Symptomatic Clusters Related to Amyloid Positivity in Cognitively Unimpaired Individuals.

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 Aß42/40 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 Aß42/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.

Plasma extracellular vesicle tau and TDP-43 as diagnostic biomarkers in FTD and ALS.

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.

Plasma amyloid beta X-42/X-40 ratio and cognitive decline in suspected early and preclinical Alzheimer's disease.

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 (Aß)X-40 and AßX-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 Aß42/40 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 AßX-42/X-40 ratios were associated with negative PACC5 slopes, suggesting cognitive decline. DISCUSSION: Our results suggest that assessing the plasma AßX-42/X-40 ratio via our semiautomated IP-IA is a promising biomarker when examining patients with early or preclinical AD. HIGHLIGHTS: New plasma Aß42/Aß40 measurement using immunoprecipitation-immunoassay Plasma Aß42/Aß40 associated with longitudinal cognitive decline Promising biomarker to detect subjective cognitive decline at-risk for brain amyloid positivity.

Inferior Frontal Sulcal Hyperintensities on Brain MRI Are Associated with Amyloid Positivity beyond Age-Results from the Multicentre Observational DELCODE Study.

Inferior frontal sulcal hyperintensities (IFSHs) on fluid-attenuated inversion recovery (FLAIR) sequences have been proposed to be indicative of glymphatic dysfunction. Replication studies in large and diverse samples are nonetheless needed to confirm them as an imaging biomarker. We investigated whether IFSHs were tied to Alzheimer's disease (AD) pathology and cognitive performance. We used data from 361 participants along the AD continuum, who were enrolled in the multicentre DELCODE study. The IFSHs were rated visually based on FLAIR magnetic resonance imaging. We performed ordinal regression to examine the relationship between the IFSHs and cerebrospinal fluid-derived amyloid positivity and tau positivity (Aß42/40 ratio ≤ 0.08; pTau181 ≥ 73.65 pg/mL) and linear regression to examine the relationship between cognitive performance (i.e., Mini-Mental State Examination and global cognitive and domain-specific performance) and the IFSHs. We controlled the models for age, sex, years of education, and history of hypertension. The IFSH scores were higher in those participants with amyloid positivity (OR: 1.95, 95% CI: 1.05-3.59) but not tau positivity (OR: 1.12, 95% CI: 0.57-2.18). The IFSH scores were higher in older participants (OR: 1.05, 95% CI: 1.00-1.10) and lower in males compared to females (OR: 0.44, 95% CI: 0.26-0.76). We did not find sufficient evidence linking the IFSH scores with cognitive performance after correcting for demographics and AD biomarker positivity. IFSHs may reflect the aberrant accumulation of amyloid ß beyond age.

Short communication: Lifetime musical activity and resting-state functional connectivity in cognitive networks.

BACKGROUND: Participation in multimodal leisure activities, such as playing a musical instrument, may be protective against brain aging and dementia in older adults (OA). Potential neuroprotective correlates underlying musical activity remain unclear. OBJECTIVE: This cross-sectional study investigated the association between lifetime musical activity and resting-state functional connectivity (RSFC) in three higher-order brain networks: the Default Mode, Fronto-Parietal, and Salience networks. METHODS: We assessed 130 cognitively unimpaired participants (≥ 60 years) from the baseline cohort of the DZNE-Longitudinal Cognitive Impairment and Dementia Study (DELCODE) study. Lifetime musical activity was operationalized by the self-reported participation in musical instrument playing across early, middle, and late life stages using the Lifetime of Experiences Questionnaire (LEQ). Participants who reported musical activity during all life stages (n = 65) were compared to controls who were matched on demographic and reserve characteristics (including education, intelligence, socioeconomic status, self-reported physical activity, age, and sex) and never played a musical instrument (n = 65) in local (seed-to-voxel) and global (within-network and between-network) RSFC patterns using pre-specified network seeds. RESULTS: Older participants with lifetime musical activity showed significantly higher local RSFC between the medial prefrontal cortex (Default Mode Network seed) and temporal as well as frontal regions, namely the right temporal pole and the right precentral gyrus extending into the superior frontal gyrus, compared to matched controls. There were no significant group differences in global RSFC within or between the three networks. CONCLUSION: We show that playing a musical instrument during life relates to higher RSFC of the medial prefrontal cortex with distant brain regions involved in higher-order cognitive and motor processes. Preserved or enhanced functional connectivity could potentially contribute to better brain health and resilience in OA with a history in musical activity. TRIAL REGISTRATION: German Clinical Trials Register (DRKS00007966, 04/05/2015).

Single-value brain activity scores reflect both severity and risk across the Alzheimer's continuum.

Single-value scores reflecting the deviation from (FADE score) or similarity with (SAME score) prototypical novelty-related and memory-related functional magnetic resonance imaging (fMRI) activation patterns in young adults have been proposed as imaging biomarkers of healthy neurocognitive aging. Here, we tested the utility of these scores as potential diagnostic and prognostic markers in Alzheimer's disease (AD) and risk states like mild cognitive impairment (MCI) or subjective cognitive decline (SCD). To this end, we analyzed subsequent memory fMRI data from individuals with SCD, MCI, and AD dementia as well as healthy controls (HC) and first-degree relatives of AD dementia patients (AD-rel) who participated in the multi-center DELCODE study (N = 468). Based on the individual participants' whole-brain fMRI novelty and subsequent memory responses, we calculated the FADE and SAME scores and assessed their association with AD risk stage, neuropsychological test scores, CSF amyloid positivity, and ApoE genotype. Memory-based FADE and SAME scores showed a considerably larger deviation from a reference sample of young adults in the MCI and AD dementia groups compared to HC, SCD and AD-rel. In addition, novelty-based scores significantly differed between the MCI and AD dementia groups. Across the entire sample, single-value scores correlated with neuropsychological test performance. The novelty-based SAME score further differed between Aß-positive and Aß-negative individuals in SCD and AD-rel, and between ApoE ε4 carriers and non-carriers in AD-rel. Hence, FADE and SAME scores are associated with both cognitive performance and individual risk factors for AD. Their potential utility as diagnostic and prognostic biomarkers warrants further exploration, particularly in individuals with SCD and healthy relatives of AD dementia patients.

Machine Learning-Based Perivascular Space Volumetry in Alzheimer Disease.

OBJECTIVES: Impaired perivascular clearance has been suggested as a contributing factor to the pathogenesis of Alzheimer disease (AD). However, it remains unresolved when the anatomy of the perivascular space (PVS) is altered during AD progression. Therefore, this study investigates the association between PVS volume and AD progression in cognitively unimpaired (CU) individuals, both with and without subjective cognitive decline (SCD), and in those clinically diagnosed with mild cognitive impairment (MCI) or mild AD. MATERIALS AND METHODS: A convolutional neural network was trained using manually corrected, filter-based segmentations (n = 1000) to automatically segment the PVS in the centrum semiovale from interpolated, coronal T2-weighted magnetic resonance imaging scans (n = 894). These scans were sourced from the national German Center for Neurodegenerative Diseases Longitudinal Cognitive Impairment and Dementia Study. Convolutional neural network-based segmentations and those performed by a human rater were compared in terms of segmentation volume, identified PVS clusters, as well as Dice score. The comparison revealed good segmentation quality (Pearson correlation coefficient r = 0.70 with P < 0.0001 for PVS volume, detection rate in cluster analysis = 84.3%, and Dice score = 59.0%). Subsequent multivariate linear regression analysis, adjusted for participants' age, was performed to correlate PVS volume with clinical diagnoses, disease progression, cerebrospinal fluid biomarkers, lifestyle factors, and cognitive function. Cognitive function was assessed using the Mini-Mental State Examination, the Comprehensive Neuropsychological Test Battery, and the Cognitive Subscale of the 13-Item Alzheimer's Disease Assessment Scale. RESULTS: Multivariate analysis, adjusted for age, revealed that participants with AD and MCI, but not those with SCD, had significantly higher PVS volumes compared with CU participants without SCD (P = 0.001 for each group). Furthermore, CU participants who developed incident MCI within 4.5 years after the baseline assessment showed significantly higher PVS volumes at baseline compared with those who did not progress to MCI (P = 0.03). Cognitive function was negatively correlated with PVS volume across all participant groups (P ≤ 0.005 for each). No significant correlation was found between PVS volume and any of the following parameters: cerebrospinal fluid biomarkers, sleep quality, body mass index, nicotine consumption, or alcohol abuse. CONCLUSIONS: The very early changes of PVS volume may suggest that alterations in PVS function are involved in the pathophysiology of AD. Overall, the volumetric assessment of centrum semiovale PVS represents a very early imaging biomarker for AD.

A generalizable data-driven model of atrophy heterogeneity and progression in memory clinic settings.

Memory clinic patients are a heterogeneous population representing various aetiologies of pathological aging. It is unknown if divergent spatiotemporal progression patterns of brain atrophy, as previously described in Alzheimer's disease (AD) 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 ± SD age = 70.67 ± 6.07 years, 52% females). Participants were cognitively unimpaired (CU; n = 285) or fulfilled diagnostic criteria for subjective cognitive decline (SCD; n = 342), mild cognitive impairment (MCI; n = 118), or dementia of the Alzheimer's type (n = 68). Atrophy subtypes were compared in baseline demographics, fluid AD 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 if baseline atrophy subtype and stage predicted clinical trajectories before manifest cognitive impairment, we analysed PACC-5 trajectories and MCI conversion rates of CU and SCD participants. Limbic-predominant and hippocampal-sparing atrophy subtypes were identified. Limbic-predominant atrophy first affected the medial temporal lobes, followed by further temporal and, finally, the remaining cortical regions. At baseline, this subtype was related to older age, more pathological AD 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 AD biomarkers and was associated with more generalised cognitive impairment. Limbic-predominant atrophy, in all 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 MCI 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, both on the subject and group level, were 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 AD in applied settings. The implementation of atrophy subtype- and stage-specific end-points may increase the statistical power of pharmacological trials targeting early AD.

Aß oligomers peak in early stages of Alzheimer's disease preceding tau pathology.

INTRODUCTION: Soluble amyloid beta (Aß) oligomers have been suggested as initiating Aß related neuropathologic change in Alzheimer's disease (AD) but their quantitative distribution and chronological sequence within the AD continuum remain unclear. METHODS: A total of 526 participants in early clinical stages of AD and controls from a longitudinal cohort were neurobiologically classified for amyloid and tau pathology applying the AT(N) system. Aß and tau oligomers in the quantified cerebrospinal fluid (CSF) were measured using surface-based fluorescence intensity distribution analysis (sFIDA) technology. RESULTS: Across groups, highest Aß oligomer levels were found in A+ with subjective cognitive decline and mild cognitive impairment. Aß oligomers were significantly higher in A+T- compared to A-T- and A+T+. APOE Îµ4 allele carriers showed significantly higher Aß oligomer levels. No differences in tau oligomers were detected. DISCUSSION: The accumulation of Aß oligomers in the CSF peaks early within the AD continuum, preceding tau pathology. Disease-modifying treatments targeting Aß oligomers might have the highest therapeutic effect in these disease stages. Highlights: Using surface-based fluorescence intensity distribution analysis (sFIDA) technology, we quantified Aß oligomers in cerebrospinal fluid (CSF) samples of the DZNE-Longitudinal Cognitive Impairment and Dementia (DELCODE) cohortAß oligomers were significantly elevated in mild cognitive impairment (MCI)Amyloid-positive subjects in the subjective cognitive decline (SCD) group increased compared to the amyloid-negative control groupInterestingly, levels of Aß oligomers decrease at advanced stages of the disease (A+T+), which might be explained by altered clearing mechanisms.

Whole-body metabolic modelling reveals microbiome and genomic interactions on reduced urine formate levels in Alzheimer's disease.

In this study, we aimed to understand the potential role of the gut microbiome in the development of Alzheimer's disease (AD). We took a multi-faceted approach to investigate this relationship. Urine metabolomics were examined in individuals with AD and controls, revealing decreased formate and fumarate concentrations in AD. Additionally, we utilised whole-genome sequencing (WGS) data obtained from a separate group of individuals with AD and controls. This information allowed us to create and investigate host-microbiome personalised whole-body metabolic models. Notably, AD individuals displayed diminished formate microbial secretion in these models. Additionally, we identified specific reactions responsible for the production of formate in the host, and interestingly, these reactions were linked to genes that have correlations with AD. This study suggests formate as a possible early AD marker and highlights genetic and microbiome contributions to its production. The reduced formate secretion and its genetic associations point to a complex connection between gut microbiota and AD. This holistic understanding might pave the way for novel diagnostic and therapeutic avenues in AD management.

The comorbidity profiles and medication issues of patients with multiple system atrophy: a systematic cross-sectional analysis.

BACKGROUND: Multiple system atrophy (MSA) is a complex and fatal neurodegenerative movement disorder. Understanding the comorbidities and drug therapy is crucial for MSA patients' safety and management. OBJECTIVES: To investigate the pattern of comorbidities and aspects of drug therapy in MSA patients. METHODS: Cross-sectional data of MSA patients according to Gilman et al. (2008) diagnostic criteria and control patients without neurodegenerative diseases (non-ND) were collected from German, multicenter cohorts. The prevalence of comorbidities according to WHO ICD-10 classification and drugs administered according to WHO ATC system were analyzed. Potential drug-drug interactions were identified using AiDKlinik®. RESULTS: The analysis included 254 MSA and 363 age- and sex-matched non-ND control patients. MSA patients exhibited a significantly higher burden of comorbidities, in particular diseases of the genitourinary system. Also, more medications were prescribed MSA patients, resulting in a higher prevalence of polypharmacy. Importantly, the risk of potential drug-drug interactions, including severe interactions and contraindicated combinations, was elevated in MSA patients. When comparing MSA-P and MSA-C subtypes, MSA-P patients suffered more frequently from diseases of the genitourinary system and diseases of the musculoskeletal system and connective tissue. CONCLUSIONS: MSA patients face a substantial burden of comorbidities, notably in the genitourinary system. This, coupled with increased polypharmacy and potential drug interactions, highlights the complexity of managing MSA patients. Clinicians should carefully consider these factors when devising treatment strategies for MSA patients.

Fornix fractional anisotropy mediates the association between Mediterranean diet adherence and memory four years later in older adults without dementia.

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.

Association of latent factors of neuroinflammation with Alzheimer's disease pathology and longitudinal cognitive decline.

INTRODUCTION: We investigated the association of inflammatory mechanisms with markers of Alzheimer's disease (AD) pathology and rates of cognitive decline in the AD spectrum. METHODS: We studied 296 cases from the Deutsches Zentrum für Neurodegenerative Erkrankungen Longitudinal Cognitive Impairment and Dementia Study (DELCODE) cohort, and an extension cohort of 276 cases of the Alzheimer's Disease Neuroimaging Initiative study. Using Bayesian confirmatory factor analysis, we constructed latent factors for synaptic integrity, microglia, cerebrovascular endothelial function, cytokine/chemokine, and complement components of the inflammatory response using a set of inflammatory markers in cerebrospinal fluid. RESULTS: We found strong evidence for an association of synaptic integrity, microglia response, and cerebrovascular endothelial function with a latent factor of AD pathology and with rates of cognitive decline. We found evidence against an association of complement and cytokine/chemokine factors with AD pathology and rates of cognitive decline. DISCUSSION: Latent factors provided access to directly unobservable components of the neuroinflammatory response and their association with AD pathology and cognitive decline.

Fronto-striatal alterations correlate with apathy severity in behavioral variant frontotemporal dementia.

Structural and functional changes in cortical and subcortical regions have been reported in behavioral variant frontotemporal dementia (bvFTD), however, a multimodal approach may provide deeper insights into the neural correlates of neuropsychiatric symptoms. In this multicenter study, we measured cortical thickness (CTh) and subcortical volumes to identify structural abnormalities in 37 bvFTD patients, and 37 age- and sex-matched healthy controls. For seed regions with significant structural changes, whole-brain functional connectivity (FC) was examined in a sub-cohort of N = 22 bvFTD and N = 22 matched control subjects to detect complementary alterations in brain network organization. To explore the functional significance of the observed structural and functional deviations, correlations with clinical and neuropsychological outcomes were tested where available. Significantly decreased CTh was observed in the bvFTD group in caudal middle frontal gyrus, left pars opercularis, bilateral superior frontal and bilateral middle temporal gyrus along with subcortical volume reductions in bilateral basal ganglia, thalamus, hippocampus, and amygdala. Resting-state functional magnetic resonance imaging showed decreased FC in bvFTD between: dorsal striatum and left caudal middle frontal gyrus; putamen and fronto-parietal regions; pallidum and cerebellum. Conversely, bvFTD showed increased FC between: left middle temporal gyrus and paracingulate gyrus; caudate nucleus and insula; amygdala and parahippocampal gyrus. Additionally, cortical thickness in caudal, lateral and superior frontal regions as well as caudate nucleus volume correlated negatively with apathy severity scores of the Neuropsychiatry Inventory Questionnaire. In conclusion, multimodal structural and functional imaging indicates that fronto-striatal regions have a considerable influence on the severity of apathy in bvFTD.

The comorbidity and co-medication profile of patients with progressive supranuclear palsy.

BACKGROUND: Progressive supranuclear palsy (PSP) is usually diagnosed in elderly. Currently, little is known about comorbidities and the co-medication in these patients. OBJECTIVES: To explore the pattern of comorbidities and co-medication in PSP patients according to the known different phenotypes and in comparison with patients without neurodegenerative disease. METHODS: Cross-sectional data of PSP and patients without neurodegenerative diseases (non-ND) were collected from three German multicenter observational studies (DescribePSP, ProPSP and DANCER). The prevalence of comorbidities according to WHO ICD-10 classification and the prevalence of drugs administered according to WHO ATC system were analyzed. Potential drug-drug interactions were evaluated using AiDKlinik®. RESULTS: In total, 335 PSP and 275 non-ND patients were included in this analysis. The prevalence of diseases of the circulatory and the nervous system was higher in PSP at first level of ICD-10. Dorsopathies, diabetes mellitus, other nutritional deficiencies and polyneuropathies were more frequent in PSP at second level of ICD-10. In particular, the summed prevalence of cardiovascular and cerebrovascular diseases was higher in PSP patients. More drugs were administered in the PSP group leading to a greater percentage of patients with polypharmacy. Accordingly, the prevalence of potential drug-drug interactions was higher in PSP patients, especially severe and moderate interactions. CONCLUSIONS: PSP patients possess a characteristic profile of comorbidities, particularly diabetes and cardiovascular diseases. The eminent burden of comorbidities and resulting polypharmacy should be carefully considered when treating PSP patients.

Machine learning-based classification of Alzheimer's disease and its at-risk states using personality traits, anxiety, and depression.

BACKGROUND: Alzheimer's disease (AD) is often preceded by stages of cognitive impairment, namely subjective cognitive decline (SCD) and mild cognitive impairment (MCI). While cerebrospinal fluid (CSF) biomarkers are established predictors of AD, other non-invasive candidate predictors include personality traits, anxiety, and depression, among others. These predictors offer non-invasive assessment and exhibit changes during AD development and preclinical stages. METHODS: In a cross-sectional design, we comparatively evaluated the predictive value of personality traits (Big Five), geriatric anxiety and depression scores, resting-state functional magnetic resonance imaging activity of the default mode network, apoliprotein E (ApoE) genotype, and CSF biomarkers (tTau, pTau181, Aß42/40 ratio) in a multi-class support vector machine classification. Participants included 189 healthy controls (HC), 338 individuals with SCD, 132 with amnestic MCI, and 74 with mild AD from the multicenter DZNE-Longitudinal Cognitive Impairment and Dementia Study (DELCODE). RESULTS: Mean predictive accuracy across all participant groups was highest when utilizing a combination of personality, depression, and anxiety scores. HC were best predicted by a feature set comprised of depression and anxiety scores and participants with AD were best predicted by a feature set containing CSF biomarkers. Classification of participants with SCD or aMCI was near chance level for all assessed feature sets. CONCLUSION: Our results demonstrate predictive value of personality trait and state scores for AD. Importantly, CSF biomarkers, personality, depression, anxiety, and ApoE genotype show complementary value for classification of AD and its at-risk stages.

Relevance of Minor Neuropsychological Deficits in Patients With Subjective Cognitive Decline.

BACKGROUND AND OBJECTIVES: To determine the relevance of minor neuropsychological deficits (MNPD) in patients with subjective cognitive decline (SCD) with regard to CSF levels of Alzheimer disease (AD) biomarkers, cognitive decline, and clinical progression to mild cognitive impairment (MCI). METHODS: This study included patients with clinical SCD and SCD-free, healthy control (HC) participants with available baseline CSF and/or longitudinal cognitive data from the observational DZNE Longitudinal Cognitive Impairment and Dementia study. We defined MNPD as a performance of at least 0.5SD below the mean on a demographically adjusted total score derived from the Consortium to Establish a Registry for Alzheimer's Disease neuropsychological assessment battery. We compared SCD patients with MNPD and those without MNPD with regard to CSF amyloid-ß (Aß)42/Aß40, phosphorylated tau (p-tau181), total tau and Aß42/p-tau181 levels, longitudinal cognitive composite trajectories, and risk of clinical progression to incident MCI (follow-up M ± SD: 40.6 ± 23.7 months). In addition, we explored group differences between SCD and HC in those without MNPD. RESULTS: In our sample (N = 672, mean age: 70.7 ± 5.9 years, 50% female), SCD patients with MNPD (n = 55, 12.5% of SCD group) showed significantly more abnormal CSF biomarker levels, increased cognitive decline, and a higher risk of progression to incident MCI (HR: 4.07, 95% CI 2.46-6.74) compared with SCD patients without MNPD (n = 384). MNPD had a positive predictive value of 57.0% (95% CI 38.5-75.4) and a negative predictive value of 86.0% (95% CI 81.9-90.1) for the progression of SCD to MCI within 3 years. SCD patients without MNPD showed increased cognitive decline and a higher risk of incident MCI compared with HC participants without MNPD (n = 215; HR: 4.09, 95% CI 2.07-8.09), while AD biomarker levels did not differ significantly between these groups. DISCUSSION: Our results suggest that MNPD are a risk factor for AD-related clinical progression in cognitively normal patients seeking medical counseling because of SCD. As such, the assessment of MNPD could be useful for individual clinical prediction and for AD risk stratification in clinical trials. However, SCD remains a risk factor for future cognitive decline even in the absence of MNPD.

Cognitive Trajectories in Preclinical and Prodromal Alzheimer's Disease Related to Amyloid Status and Brain Atrophy: A Bayesian Approach.

Background: Cognitive decline is a key outcome of clinical studies in Alzheimer's disease (AD). Objective: To determine effects of global amyloid load as well as hippocampus and basal forebrain volumes on longitudinal rates and practice effects from repeated testing of domain specific cognitive change in the AD spectrum, considering non-linear effects and heterogeneity across cohorts. Methods: We included 1,514 cases from three cohorts, ADNI, AIBL, and DELCODE, spanning the range from cognitively normal people to people with subjective cognitive decline and mild cognitive impairment (MCI). We used generalized Bayesian mixed effects analysis of linear and polynomial models of amyloid and volume effects in time. Robustness of effects across cohorts was determined using Bayesian random effects meta-analysis. Results: We found a consistent effect of amyloid and hippocampus volume, but not of basal forebrain volume, on rates of memory change across the three cohorts in the meta-analysis. Effects for amyloid and volumetric markers on executive function were more heterogeneous. We found practice effects in memory and executive performance in amyloid negative cognitively normal controls and MCI cases, but only to a smaller degree in amyloid positive controls and not at all in amyloid positive MCI cases. Conclusions: We found heterogeneity between cohorts, particularly in effects on executive functions. Initial increases in cognitive performance in amyloid negative, but not in amyloid positive MCI cases and controls may reflect practice effects from repeated testing that are lost with higher levels of cerebral amyloid.

Long-term environmental enrichment is associated with better fornix microstructure in older adults.

Background: Sustained environmental enrichment (EE) through a variety of leisure activities may decrease the risk of developing Alzheimer's disease. This cross-sectional cohort study investigated the association between long-term EE in young adulthood through middle life and microstructure of fiber tracts associated with the memory system in older adults. Methods: N = 201 cognitively unimpaired participants (≥ 60 years of age) from the DZNE-Longitudinal Cognitive Impairment and Dementia Study (DELCODE) baseline cohort were included. Two groups of participants with higher (n = 104) or lower (n = 97) long-term EE were identified, using the self-reported frequency of diverse physical, intellectual, and social leisure activities between the ages 13 to 65. White matter (WM) microstructure was measured by fractional anisotropy (FA) and mean diffusivity (MD) in the fornix, uncinate fasciculus, and parahippocampal cingulum using diffusion tensor imaging. Long-term EE groups (lower/higher) were compared with adjustment for potential confounders, such as education, crystallized intelligence, and socio-economic status. Results: Reported participation in higher long-term EE was associated with greater fornix microstructure, as indicated by higher FA (standardized ß = 0.117, p = 0.033) and lower MD (ß = -0.147, p = 0.015). Greater fornix microstructure was indirectly associated (FA: unstandardized B = 0.619, p = 0.038; MD: B = -0.035, p = 0.026) with better memory function through higher long-term EE. No significant effects were found for the other WM tracts. Conclusion: Our findings suggest that sustained participation in a greater variety of leisure activities relates to preserved WM microstructure in the memory system in older adults. This could be facilitated by the multimodal stimulation associated with the engagement in a physically, intellectually, and socially enriched lifestyle. Longitudinal studies will be needed to support this assumption.

Whole-body modelling reveals microbiome and genomic interactions on reduced urine formate levels in Alzheimer's disease.

In this study, we aimed to understand the potential role of the gut microbiome in the development of Alzheimer's disease (AD). We took a multi-faceted approach to investigate this relationship. Urine metabolomics were examined in individuals with AD and controls, revealing decreased formate and fumarate concentrations in AD. Additionally, we utilized whole-genome sequencing (WGS) data obtained from a separate group of individuals with AD and controls. This information allowed us to create and investigate host-microbiome personalized models. Notably, AD individuals displayed diminished formate microbial secretion in these models. Additionally, we identified specific reactions responsible for the production of formate in the host, and interestingly, these reactions were linked to genes that have correlations with AD. This study suggests formate as a possible early AD marker and highlights genetic and microbiome contributions to its production. The reduced formate secretion and its genetic associations point to a complex connection between gut microbiota and AD. This holistic understanding might pave the way for novel diagnostic and therapeutic avenues in AD management.