Importance:Postoperative delirium (POD) is a frequent and severe complication after cardiac surgery that is associated with increased risk of dementia and adverse outcomes. Early identification of high-risk patients remains challenging. Objective:To examine whether preoperative plasma Alzheimer disease biomarkers are associated with baseline cognition and can independently estimate POD in patients undergoing elective cardiac surgery. Design, Setting, and Participants:This prospective, observational cohort study (FIND Delirium Risk Factors [FINDERI]) included patients 50 years or older undergoing elective cardiac surgery at a comprehensive cardiac surgery center in Germany between February 1, 2021, and October 31, 2022. Statistical analysis was performed from January to December 2025. Exposures:Preoperative plasma concentrations of amyloid-β 1-40 (Aβ1-40), amyloid-β 42 (Aβ1-42), phosphorylated tau 181 (pTau181), and phosphorylated tau 217 (pTau217) were measured using validated immunoassays between November 1, 2022, and July 31, 2024. Main Outcomes and Measures:The primary outcome was POD, assessed daily for 5 days postoperatively using the Confusion Assessment Method algorithm. Baseline cognitive function was assessed using the Montreal Cognitive Assessment (MoCA). Risk estimation accuracy was evaluated using receiver operating characteristic analysis and multivariate logistic regression, adjusting for relevant clinical covariates. Results:Of 504 enrolled patients, 491 completed POD assessment (mean [SD] age, 68.4 [8.3] years; 385 [78.4%] male), of whom 106 (21.6%) developed POD. In multiple linear regression, pTau217 (β = -0.51; 95% CI, -0.89 to -0.12; P = .01) and age (β = -0.12; 95% CI, -0.16 to -0.08; P < .001) remained significant factors associated with lower MoCA scores. Patients who developed POD had higher preoperative Aβ1-40, Aβ1-42, pTau217, and Aβ1-40/Aβ1-42 × pTau217, and lower Aβ1-42/Aβ1-40. Aβ1-40 was the independent biomarker most strongly associated with POD (area under the receiver operating curve [AUC], 0.65; 95% CI, 0.59-0.71; P < .001). Combining biomarkers with clinical factors improved risk estimation (AUC, 0.74; 95% CI, 0.69-0.79; P < .001) compared with clinical factors alone (AUC, 0.73; 95% CI, 0.67-0.78; P < .001). A combined model including MoCA achieved an AUC of 0.77 (95% CI, 0.72-0.82; P < .001), driven primarily by Aβ1-40. Conclusions and Relevance:In this prospective cohort study, preoperative Aβ1-40 showed the strongest association with POD risk among the measured biomarkers. These findings suggest that preoperative plasma Aβ1-40 may contribute to POD risk stratification, but further research is needed to validate these findings and determine clinical utility.

BACKGROUND:The study aim is to investigate whether blood biomarkers (BBMs) of Alzheimer's disease (AD) pathology are associated with postoperative cognitive dysfunction (POCD) after cardiac surgery. METHODS:Cognitive performance was assessed before and 12 months postoperatively using the Montreal Cognitive Assessment (MoCA) and categorized into stages-minimal (1), notable (2), and substantial (3) decline-in the FIND DElirium RIsk factors (FINDERI) study of patients undergoing cardiac surgery. BBMs were measured preoperatively (amyloid beta [Aβ]1-42, Aβ1-40, phosphorylated tau 181 [p-tau181], p-tau217, apolipoprotein E ε4 [apoE4] and apoE). RESULTS:A total of 394 patients completed follow-up investigations. POCD Stage 1 was observed in 105 (26.6%), POCD Stage 2 in 52 patients (13.2%), and POCD Stage 3 in 30 patients (7.6%). The AT217term (ratio Aβ1-40/1-42 * p-tau217) was significantly associated with POCD stages in multiple logistic regression. DISCUSSION:Early Alzheimer's BBMs are associated with POCD in patients, suggesting that our exploratory findings assessing BBMs may support risk stratification, inform decision-making, and contribute to strategies aimed at preventing POCD.

Preserving cognitive and brain health is central for healthy aging. Cognitive reserve (CR) and brain maintenance (BM) support resilience against age- and disease-related cognitive decline. Physical fitness represents a plausible pathway to both CR and BM, yet the underlying neurobiological mechanisms remain insufficiently understood. This study examined how fitness relates to Alzheimer’s pathology and whether it moderates or mediates the pathology–cognition relationship. Data were obtained from 345 cognitively unimpaired older adults (mean age = 73.11 ± 8.03 years; 177 females) participating in the ongoing SFB1436 study. We assessed global cognition and delayed verbal memory performance, aerobic fitness (VO₂max), and muscular capacity. Blood biomarkers included plasma Aβ₁₋₄₂/Aβ₁₋₄₀, p-tau217, and GFAP (glial fibrillary acidic protein), and serum BDNF (brain-derived neurotrophic factor), VEGF (vascular endothelial growth factor), and Cathepsin-B. Neuroimaging measures comprised medial temporal lobe (MTL) tau burden ([¹⁸F]PI-2620 PET), MRI-derived hippocampal volumes, white matter hyperintensities, perivascular spaces (PVS) in basal ganglia (BG) and centrum semiovale, gray matter volume (GMV), and MTL thickness. To examine BM, we tested associations between fitness and brain pathology. To examine CR, we conducted moderation analyses assessing whether fitness attenuated the negative impact of pathology on cognition. Mediation analyses further evaluated whether hippocampal volume, total GMV, or MTL thickness mediated a potential association between fitness and cognition. All models controlled for age and sex (and education in mediation analyses), and multiple comparisons were FDR-corrected. Physical fitness was not related to cognitive performance. Higher muscular capacity was associated with lower BG PVS volumes, while higher aerobic fitness was related to higher MTL thickness and total GMV. Elevated MTL tau burden was associated with poorer verbal memory performance. Although physical fitness did not significantly moderate the tau–memory relationship, model comparison provided weak evidence for CR effects (p = .015). Muscular capacity was linked to lower BG PVS volumes, supporting resistance against pathology, while aerobic fitness related to preserved cortical integrity and tended to act as a CR proxy against MTL tau pathology. Physical fitness may support cerebrovascular and glymphatic function, thereby promoting cognitive resilience and extending healthspan by sustaining functional brain health and mitigating tau-related cognitive decline. The study was retrospectively registered in the German Clinical Trials Register (DRKS00032449; date of registration: 2025-05-07; recruiting ongoing).

Abstract INTRODUCTION Carriers of the ε4 allele of the apolipoprotein E (APOE) gene have an increased risk for Alzheimer's disease (AD) and amyloid‐related imaging abnormalities (ARIAs) upon anti‐amyloid beta (Αβ) immunotherapy. Measuring apoE4 and pan‐apoE proteins in blood plasma for apoE4 proteotyping may offer an alternative to APOE genotyping. METHODS We assessed apoE4 proteotyping accuracy in 479 participants of the prospective FINd DElirium RIsk factors (FINDERI) study in patients undergoing cardiac surgery and compared results to quantitative polymerase chain reaction (qPCR) genotyping. RESULTS Proteotype–genotype discordance occurred in 8 of 479 participants (1.67%). Five of 17 proteotype homozygotes were genotypically heterozygous. Replacing manufacturer provided cut points with custom data‐driven thresholds substantially improved classification performance. DISCUSSION We confirm the reported overall high classification performance of apoE4 proteotyping but underscore the need to re‐evaluate the generalizability of the cut points provided with the assay kits. Misclassification of heterozygous APOE ε4 carriers as homozygous could erroneously exclude eligible patients from anti‐amyloid therapies.

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.

[18F]PI-2620 is a second-generation tau PET tracer that may detect early tau accumulation in aging. We investigated whether temporal lobe [18F]PI-2620 binding is associated with age, sex, genetic Alzheimer disease (AD) risk, plasma biomarkers of AD (plasma phosphorylated tau 217 [p-tau217], Aβ1-42/Aβ1-40), astrogliosis (glial fibrillary acidic protein), and domain-specific cognition in cognitively unimpaired (CU) older adults. Methods: In this study, 166 CU older adults (mean age, 72 ± 7 y; females, 46%; apolipoprotein ϵ4 [APOE4] carriers, 23%) and 13 young adults underwent extensive cognitive testing, blood sampling, MRI, and dynamic [18F]PI-2620 PET (0-60 min postinjection). Associations of regional [18F]PI-2620 distribution volume ratio (DVR) with age, sex, APOE4 genotype, and plasma biomarkers were examined using region-of-interest and voxelwise analyses. Additional imaging markers of age-related pathology included hippocampal volume, medial temporal lobe thickness, white matter (WM) hyperintensities, perivascular spaces, and hippocampal perfusion (R1-derived maps). Associations among temporal lobe DVR, other imaging markers, and domain-specific cognitive performance (from factor analysis) were tested. Results: In older adults, temporal [18F]PI-2620 binding was higher in women (β = 0.543, P < 0.001) and APOE4 carriers (β = 0.395, P = 0.030) and was positively associated with plasma p-tau217 (β = 0.22, P = 0.008). Voxelwise analyses showed age-related increases in basal ganglia signal, whereas WM signal was higher in younger adults. In a multiple regression model, higher temporal DVR (β = -0.36, P = 0.003) and lower hippocampal volume (β = 0.22, P = 0.007) predicted worse episodic memory and, together with demographic factors, explained approximately 30% of the variance. Conclusion: Temporal [18F]PI-2620 binding is associated with genetic AD risk, plasma p-tau217, female sex, and episodic memory deficits in CU older adults, supporting its sensitivity to early tau pathology, while highlighting the need to consider potential WM binding.

Abstract The medial temporal lobe (MTL) is crucial for episodic memory. Tau pathology is a hallmark of Alzheimer’s disease (AD) and accumulates in layer-specific patterns in the MTL during aging. It is, however, unclear whether early AD pathology relates to mesoscale network signatures distinct from non-pathological aging. To address this gap, we acquired 7 Tesla submillimeter-resolution resting-state fMRI, plasma-based AD biomarkers, glial fibrillary acidic protein (GFAP) levels, APOE genotype, regional [ 18 F]PI-2620 tau PET burden, and longitudinal episodic memory data in 75 cognitively unimpaired older adults. Older age was associated with lower perirhinal– hippocampal connectivity and lower network segregation, whereas higher plasma-based AD pathology was associated with higher perirhinal–hippocampal connectivity. Furthermore, temporal-lobe tau burden was related to altered connectivity patterns in tau-vulnerable MTL subfields and layers, dependent on GFAP levels. Retrosplenial tau burden was associated with higher hippocampal-retrosplenial connectivity consistent with tau spread along canonical hippocampal output pathways. Finally, higher connectivity within the hippocampus attenuated the negative association between temporal-lobe tau burden and memory performance but predicted unfavorable memory trajectories. Our findings show differential associations of age and AD pathology with mesoscale MTL-connectivity patterns. Importantly, increased hippocampal connectivity may support memory function in the short term while contributing to subsequent memory decline.

While aging almost inevitably leads to some degree of cognitive decline, the interindividual heterogeneity in the trajectories of decline raises the question of the extent to which resistance against pathology and cognitive resilience are involved. Using a multimodal approach including neuroimaging, fitness assessment, questionnaire data, and Alzheimer's disease (AD) genetic risk and plasma biomarkers (Figure 1), we aimed to characterize latent structures of lifestyle, mental and bodily health, estimate indices of brain (pathological) and cognitive aging, and relate lifestyle/health profiles and AD genetic risk to these indices. We analyzed a subsample of 211 cognitively normal older adults aged ≥ 60 years from an ongoing study (CRC1436) (age=71.0±7.4years, 46% female). Using principal component analysis, we derived seven principal components (PCs) that capture latent structures of lifestyle and general health from thirty variables (Figure 2B). To characterize successful brain/cognitive aging, we calculated a brain (BAG) and cognitive age gap (CAG) as the difference between brain pathology-/cognition-predicted age and chronological age (Figure 2A). Our novel BAG estimate incorporated also AD pathology, white matter hyperintensities and enlarged perivascular spaces. We regressed the first seven principal components (PC) on BAG and CAG to estimate the association of lifestyle/health profiles with successful brain/cognitive aging. We further assessed whether APOE4 carriers had higher BAG/CAG using a two-sample t-test. We named the PCs according to their main factor loadings (Figure 2B). PC1 ( Low Mental Health) , PC2 ( Active Life) , and PC5 ( Mentally Inactive & Physically Active) were significantly associated with CAG, whereas only PC2 was significantly associated with BAG (Figure 3A). BAG partly explained the relationship between PC2 and CAG (partial mediation of 18.0% of total effect, p  = 0.027; Figure 3B). Finally, APOE e4 carrier had significantly higher BAG ( p  = 0.049), but not CAG ( p  = 0.155). Our results suggest that factors of cognitive resilience and brain maintenance are to some extent unified in an active lifestyle described by physical fitness, mental leisure activities, and lower cardiovascular risk. In addition, engagement in mental leisure activities may explain cognitive resilience independent of brain pathology. Finally, genetic risk for AD may also accelerate brain aging in cognitively healthy older adults.

Background:Postoperative delirium (POD) is a severe complication following cardiac surgery and is associated with increased morbidity and mortality. The impact of intra- and early postoperative factors on the occurrence of POD following cardiac surgery remains controversial. To close this gap, we investigated intra- and early postoperative factors and their predictive values for POD. Methods:We performed a prospective observational study that aimed to FIND DElirium RIsk factors (FINDERI) for patients undergoing elective cardiac surgery. POD was assessed using the Confusion Assessment Method algorithm. Intra- and early postoperative factors were extracted from electronic medical records and reviewed by cardiac surgeons. To identify potential predictors of POD, we used univariate and multivariate logistic regression along with machine learning (ML) with ten-fold cross-validation. Results:In our study cohort of 490 patients, 106 screened positive for POD (21.6%). In the multivariate analysis, we found a positive association between POD occurrence and age (P < 0.001), duration of surgery (P = 0.027), combined (versus isolated) surgical procedures (P = 0.024), opening of the cardiac chambers (P = 0.046), and ventilation time (P < 0.001). The ML-based decision tree identified a two level-algorithm including ventilation time and aortic cross-clamping time, with an AUC of 0.7116 (P = 0.0002) in the validation set. In the ML-based LASSO regression analysis, we identified ventilation time, administration of erythrocyte concentrates (EC), and usage of cardiopulmonary bypass (CPB) as predictors of POD, with an AUC of 0.7407 (P < 0.0001) in the validation set. Conclusion:The results of this analysis highlight the associations between ventilation time, aortic cross-clamping time, administration of EC, and usage of CPB and POD. Additionally, they suggest that the optimization of surgical protocols has the potential to reduce POD risk in individuals undergoing cardiac surgery.

Cognitive reserve (CR) and brain maintenance enable the brain to maintain performance despite injury and disease while also reducing neural decline by safeguarding brain structure and function. Physical activity is a potential pathway to BM and CR, as fitness relates to better cognition in older adults, though the underlying mechanisms remain unclear. To explore the role of physical fitness in BM and CR, we tested its association with brain pathology and its potential moderation of pathology's impact on cognitive performance. We collected data from 167 cognitively unimpaired participants (mean age 71.57±7.50 years; 70 females) of the ongoing SFB1436 study ( www.sfb1435.de ; Figure 1). We collected many markers, including global and verbal cognitive performance; aerobic (VO 2max ) and muscular capacity; blood-based biomarkers of Alzheimer's disease (plasma Aβ1-42/1-40, ptau217) and plasticity (serum BDNF, VEGF and Cathepsin-B); PET-derived medial temporal lobe tau burden (MTL DVR, 18 F-PI-2620 PET); and MRI-derived volumes of hippocampi, white matter hyperintensities, and perivascular spaces (PVS) in the basal ganglia (BG) and centrum semiovale regions. The tests were two-fold. We first tested whether fitness was associated with lower MTL DVR values, reduced MRI-derived volumes of brain pathology, and better cognition. Using moderation analysis, we then tested whether physical fitness moderated the relationship between pathology and cognition. We relied on ANOVA for model comparison. We adjusted models for age and sex and FDR-corrected multiple comparisons. Participants with better aerobic capacity (VO 2max ) had lower BG-PVS volumes (Figure 2a) and better global cognitive performance. Those with higher MTL tau burden had worse verbal memory (Figure 2b). We found no evidence of a relationship between physical fitness and Alzheimer's markers, plasticity-related markers, or hippocampal volume. Moderation analysis revealed that physical fitness did not moderate the relationship between MTL tau burden and verbal memory, but model comparison revealed weak evidence for CR against MTL tau. We demonstrated that aerobic fitness is related to lower BG-PVS volumes in old age and showed that aerobic fitness tends to act as CR proxy against MTL tau pathology. Aerobic fitness may help maintain cerebrovascular and glymphatic dysfunction in old age, thereby mitigating cognitive decline.

Postoperative delirium (POD) following cardiac surgery is a severe complication. There is evidence of a link between neuroinflammation and neurodegeneration in POD. We investigated the preoperative proinflammatory interleukin-6 (IL-6) and neuronal damage marker phosphorylated tau protein 181 (p-tau181) to POD while considering preoperative heart-brain axis related factors. The prospective FINd DElirium RIsk factors (FINDERI) is an observational study in patients undergoing cardiac surgery. Biomarkers IL-6 and p-tau181 were measured in blood samples. For statistics, we utilized multiple logistic regression analyses and advanced machine learning techniques. In 491 patients, 106 (21.6%) developed POD. The age of patients with POD was significantly higher than that of patients without POD (p < 0.001). Preoperative IL-6 and p-tau181 levels independently predicted POD [IL-6: area under the curve (AUC) = 0.605, p < 0.005; p-tau181: AUC = 0.641, p < 0.0001)]. A multiple logistic regression analysis of preoperative log-transformed biomarkers levels (p-tau181, IL-6), female sex and cognitive performance increased the AUC (0.710, p < 0.0001) in predicting POD. We created a decision tree prediction model including preoperative p-tau181, IL-6, and the severity of mitral valve disease (training data: AUC = 0.672, p < 0.0001; validation data: AUC = 0.642, p < 0.05). The LASSO regression showed an increased AUC in the training (0.751, p < 0.0001) and validation dataset (0.652, p < 0.05). Our results demonstrate that the combined assessment of preoperatively measured p-tau181 and IL-6, preoperative mitral valve disease, cognitive performance and female sex, significantly predicts POD. These findings provide evidence that neuroinflammation and neuronal cell damage are associated with POD.

While some memory decline in old age is “normal”, there are some older individuals with maintained high cognitive performance. Using a multimodal approach including neuroimaging, fitness, genetic and questionnaire data (Figure 1A), we aimed to identify factors that are related to successful cognitive aging and whether these differ between sexes. We analyzed 165 cognitively normal older adults age ≥ 60 years from an ongoing study (SFB1436) (age=71±8years, 43% female). For all participants, we determined plasma Abeta 1-42 /Abeta 1-40 . Temporal lobe tau burden was estimated by [ 18 F]PI-2620 in a subsample (see Figure 1A for sample sizes). We assessed global white matter hyperintensity (WMH) volumes and gray matter thickness for medial temporal lobe (MTL), anterior cingulate cortex (ACC) and whole brain. We measured aerobic and muscular capacity (and blood pressure) by fitness assessment and trait/state anxiety by self-reports. Genetic profiling included KLOTHO and KIBRA polymorphisms and APOE genotype. To phenotype successful cognitive aging, we i) grouped individuals age ≥ 79.5 years into SuperAgers (N=18) based on delayed verbal recall performance ≥ normative values at age of 50-60 years versus typical agers (N=19). For the whole sample we ii) calculated cognitive age gap (CAG) as the difference between cognition-predicted age and chronological age (Figure 3A). We assessed how markers of pathology, brain structure, fitness, mental health and genetics were related to CAG, covarying for chronological age, sex and education. SuperAgers and typical agers did not differ in age, sex, education, fitness, anxiety or Abeta42/40 (all p-values>0.1). However, SuperAgers had less WMH volume, higher ACC thickness, lower blood pressure and less temporal lobe tau-tracer binding (small subgroup; ). In the whole sample, younger cognitive age related to higher MTL and global cortical thickness, less temporal tau-tracer binding, less anxiety (all p<0.05; Figure 3B) and marginally to higher muscular capacity (p=.06). Only the association between anxiety measures and CAG was moderated by sex (Figure 3B). CAG was not related to genotype. Our results suggest that successful cognitive aging is related to resistance against age-related pathology and higher brain integrity. Younger cognitive age is linked to better mental health, especially in females.

INTRODUCTION:Structural magnetic resonance imaging (MRI) often lacks diagnostic, prognostic, and monitoring value in Alzheimer's disease (AD), particularly in early disease stages. To improve its utility, we aimed to identify optimal atrophy markers for different intended uses. METHODS:We included 363 older adults; cognitively unimpaired individuals who were negative or positive for amyloid beta (Aβ) and Aβ-positive patients with subjective cognitive decline, mild cognitive impairment, or dementia of the Alzheimer type. MRI and neuropsychological assessments were administered annually for up to 3 years. RESULTS:Accelerated atrophy of medial temporal lobe subregions was evident already during preclinical AD. Symptomatic disease stages most notably differed in their hippocampal and parietal atrophy signatures. Atrophy-cognition relationships varied by intended use and disease stage. DISCUSSION:With the appropriate marker, MRI can detect abnormal atrophy already during preclinical AD. To optimize performance, atrophy markers should be tailored to the targeted disease stage and intended use. HIGHLIGHTS:Subregional atrophy markers detect ongoing atrophy in preclinical Alzheimer's disease (AD). Subjective cognitive decline in preclinical AD links to manifest atrophy. Optimal atrophy markers differ by the disease stage and intended use.

Plasma phosphorylated Tau217 (pTau217) represents a sensitive blood-based biomarker for Alzheimer’s disease (AD). This study investigated the performance of plasma pTau217 alone and as a composite score (Aβ1-40/Aβ1-42*pTau217) for detecting low Aβ1-42/1-40 in cerebrospinal fluid (CSF) as a surrogate marker of brain β-amyloid pathological changes. We analysed plasma samples from 82 pre-selected participants who were dichotomized according to their CSF Aβ42/40 ratio after data-driven cutoff determination by Gaussian mixture modelling. The study cohort included patients in very early disease stages with mild cognitive impairment (MCI) due to AD and mild dementia due to AD in the Aβ-positive group and MCI due to other causes and mild dementia due to other causes in the Aβ-negative group. Concentrations of plasma pTau181 and pTau217 were determined on the fully automated LUMIPULSE platform. Additionally, plasma Aβ1-42/1-40 and pTau217 were assessed after consecutive Aβ- and Tau-immunoprecipitations (IPs). Corrections for age and sex effects in primary variables were done using a multivariate linear model on a logarithmic scale. Results are reported using both adjusted and unadjusted values. After adjustment for age and sex, median plasma pTau217 was increased by 203

Alzheimer's Disease (AD) pathology accumulates early in the medial temporal lobe (MTL), crucial for spatial navigation. As spatial navigation is among the first cognitive functions affected by AD, it may benefit from targeted behavioral interventions. We investigated the potential of a novel smartphone‐assisted real‐world wayfinding training, tailored for healthy older adults, to improve their spatial abilities and explored associations with hippocampal vascularization and AD biomarkers. 38 cognitively healthy older adults (62–84 years; 18 females) participated in a 3‐week navigation training, using our smartphone application “Explore” (Figure 1). Training involved finding several locations displayed on a map in the medical campus area of Magdeburg, Germany, while GPS data were recorded. Pre‐ and post‐training, participants underwent fMRI, performed a pointing task in a virtual campus version, and completed the VWLT. At pre‐assessment, AD pathology was characterized by plasma sampling (Abeta1‐42/1‐40, Ptau217) and [18F]PI‐2620 PET in a subsample. Hippocampal vascularization was assessed by 7T angiography. Performance in the virtual pointing task and a map drawing test was compared to a control group ( n = 20) who performed a walking task of equal length without a navigational component. Additionally, changes in different mobile wayfinding performance indicators and their associations with AD biomarkers and hippocampal vascularization (i.e., mean distance of hippocampus to surrounding vessels) were examined. Performance in the pointing task and map drawing, but not in the VWLT ( p = .321), significantly improved due to the training (all p <.001; Figure 2A C). The control group showed no improvements in navigation. Training benefits were also evident in the mobile data (all p ≤.017; Figure 3A‐E). Better wayfinding efficiency was associated with less vessel distance to hippocampus, r=.44, p = .012, and the number of orientation stops was negatively related to pTau217, r=‐.38, p = .019 (Figure 3F). We provide evidence that a remotely administered real‐world wayfinding training enhances wayfinding abilities and improves spatial memory in older adults. Importantly, hippocampal vascularization may benefit wayfinding efficiency. Higher pTau217 was related to fewer orientation stops during navigation. As a next step, potential mediating effects between vascularization and AD pathology on wayfinding performance will be investigated.

A history of viral infection has been associated with a higher risk for psychiatric disorders. One potential underlying mechanism is that antiviral immunological responses could trigger cross-reactivity between viral and neural antigens, which would raise the co-occurrence of antiviral antibodies and anti-neural autoantibodies. We studied 619 patients’ psychiatric diagnoses from the Department of Psychiatry and Psychotherapy, University Medical Center Göttingen, Germany. Anti-neural autoantibodies and antiviral antibody specific indices were measured in serum and/or cerebrospinal fluid (CSF) from all patients. Among these 619 patients, 115 tested positive for serum and/or CSF neural autoantibodies (18.6

Objectives: Mild cognitive impairment (MCI) is a heterogeneous clinical syndrome and is important for the diagnosis and management of Alzheimer’s disease (AD). With the expansion of biomarker-based diagnostics, the aim of this study is to clarify the current attitudes towards and the use of MCI, and MCI due to AD, in German memory clinics. Methods: An online survey (50 items) was performed in 2022 among specialized clinicians (N = 45) in German memory clinics to assess the use of MCI and biomarkers in current diagnosis and treatment. Attitudinal and frequency items were assessed with a five-point numeric scale (strongly disagree = 1 to completely agree = 5 and never = 1 to always = 5, respectively). Results: All respondents used MCI as a clinical diagnosis. The benefits of diagnosing MCI were labeling deficits as disease symptoms (M = 4.4, SD = 0.7), improving coping with symptoms (M = 4.1, SD = 0.9), and motivating risk reduction activities (M = 4.0, SD = 0.9). Overall, 37 respondents used specialized diagnostic criteria for MCI due to AD, and all had access to biomarker diagnostics. Patients with MCI due to AD received more frequent counseling on memory training (p < 0.001), other non-pharmacological treatments (p < 0.001), and antidementive drug treatment (p < 0.001) than patients with MCI of other etiologies. Acetylcholinesterase inhibitors were prescribed significantly more frequently to patients with MCI due to AD (p < 0.001) compared to other MCI patients. Conclusions: MCI is commonly used as a clinical diagnosis in German memory clinics. AD biomarker assessment is well established and influences patient counseling and treatment recommendations.

Resistance to age-related pathological changes (brain maintenance), including Alzheimer’s disease, cerebrovascular disease, and neurodegeneration may promote cognitive resilience in aging. However, how lifestyle and health profiles relate to successful cognitive and brain aging remains poorly understood. In a novel, deeply phenotyped cohort of 211 cognitively unimpaired older adults (age = 71.0 ± 7.4 years, 46

Regions of the medial temporal lobe and posteromedial cortex are crucial for episodic memory and are among the first to be affected by Alzheimer´s disease (AD) pathology. Hyperconnectivity in association with amyloid and tau pathology has been found in preclinical stages of AD, and may be compensatory or detrimental to memory function. Aiming to identify distinct connections displaying aberrant resting-state functional connectivity (rsFC), we hypothesized lower rsFC with higher age in non-pathological aging, and higher rsFC with higher pathology burden, especially in APOE4 carriers. In this preregistered study, we analysed cross-sectional resting-state fMRI data and blood- and PET-markers of amyloid, tau and APOE status from an observational aging cohort (SFB1436). RsFC strength was examined between predefined ROIs. The sample included 187 cognitively unimpaired older adults (71±7years, 92 female, 44 APOE4 carrier). We investigated associations between rsFC, AD pathology burden, and CAG (cognitive age gap) and potential APOE interactions. Multiple regression models and a moderation analysis with rsFC strength were used. An A-T- subcohort was formed to investigate the effect of age on rsFC and to differentiate it from the effect of pathology. We found a significant association between higher blood-based pathology and low rsFC in the right posterior hippocampus to bilateral subgenual medial prefrontal cortex (mPFC). No significant association was observed between rsFC and tau-PET burden, APOE4 status or age (within A-T-subcohort). Additionally, there was no significant effect of pathology on CAG. Furthermore, we found no evidence of rsFC moderating the relationship between pathology and CAG. Our results do not support the initial hypothesis, which predicted hyperconnectivity in distinct brain regions with high pathology. This could be due to relatively low overall pathology burden, consistent with an early preclinical stage of potential disease progression. This interpretation is further supported by the absence of significant associations between pathology or rsFC strength and memory performance. We identified lower rsFC strength in two distinct connections with higher blood-based pathology. These alterations were not observed in the A-T- subcohort, suggesting it to be an early marker differentiating pathological from healthy aging.

Objective: Postoperative delirium (POD) is a common complication of cardiac surgery that is associated with higher morbidity, longer hospital stay, cognitive decline, and mortality. Preoperative assessments may help to identify patients' POD risk. However, a standardized screening assessment for POD risk has not been established. Design: Prospective observational FINd DElirium RIsk factors (FINDERI) study. Participants: Patients aged >= 50 years undergoing cardiac surgery. Measurements: The primary aim was to analyze the predictive value of the Delirium Risk Screening Questionnaire (DRSQ) prior to cardiac surgery. Secondary aims are to investigate cognitive, frailty, and geriatric assessments, and to use data -driven machine learning (ML) in predicting POD. Predictive properties were assessed using receiver operating characteristics analysis and multivariate approaches (regularized LASSO regression and decision trees). Results: We analyzed a data set of 504 patients (68.3 8.2 years, 21.4% women) who underwent cardiac surgery. The incidence of POD was 21%. The preoperatively administered DRSQ showed an area under the curve (AUC) of 0.68 (95% CI 0.62, 0.73), and the predictive OR was 1.25 (95% CI 1.15, 1.35, p <0.001). Using a ML approach, a three -rule decision tree prediction model including DRSQ (score>7), Trail Making Test B (time>118), and Montreal Cognitive Assessment (score <= 22) was identified. The AUC of the three -rule decision tree on the training set was 0.69 (95% CI 0.63, 0.75) and 0.62 (95% CI 0.51, 0.73) on the validation set. Conclusion: Both the DRSQ and the three -rule decision tree might be helpful in predicting POD risk before cardiac surgery.