Individuals with Alzheimer's disease dementia show Alzheimer's disease pathology and a heterogeneous degeneration of the Substantia Nigra (SN) post-mortem. However, it is unclear how SN degeneration is related to cognitive dysfunction across the Alzheimer's disease dementia continuum. In this study, using data from the prospective DZNE-Longitudinal Cognitive Impairment and Dementia Study (DELCODE), we investigated whether in vivo SN MRI measures are lower in individuals with clinically defined Alzheimer's disease dementia than in healthy control subjects (HC) and if they are associated with hippocampal functional activity during the processing of novel visual stimuli and subsequent recognition memory. One hundred and sixty DELCODE participants (69 years ± 6 years, 88 men), including 79 HC, 70 individuals with subjective cognitive decline (SCD), 17 individuals with mild cognitive impairment (MCI) and 10 individuals with Alzheimer's disease dementia, completed a scene novelty and encoding task and a 3T SN-sensitive MRI scan, from which the two in vivo SN measures MRI contrast and volume were calculated and harmonized between scanner sites while preserving diagnostic group differences. For 71 individuals, CSF levels of phosphoTau, total tau and amyloid-beta 42/40 ratio (Aß42/40) were available. All individuals completed a neuropsychological task battery from which a global cognitive score was calculated. In separate models, we assessed the relationship between SN MRI markers and CSF levels of Alzheimer's disease, the global cognitive score, hippocampal novelty activation and recognition memory while accounting for age, sex, years of education and total intracranial volume (TIV). SN volume but not SN MRI contrast was lower in individuals with clinical Alzheimer's disease dementia [one-way analyses of covariance (ANCOVA); F(156,4) = 5.6665, P = 0.0010, n = 160]. SN MRI contrast and volume were not associated with Aß42/40, ptau and total tau CSF levels (all P > 0.1) or hippocampal novelty activation (all P > 0.1). Moreover, SN volume was positively associated with recognition memory (R 2 = 0.07, P < 0.001, n = 159), global cognition (R 2= 0.38, P < 0.0001, n = 160) and years of education (R 2 = 0.03, P = 0.036, n = 160). Our study emphasizes the potential of using in vivo SN MRI markers to study the impact of SN degeneration on general cognitive impairment and recognition memory in an Alzheimer's disease dementia cohort. Our results motivate future longitudinal studies to explore how SN volume and SN contrast change with disease progression, how these are differentially associated with cognitive decline, and how SN volume and SN contrast might be related to other dopamine-dependent cognitive functions and dysfunctions.

Alzheimer’s disease (AD) is characterised by the accumulation of β-amyloid (Aβ) and tau proteins, resulting in neurodegeneration and cognitive decline. Although Aβ and tau disrupt synaptic function, the association linking these molecular pathologies to network-level dysfunction and memory impairment remains poorly understood. Here, we investigated the effects of Aβ and tau pathology (CSF Aβ42/40 ratio and tau phosphorylated at position 181, p-tau-181, respectively) on effective connectivity related to memory encoding, which may provide a link between synaptic pathology and cognitive outcomes. Functional magnetic resonance imaging (fMRI) during visual memory encoding was acquired from 205 participants in the multicentric DZNE Longitudinal Cognitive Impairment and Dementia Study (DELCODE) across the AD spectrum. Effective connectivity was assessed using Dynamic Causal Modelling (DCM) of task-fMRI data, focusing on the parahippocampal place area (PPA), hippocampus (HC), and precuneus (PCU)—regions central to memory encoding. Disruptions in connectivity between temporal and parietal lobes were associated with both memory impairment and indices of AD pathology. Specifically, reduced positive effective connectivity from the PCU to the PPA and from the HC to the PCU were linked to higher p-tau-181 levels, with an amplification effect observed in the presence of amyloid accumulation for the latter connectivity. The disruption from the PCU to the PPA was found to be associated with decreased memory performance. Together, these findings indicate that temporo-parietal connectivity is associated with both AD molecular pathology and, for a subset of connections, with memory performance.

Background: Artificial intelligence (AI) is expected to become increasingly important in hospitals and clinical care. However, successful implementation depends on technical, organizational, and user-related factors. We aimed to identify the key requirements for equitable and effective adoption of AI-based applications in clinical practice. Methods: Within the “Clinical AI-Based Diagnostics” (CAIDX) project, we conducted systematic expert interviews with 51 stakeholders from four European countries working across the healthcare sector. Interviews explored the perceived added value of AI, barriers to implementation, usability requirements, and potential health-economic implications. Findings: Stakeholder analysis revealed several recurrent sources of tension affecting implementation: limited physician involvement, differing perspectives between IT specialists and clinicians, unclear distribution of tasks and responsibilities, and low institutional commitment driven by concerns about inefficient use of time and resources. We also identified structural and workforce-related constraints that make implementation particularly challenging, including the large number of actors involved and the highly individual organizational setup of hospitals, which limits transferability of implementation models. Interpretation: Implementation of clinical AI requires targeted action at hospital, vendor, and health-system levels. Compared with earlier healthcare technologies, AI adoption is shaped more strongly by AI literacy, professional attitudes, and perceptions of trust and responsibility. Based on these findings, we propose practical recommendations to support implementation of AI applications in routine care.

Background Early and accurate detection of Alzheimer’s disease (AD) is essential for timely intervention and development of disease-modifying treatments. The DZNE-Longitudinal Cognitive Impairment and Dementia Study (DELCODE) provides a deeply phenotyped cohort covering preclinical and early clinical stages, including subjective cognitive decline (SCD) and mild cognitive impairment (MCI). Astrocyte reactivity and its biomarkers, particularly glial fibrillary acidic protein (GFAP), have gained increasing attention in AD research; however, the relationship between GFAP and amyloid in early disease, as well as its potential prognostic value beyond its association with amyloid status, remains insufficiently understood. Objectives To evaluate the performance of CSF and plasma GFAP across early disease stages, compare these measures according to amyloid status, and assess the prognostic value of GFAP for clinical progression across diagnostic stages during longitudinal follow-up. Setting This study used data from the multicenter DELCODE cohort in Germany, including participants with available plasma and/or CSF samples and standardized clinical, cognitive, imaging, and biomarker assessments. Measurements GFAP concentrations in plasma and CSF were quantified using validated immunoassay platforms. Standard CSF AD biomarkers and ApoE genotype were measured using established assays. Amyloid status was defined by the CSF Aβ42/40 ratio. Longitudinal follow-up occurred annually for up to ∼10 years, with clinical conversion determined according to NIA-AA criteria. Results Plasma and CSF GFAP increased across the AD continuum, with higher levels in MCI and AD (p < 0.001). Plasma GFAP showed a stronger association with amyloid status than CSF GFAP across all groups. In MCI, plasma GFAP combined with age and ApoE4 yielded an AUC of 0.87. Elevated plasma GFAP predicted increased risk of conversion to MCI (HR = 2.19, p < 0.001; adjusted HR = 1.70, p = 0.0056) and AD dementia (HR = 3.5; adjusted HR = 2.49 both p < 0.001). Conclusion Plasma GFAP is a sensitive, minimally invasive biomarker with diagnostic relevance for amyloid detection and prognostic relevance for clinical progression in early AD.

The role of the peripheral immune system in Alzheimer’s Disease (AD) remains insufficiently resolved, limiting the understanding of systemic disease effects and mechanisms. Here, we employed three high-resolution single-cell techniques, including flow cytometry, single-cell RNA- and ATAC-sequencing, to investigate peripheral immunity in AD dementia and earlier stages of the AD trajectory in over 100 patients. We identified reduced humoral immune responses in AD, characterized by a diminished B cell compartment displaying an impaired activation phenotype. Classical monocytes expanded in mild cognitive impairment and early AD dementia, acquiring a NF-kB/AP-1-mediated low-grade inflammation phenotype. Our findings link peripheral dysregulation in innate and adaptive immunity at cell frequency, transcriptional and epigenetic levels to the AD trajectory and provide insights into distinct phenotypes that define AD progression in contrast to healthy aging across cohorts. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This work was supported by the National Dementia Strategy for Germany. MDB is supported by the Helmholtz Association and the German Research Foundation (DFG) (SFB1454 project number 432325352, IGK2168/2 project number 272482170). LB, ACA, MB, TU, JLS and MDB are members of the excellence cluster ImmunoSensation2 (EXC2151 project number 390873048). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: All participants or their representatives provided informed consent. Ethics committees of the medical faculties of all participating sites - the ethical committees of Berlin (Charité, University Medicine), Bonn, Cologne, Göttingen, Magdeburg, Munich (Ludwig-Maximilians-University), Rostock, and Tübingen - gave ethical approval for this work. The process was led and coordinated by the ethical committee of the medical faculty of the University of Bonn. The registration number of the trial at the ethical committee in Bonn is 117/13 (please refer to Jessen, F., Spottke, A., Boecker, H., Brosseron, F., Buerger, K., Catak, C., Fliessbach, K., Franke, C., Fuentes, M., Heneka, M.T., et al., 2018. Design and first baseline data of the DZNE multicenter observational study on predementia Alzheimers disease (DELCODE). Alzheimers Res Ther 10, 15. 10.1186/s13195-017-0314-2). The ethics committee of the medical faculty of the University of Bonn gave ethical approval for the analysis of single-cell RNA-seq data under 227/19. DELCODE and DESCRIBE were conducted in accordance with the Helsinki Declaration from 1975. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes scRNA-seq, scATAC-seq and MCFC data are deposited at the DZNE Clinical Research Platform. Code will be deposited at Zenodo and will be available as of the date of publication. Any additional information required for data reanalysis is available from the lead contact upon request.

Alzheimer's disease (AD) is a major cause of dementia and cognitive decline. Here, we assessed how episodic memory (EM) network dysfunction, a hallmark of AD, is related to the longitudinal progression of AD biomarkers, neurodegeneration and cognition using data from the DZNE DELCODE study. This data set includes over 1000 longitudinal functional magnetic resonance imaging measurements of EM network function. We related activation and deactivation of EM to individual disease progression scores from a disease progression model. Voxel-wise analyses revealed widespread loss of deactivation and activation with disease progression. Trajectories for the loss of deactivation were nonlinear, associated with amyloid- and tau-positivity and visually preceded trajectories of cognitive decline. The relationship between deactivation and cognitive decline was partly independent of neurodegeneration. Our results provide evidence that synaptic dysfunction and neurodegeneration are independent drivers of cognitive decline, providing a rationale for targeting synaptic dysfunction along the AD cascade.

Alzheimer’s disease (AD) is characterised by the accumulation of beta-amyloid (Aβ) and tau proteins, leading to neurodegeneration and cognitive decline. While Aβ and tau are known to disrupt synaptic function, the mechanisms linking these molecular pathologies to network-level dysfunction and memory impairment remain poorly understood. Here we investigated the effects of Aβ and tau pathology (CSF Aβ42/40 ratio and tau phosphorylated at position 181, p-tau-181, respectively) on effective connectivity (EC) related to memory encoding, which may constitute a link between synaptic pathology and cognitive outcomes. Functional magnetic resonance imaging (fMRI) during visual memory encoding was acquired from participants of the multicentric DZNE Longitudinal Cognitive Impairment and Dementia Study (DELCODE), including 203 cognitively normal older participants (CN) as well as individuals with subjective cognitive decline (SCD; N = 204), mild cognitive impairment (MCI; N = 65), and early dementia due to AD (DAT; N = 21). EC was assessed by applying Dynamic causal modelling (DCM) to the fMRI data, using brain regions previously implicated in memory-encoding: the parahippocampal place area (PPA), the hippocampus (HC) and the precuneus (PCU). Disruptions in forward connectivity from the PPA to the HC and PCU were associated with both memory impairment and indices of AD pathology. Specifically, reduced excitatory EC from the PPA to the HC was associated with higher p-tau-181 levels and correlated with poorer memory performance. Diminished inhibitory EC from the PPA to the PCU was driven by both tau and amyloid pathology and was likewise linked to memory decline. Our findings suggest that disrupted forward connectivity within the temporo-parietal memory network constitutes a candidate mechanism mediating the relationship between molecular pathology and cognitive dysfunction. ### Competing Interest Statement E.D. is one of co-founders of neotiv GmbH and conducted paid consultancy work for Eisai, Lilly, Biogen, Roche and RoxHealth (unrelated to this study). C.B. received honoraria as a commercial advisory board member for Lilly (April 2024); honoria for lectures from Boehringer Ingelheim (September 2024), Roche (June 2021), Lilly (March 2025) and Eisai (April 2024); and funding from the German Alzheimer Association (DAlzG; 2021-2023). * AB : beta-amyloid AD : Alzheimer’s disease CN : cognitively normal DAT : dementia of Alzheimer’s type DCM : Dynamic causal modelling DELCODE : DZNE - Longitudinal Cognitive Impairment and Dementia Study DZNE : German Centre for Neurodegenerative Diseases GAMs : Generalised additive models HC : hippocampus MCI : mild cognitive impairment PPA : parahippocampal place area PCU : precuneus p-tau : phosphorylated tau SCD : subjective cognitive decline Deutsche Forschungsgemeinschaft, 362321501/RTG 2413 'SynAGE', 374011584/3T Ganzkörper MR-Tomograf, CRC 1436, projects C01, B02, and A05 German Center for Neurodegenerative Diseases, https://ror.org/043j0f473, BN012

Inadequate glymphatic clearance through perivascular spaces (PVS) is hypothesized to contribute to the formation of white matter hyperintensities (WMH). However, longitudinal evidence for such a mechanistic link in aging remains limited. Using multivariate modelling, we investigated the interrelationship between PVS and WMH over time to elucidate potential cascades of early cerebrovascular alterations and tested whether AD-biomarkers and inflammatory markers associated with vascular disease can explain individual variability in their occurrence and progression. We quantified PVS and WMH using T1w MPRAGE and T2w FLAIR imaging of 439 cognitively unimpaired participants from the DELCODE study (52.85% females; mean age = 69.88±5.72), who underwent annual scans over a four-year period and attended at least three visits ( n observations = 1790; mean number of visits = 4.08±0.79). We employed latent growth curve modelling to assess reciprocal connections between PVS and WMH, focusing on their initial volumes (latent intercepts) and their rates of change over four years (latent slopes). We used log10-transformed total PVS and WMH volumes, and controlled for age, sex, years of education, total cardiovascular risk score, and total intracranial volume. We then derived interindividual latent factor scores and tested their relation to CSF-derived AD-biomarkers (Aβ42/40, pTau181; available for n = 195; z-scored) and inflammatory markers (CRP, IL-6; available for n = 125; Box-Cox-transformed) via Spearman’s correlation (FDR-corrected). The model showed good model fit ( CFI = 0.997; RMSEA = 0.021; SRMR = 0.017; Fig. 1A ). WMH and PVS volumes increased over time ( intercept WMH-slope = 0.068, SE = 0.004, Z = 16.490, p< 0.001; intercept PVS-slope = 0.036, SE = 0.007, Z = 4.927, p< 0.001; Fig. 1B ). Participants with higher baseline PVS volumes not only had higher baseline WMH volumes ( covariance PVS-intercept&WMH-intercept = 0.120, SE = 0.040, Z = 2.936, p = 0.003; Fig. 1C ) but also tended to exhibit faster WMH volume increase over time ( covariance PVS-intercept&WMH-slope = 0.007, SE = 0.004, Z = 1.796, p = 0.072; Fig. 1C ). In this sample of cognitively unimpaired participants, biomarkers of AD and inflammation did neither relate to individual baseline differences nor progression rates ( Table 1 ). Our findings are consistent with the notion that PVS dysfunction might contribute to and precede WMH progression ( Fig. 1D ). However, the individual variability requires further investigation to elucidate mechanisms driving PVS dysfunction in the first place. Unraveling the interrelationships and further factors contributing to cerebrovascular alterations will be crucial to understand pathological cascades in aging that could inform targeted treatment strategies.

Promising elements of assistive technologies are available to help people with cognitive impairment in their daily lives. However, there has been limited research on how smartwatches can directly interact with persons who have cognitive impairments. We looked at the factors that affect the effectiveness of interventions provided via a smartwatch. We designed two tasks delivered by smartwatch: A) drinking water and B) circling bells on a worksheet. We created two modes of intervention-intensity affecting vibration, alarm sounds, text sizes and images. In case of failure, interventions were repeated up to three times. We observed n = 40 patients’ reactions to interventions via cameras and rated success on a 5-step scale from 0 to 2. Patients were assigned (n = 20/20) either to mode “regular” or mode “intensive”. All patients received both tasks in the mode corresponding to the group. In both groups, half received the tasks in order AB, the other half in BA. Participants answered questionnaires and underwent neuropsychological testing. People were diagnosed with MCI (n = 12) or dementia (n = 28). We hypothesized that the mode, the sequence of tasks, age, affinity for technology (ATI) and cognitive status (MMSE) would influence the success of the interventions. We expected that intensive interventions would be more successful than regular interventions. The groups statistically did not differ with respect to mean age, MMSE or ATI. The intensive group was more successful than regular group, for each task and global success score (mean 1.7, SD 0.3 vs. 1.2, SD 0.7., Welch t-test p = 0.03). Testing of linear regression models showed that “mode” significantly increases model fit: H 1 age + sex + MMSE + ATI + task sequence + mode p = 0.045, adjusted R² = 19%, compared to H 0 age + sex + MMSE + ATI + task sequence p = 0.399, adjusted R² = 0.8%. Controlling for covariance (ANCOVA) showed only for “mode” a significant influence on success (p = 0.003) not of MMSE, sex or diagnosis (p<0.05, respectively). Tasks delivered from a smartwatch as intensive interventions are more likely to be solved by patients than regularly delivered ones. Intensity is more critical than the patient’s baseline status with respect to cognition and technology-affinity.

Amyloid PET imaging is an established diagnostic tool for Alzheimer's disease, but its successful integration into clinical practice requires a comprehensive understanding of its impact on patients and the healthcare system. In 2022, the coverage with evidence development (CED) ENABLE study has been approved by the German Federal Joint Committee (trial registration: DRKS00030839). The study is scheduled to start in early 2024. Primary outcome of ENABLE is the change in patients' functional abilities at 18 months after diagnosis with amyloid PET versus without amyloid-PET. Here we describe the design of an ENABLE sub-study aimed at performing a process evaluation. We will conduct an outcome and process evaluation using a pre-post descriptive design nested in ENABLE (Figure), based on the Medical Research Council's Process Evaluation (PE) framework. The PE will focus on acceptability and reach of the target groups of patients and care providers, as well as fidelity of delivery (% of adherence to protocol, study duration), contextual changes and mechanisms (e.g., ability to mirror routine care). We will collect patients’ data independently, but in parallel with ENABLE, using interviews, surveys and checklists to assess acceptance of the intervention, fidelity of adherence to the follow-up procedures, perceived benefits and challenges. Healthcare providers and administrators will be interviewed to identify implementation hurdles and facilitators, contextual factors influencing uptake and underlying mechanisms. For data analysis we will employ a mixed-methods approach. Expected outcomes will include acceptability and adherence, barriers and facilitators to implementation, contextual factors influencing implementation, perceived utility of the intervention by patients and providers, and mechanisms by which the intervention can be delivered as part of normal care. This process evaluation can inform researchers on how to design future CED studies to be implemented into clinical care. The lessons learned during the development and approval process of the ENABLE project in Germany, as well as its process evaluation, can benefit other European CED studies and policy-makers stakeholders in making informed decisions. Likewise, these findings can be generalized beyond the context of amyloid PET to other diagnostic biomarkers, ultimately improving the diagnosis and management of Alzheimer's disease.

INTRODUCTION:The locus coeruleus (LC) is linked to the development and pathophysiology of neurodegenerative diseases such as Alzheimer's disease (AD). Magnetic resonance imaging-based LC features have shown potential to assess LC integrity in vivo. METHODS:We present a deep learning-based LC segmentation and feature extraction method called Ensemble-based Locus Coeruleus Segmentation Network (ELSI-Net) and apply it to healthy aging and AD dementia datasets. Agreement to expert raters and previously published LC atlases were assessed. We aimed to reproduce previously reported differences in LC integrity in aging and AD dementia and correlate extracted features to cerebrospinal fluid (CSF) biomarkers of AD pathology. RESULTS:ELSI-Net demonstrated high agreement to expert raters and published atlases. Previously reported group differences in LC integrity were detected and correlations to CSF biomarkers were found. DISCUSSION:Although we found excellent performance, further evaluations on more diverse datasets from clinical cohorts are required for a conclusive assessment of ELSI-Net's general applicability. Highlights:We provide a thorough evaluation of a fully automatic locus coeruleus (LC) segmentation method termed Ensemble-based Locus Coeruleus Segmentation Network (ELSI-Net) in aging and Alzheimer's disease (AD) dementia.ELSI-Net outperforms previous work and shows high agreement with manual ratings and previously published LC atlases.ELSI-Net replicates previously shown LC group differences in aging and AD.ELSI-Net's LC mask volume correlates with cerebrospinal fluid biomarkers of AD pathology.

A screening tool may help determine who in the population is exposed to which dementia risk factor and, in this way, prevent or delay symptoms. With this study, we examined the practically of using a patient self-completion screening checklist for detecting dementia risk factors with general practitioners (GP). The checklist 'CogFit' was developed based on systematic reviews and meta-analyses. Fourteen GPs (average age 44.8 years; 71.4% female) tested it with their patients and reported their experiences in a questionnaire and the System Usability Scale (SUS). In our survey, 57.2% of the GPs considered the checklist useful and most GPs (83%) indicated that the current version is sufficient. The user-friendliness of the CogFit checklist was good (SUS score M = 73.13, SD = 10.45). Most GPs (71.4%) reported having gained important information about their patients. 69% gave lifestyle advice and 61.5% referred their patients to brochures or courses. Yet, about two thirds (64.3%) reported an increased workload and four GPs disagreed to use the checklist in future. Our results indicate an overall good practicality of our patient self-completion checklist (CogFit) in primary care. Further research involving patients and estimating the overall effectiveness on cognitive health is needed.

Neurotransmitter systems of noradrenaline, dopamine, serotonin and acetylcholine are implicated in cognitive functions such as memory, learning and attention and are known to be altered in neurodegenerative diseases like Alzheimer's disease. Specific brain structures involved in these systems, e.g. the locus coeruleus, the main source of noradrenaline in the cortex, are in fact affected earliest by Alzheimer's disease tau pathology. Preserved volumetric neurotransmitter specific brain areas could therefore be an important neural resource for cognitive reserve in aging. The aim of this study was to determine whether volumes of brain areas known to be high in neurotransmitter receptors are relatively preserved in individuals with lower levels of Alzheimer's disease pathology. Based on the Human Protein Atlas for neurotransmitter receptor distribution, we distinguished between 'areas high and low' in noradrenaline, dopamine, serotonin and acetylcholine and assessed associations of atrophy in those areas with CSF amyloid-ß 42/40, CSF phosphorylated tau protein and cognitive function across healthy controls (n = 122), individuals with subjective cognitive decline (n = 156), mild cognitive impairment or mild Alzheimer's disease dementia (n = 126) using structural equation modelling. CSF pathology markers were inversely correlated and showed a stronger association with disease severity, suggesting distinguishable interrelatedness of these biomarkers depending on the stage of Alzheimer's disease dementia. Across groups, amyloid pathology was linked to atrophy in areas high as well as low in neurotransmitter receptor densities, while tau pathology did not show any significant link to brain area volumes for any of the neurotransmitters. Within disease severity groups, individuals with more amyloid pathology showed more atrophy only in 'areas high in noradrenaline', whereas for dopamine tau pathology was linked to higher volumes in areas low in receptor density possibly indicating compensatory mechanisms. Furthermore, individuals with more tau pathology showed a selective decrease in memory function while amyloid pathology was related to a decline in executive function and language capacity as well as memory function. In summary, our analyses highlight the benefits of investigating disease-relevant factors in Alzheimer's disease using a multivariate multigroup approach. Assessing multivariate dependencies in different disease stages and across individuals revealed selective links of pathologies, cognitive decline and atrophy in particular for areas modulated by noradrenaline, dopamine and serotonin.

This study introduces the Structural MRI-based Alzheimer's Disease Score (SMAS), a novel index intended to quantify Alzheimer's Disease (AD)-related morphometric patterns using a deep learning Bayesian-supervised Variational Autoencoder (Bayesian-SVAE). The SMAS index was constructed using baseline structural MRI data from the DELCODE study and evaluated longitudinally in two independent cohorts: DELCODE (n=415) and ADNI (n=190). Our findings indicate that SMAS has strong associations with cognitive performance (DELCODE: r=-0.83; ADNI: r=-0.62), age (DELCODE: r=0.50; ADNI: r=0.28), hippocampal volume (DELCODE: r=-0.44; ADNI: r=-0.66), and total gray matter volume (DELCODE: r=-0.42; ADNI: r=-0.47), suggesting its potential as a biomarker for AD-related brain atrophy. Moreover, our longitudinal studies indicated that SMAS may be useful for the early identification and tracking of AD. The model demonstrated significant predictive accuracy in distinguishing cognitively healthy individuals from those with AD (DELCODE: AUC=0.971 at baseline, 0.833 at 36 months; ADNI: AUC=0.817 at baseline, improving to 0.903 at 24 months). Notably, over 36 months, the SMAS index outperformed existing measures such as SPARE-AD and hippocampal volume. The relevance map analysis revealed significant morphological changes in key AD-related brain regions, including the hippocampus, posterior cingulate cortex, precuneus, and lateral parietal cortex, highlighting that SMAS is a sensitive and interpretable biomarker of brain atrophy, suitable for early AD detection and longitudinal monitoring of disease progression.

ABSTRACT Here, we investigated whether fractional anisotropy (FA) of hippocampus-relevant white-matter tracts mediates the association between baseline Mediterranean diet adherence (MeDiAd) and verbal episodic memory over four years. Participants were healthy older adults with and without subjective cognitive decline and patients with amnestic mild cognitive impairment from the DELCODE cohort study ( n = 376; age: 71.47 ± 6.09 years; 48.7% female). MeDiAd and diffusion data were obtained at baseline. Verbal episodic memory was assessed at baseline and four yearly follow-ups. The associations between baseline MeDiAd and white matter, and verbal episodic memory’s mean and rate of change over four years were tested with latent growth curve modeling. Baseline MeDiAd was associated with verbal episodic memory four years later (95% confidence interval, CI [0.01, 0.32]) but not with its rate of change over this period. Baseline Fornix FA mediated – and, thus, explained – that association (95% CI [0.002, 0.09]). Fornix FA may be an appropriate response biomarker of Mediterranean diet interventions on verbal memory in older adults.

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.

Memory clinic patients are a heterogeneous population representing various aetiologies of pathological ageing. It is not known whether divergent spatiotemporal progression patterns of brain atrophy, as previously described in Alzheimer's disease patients, are prevalent and clinically meaningful in this group of older adults. To uncover distinct atrophy subtypes, we applied the Subtype and Stage Inference (SuStaIn) algorithm to baseline structural MRI data from 813 participants enrolled in the DELCODE cohort (mean ± standard deviation, age = 70.67 ± 6.07 years, 52% females). Participants were cognitively unimpaired (n = 285) or fulfilled diagnostic criteria for subjective cognitive decline (n = 342), mild cognitive impairment (n = 118) or dementia of the Alzheimer's type (n = 68). Atrophy subtypes were compared in baseline demographics, fluid Alzheimer's disease biomarker levels, the Preclinical Alzheimer Cognitive Composite (PACC-5) as well as episodic memory and executive functioning. PACC-5 trajectories over up to 240 weeks were examined. To test whether baseline atrophy subtype and stage predicted clinical trajectories before manifest cognitive impairment, we analysed PACC-5 trajectories and mild cognitive impairment conversion rates of cognitively unimpaired participants and those with subjective cognitive decline. Limbic-predominant and hippocampal-sparing atrophy subtypes were identified. Limbic-predominant atrophy initially affected the medial temporal lobes, followed by further temporal regions and, finally, the remaining cortical regions. At baseline, this subtype was related to older age, more pathological Alzheimer's disease biomarker levels, APOE ε4 carriership and an amnestic cognitive impairment. Hippocampal-sparing atrophy initially occurred outside the temporal lobe, with the medial temporal lobe spared up to advanced atrophy stages. This atrophy pattern also affected individuals with positive Alzheimer's disease biomarkers and was associated with more generalized cognitive impairment. Limbic-predominant atrophy, in all participants and in only unimpaired participants, was linked to more negative longitudinal PACC-5 slopes than observed in participants without or with hippocampal-sparing atrophy and increased the risk of mild cognitive impairment conversion. SuStaIn modelling was repeated in a sample from the Swedish BioFINDER-2 cohort. Highly similar atrophy progression patterns and associated cognitive profiles were identified. Cross-cohort model generalizability, at both the subject and the group level, was excellent, indicating reliable performance in previously unseen data. The proposed model is a promising tool for capturing heterogeneity among older adults at early at-risk states for Alzheimer's disease in applied settings. The implementation of atrophy subtype- and stage-specific end points might increase the statistical power of pharmacological trials targeting early Alzheimer's disease.

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.

Individuals with Alzheimer′s disease dementia postmortem show Alzheimer′s disease pathology in and heterogeneous degeneration of the Substantia Nigra (SN). However, it is unclear how the SN degeneration is related to cognitive dysfunction across the Alzheimer′s disease dementia continuum. In this study, using data from a prospective dementia study (DELCODE), we investigated if in-vivo SN MRI measures are lower in cases with clinically defined Alzheimer′s disease dementia than in healthy control subjects (HC) and if they are associated with functional activity during the processing of novel visual stimuli and subsequent recognition memory. 161 DELCODE participants (69 years ±6 years, 88 men), including 79 HC, 71 individuals with subjective cognitive impairment (SCD), 17 individuals with mild cognitive impairment (MCI), and 10 individuals with Alzheimer′s disease dementia, completed a scene novelty and encoding task and a 3T neuromelanin (NM)-sensitive MRI scan, from which the two in-vivo SN measures MRI contrast and volume were calculated. For 71 individuals, CSF levels of phospoTau, total tau, and amyloid beta 42/40 ratio (Aβ42/40) were available. All individuals completed a neuropsychological task battery from which a global cognitive score was calculated. SN volume but not SN MRI contrast was lower in individuals with clinical Alzheimer′s disease dementia (One-way ANCOVA; F(3,156)=4,13, N=160, p=0.001). SN MRI contrast and volume were not associated with Aβ42/40, ptau, and ttau CSF levels (all p<0.1). SN MRI contrast was positively associated with anterior hippocampal functional activity during the presentation of novel stimuli in individuals with Aβ42/40 ratio levels below a pathological threshold of 0.08 (Aβ42/40 positive, p(FWE)=0.002, 157 voxels, n=28) but not in Aβ42/40 negative individuals. Moreover, SN volume was positively associated with recognition memory (N=160, p=0.017, r2=0.11) and global cognition (p<0.0001, N=160, r2=0.221) across the Alzheimer′s disease dementia continuum. Our study emphasizes the potential of using in-vivo SN MRI markers to understand the impact of Alzheimer′s disease pathology-independent SN degeneration on recognition memory and novelty processing dysfunction in Alzheimer′s disease dementia. Our results motivate future longitudinal studies exploring how SN volume and SN contrast change over time, how these are differentially associated with cognitive decline, and how the SN volume and SN contrast might be associated with other dopamine-dependent cognitive functions. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement The study was funded by the German Center for Neurodegenerative Diseases (Deutsches Zentrum fuer Neurodegenerative Erkrankungen; DZNE), reference number BN012. F.K is supported by the German Federal Ministry of Education and Research (BMBF, funding code 01ED2102B) under the aegis of the EU Joint Programme: Neurodegenerative Disease Research (JPND). He is paid from a stipend awarded by the medical faculty in Magdeburg. E.D. and M.B. are supported by Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) Project-ID 425899996 SFB 1436 ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Our dataset is a subset from the multicenter DELCODE study (Jessen et al., 2018). The Institutional Review Boards of all participating study centers of the DZNE approved the study. All participants gave written informed consent before inclusion in the study. DELCODE is retrospectively registered at the German Clinical Trials Register (DRKS00007966) (04/05/2015). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors

The cognitive reserve (CR) hypothesis posits that individuals can differ in how their brain function is disrupted by pathology associated with aging and neurodegeneration. Here, we test this hypothesis in the continuum from cognitively normal to at-risk stages for Alzheimer's Disease (AD) to AD dementia using longitudinal data from 490 participants of the DELCODE multicentric observational study. Brain function is measured using task fMRI of visual memory encoding. Using a multivariate moderation analysis, we identify a CR-related activity pattern underlying successful memory encoding that moderates the detrimental effect of AD pathological load on cognitive performance. CR is mainly represented by a more pronounced expression of the task-active network encompassing deactivation of the default mode network (DMN) and activation of inferior temporal regions including the fusiform gyrus. We devise personalized fMRI-based CR scores that moderate the impact of AD pathology on cognitive performance and are positively associated with years of education. Furthermore, higher CR scores attenuate the effect of AD pathology on cognitive decline over time. Our findings primarily provide evidence for the maintenance of core cognitive circuits including the DMN as the neural basis of CR. Individual brain activity levels of these areas during memory encoding have prognostic value for future cognitive decline. Here, the authors identify a cognitive reserve-related activity pattern underlying successful memory encoding. They further derive individual reserve scores that predict the maintenance of cognitive performance in the face of Alzheimer's disease pathology.