Addition of inflammation-related biomarkers to the CAIDE model for risk prediction of all-cause dementia, Alzheimer's disease and vascular dementia in a prospective study.

BACKGROUND: It is of interest whether inflammatory biomarkers can improve dementia prediction models, such as the widely used Cardiovascular Risk Factors, Aging and Dementia (CAIDE) model. METHODS: The Olink Target 96 Inflammation panel was assessed in a nested case-cohort design within a large, population-based German cohort study (n = 9940; age-range: 50-75 years). All study participants who developed dementia over 20 years of follow-up and had complete CAIDE variable data (n = 562, including 173 Alzheimer's disease (AD) and 199 vascular dementia (VD) cases) as well as n = 1,356 controls were selected for measurements. 69 inflammation-related biomarkers were eligible for use. LASSO logistic regression and bootstrapping were utilized to select relevant biomarkers and determine areas under the curve (AUCs). RESULTS: The CAIDE model 2 (including Apolipoprotein E (APOE) ε4 carrier status) predicted all-cause dementia, AD, and VD better than CAIDE model 1 (without APOE ε4) with AUCs of 0.725, 0.752 and 0.707, respectively. Although 20, 7, and 4 inflammation-related biomarkers were selected by LASSO regression to improve CAIDE model 2, the AUCs did not increase markedly. CAIDE models 1 and 2 generally performed better in mid-life (50-64 years) than in late-life (65-75 years) sub-samples of our cohort, but again, inflammation-related biomarkers did not improve their predictive abilities. CONCLUSIONS: Despite a lack of improvement in dementia risk prediction, the selected inflammation-related biomarkers were significantly associated with dementia outcomes and may serve as a starting point to further elucidate the pathogenesis of dementia.

Subjective cognitive complaints and blood biomarkers of neurodegenerative diseases: a longitudinal cohort study.

BACKGROUND: Subjective cognitive complaints (SCC) have been mostly studied in the context of Alzheimer's disease in memory clinic settings. The potential of combining SCC with genetic information and blood biomarkers of neurodegenerative diseases for risk assessment of dementia and depression in the absence of dementia among community-dwelling older adults has so far not been explored. METHODS: Data were based on a population-based cohort of 6357 participants with a 17-year follow-up (ESTHER study) and a clinic-based cohort of 422 patients. Participants of both cohorts were grouped according to the diagnosis of dementia (yes/no) and the diagnosis of depression in the absence of dementia (yes/no). Participants without dementia included both cognitively unimpaired participants and cognitively impaired participants. Genetic information (APOE ε4 genotype) and blood-based biomarkers of neurodegenerative diseases (glial fibrillary acidic protein; GFAP, neurofilament light chain; NfL, phosphorylated tau181; p-tau181) were available in the ESTHER study and were determined with Simoa Technology in a nested case-control design. Logistic regression models adjusted for relevant confounders were run for the outcomes of all-cause dementia and depression in the absence of dementia. RESULTS: The results showed that persistent SCC were associated both with increased risk of all-cause dementia and of depression without dementia, independently of the diagnostic setting. However, the results for the ESTHER study also showed that the combination of subjective complaints with APOE ε4 and with increased GFAP concentrations in the blood yielded a substantially increased risk of all-cause dementia (OR 5.35; 95%CI 3.25-8.81, p-value < 0.0001 and OR 7.52; 95%CI 2.79-20.29, p-value < 0.0001, respectively) but not of depression. Associations of NfL and p-tau181 with risk of all-cause dementia and depression were not statistically significant, either alone or in combination with SCC, but increased concentrations of p-tau181 seemed to be associated with an increased risk for depression. CONCLUSION: In community and clinical settings, SCC predict both dementia and depression in the absence of dementia. The addition of GFAP could differentiate between the risk of all-cause dementia and the risk of depression among individuals without dementia.

Alzheimer's polygenic risk scores, APOE, Alzheimer's disease risk, and dementia-related blood biomarker levels in a population-based cohort study followed over 17 years.

BACKGROUND: In order to utilize polygenic risk scores (PRSs) for Alzheimer's disease (AD) in a meaningful way, influential factors (i.e. training set) and prediction across groups such as APOE e4 (APOE4) genotype as well as associations to dementia-related biomarkers should be explored. Therefore, we examined the association of APOE4 and various PRSs, based on training sets that utilized differing AD definitions, with incident AD and all-cause dementia (ACD) within 17 years, and with levels of phosphorylated tau181 (P-tau181), neurofilament light (NfL), and glial fibrillary acidic protein (GFAP) in blood. Secondarily, effect modification by APOE4 status and sex was examined. METHODS: In this prospective, population-based cohort study and nested case-control study, 9,940 participants in Germany were enrolled between 2000 and 2002 by their general practitioners and followed for up to 17 years. Participants were included in this study if dementia status and genetic data were available. A subsample of participants additionally had measurements of P-tau181, NfL, and GFAP obtained from blood samples. Cox and logistic regression analyses were used to assess the association of genetic risk (APOE genotype and PRSnoAPOE) with incident ACD/AD and log-transformed blood levels of P-tau181, NfL, and GFAP. RESULTS: Five thousand seven hundred sixty-five participants (54% female, aged 50-75years at baseline) were included in this study, of whom 464 received an all-cause dementia diagnosis within 17 years. The PRSs were not more predictive of dementia than APOE4. An APOE4 specific relationship was apparent with PRSs only exhibiting associations to dementia among APOE4 carriers. In the nested case-control study including biomarkers (n = 712), APOE4 status and polygenic risk were significantly associated to levels of GFAP in blood. CONCLUSIONS: The use of PRSs may be beneficial for increased precision in risk estimates among APOE4 carriers. While APOE4 may play a crucial etiological role in initial disease processes such as Aß deposition, the PRS may be an indicator of further disease drivers as well as astrocyte activation. Further research is necessary to confirm these findings, especially the association to GFAP.

The mediating role of personality traits in the association between childhood trauma and depressive symptoms in young adulthood.

BACKGROUND: The aim of this study was to investigate the mediating role of the Big 5 personality traits (extraversion, neuroticism, openness, agreeableness, conscientiousness) in the association between early traumatization and depressive symptoms in early adulthood (20-25-year-olds) in a German population-based sample. METHODS: A total of 3176 participants from the German National Cohort (NAKO) baseline with an age between 20 and 25 years were included in this investigation. The sum score of the 9-item-version of the Patient Health Questionnaire was used for assessment of depressive symptoms. A structural equation model was built to test the paths between childhood trauma, Big 5 personality traits and depressive symptoms. RESULTS: Overall, 10.7 % of the young adult sample had a PHQ-9 sum score of ten or higher. The final mediation model fitted well for young adults. We found evidence for a partial mediating effect of Big 5 personality traits. LIMITATIONS: We only adjusted for age, sex, and year of data collection and did not include biological factors in the model. CONCLUSION: Young adults with early trauma experiences have a risk for developing depressive symptoms in young adulthood. Personality traits, especially neuroticism, partially mediated the association between early trauma and depressive symptoms for young adults and should be recognized in preventive strategies.

High cholesterol levels change the association of biomarkers of neurodegenerative diseases with dementia risk: Findings from a population-based cohort.

INTRODUCTION: This study assessed whether in a population with comorbidity of neurodegenerative and cerebrovascular disease (mixed pathology) the association of glial fibrillary acidic protein (GFAP), neurofilament light chain (NfL), and phosphorylated tau181 (p-tau181) with dementia risk varied depending on levels of total cholesterol and apolipoprotein E (APOE) ε4 genotype. METHODS: Plasma biomarkers were measured using Simoa technology in 768 participants of a nested case-control study embedded within an ongoing population-based cohort. Logistic and spline regression models, and receiver operating characteristic curves were calculated. RESULTS: The strength of the association between GFAP and NfL with risk of a clinical diagnosis of dementia changed depending on cholesterol levels and on APOE ε4 genotype. No significant association was seen with p-tau181. DISCUSSION: In individuals with mixed pathology blood GFAP and NfL are better predictors of dementia risk than p-tau181, and their associations with dementia risk are amplified by hypercholesterolemia, also depending on APOE ε4 genotype. HIGHLIGHTS: Cholesterol levels changed the association of blood biomarkers with dementia risk. Blood biomarkers seem to perform differently in community- and clinic-based cohorts. Neurofilament light chain might be a biomarker candidate for dementia risk after stroke.

Association of Kidney Function With Development of Alzheimer Disease and Other Dementias and Dementia-Related Blood Biomarkers.

Importance: Previous research has suggested an association of kidney function with risk of Alzheimer disease (AD) or other dementias and dementia-related blood biomarkers, but a distinct association remains unclear. Objective: To evaluate the association of kidney function with risk of diagnosis of incident AD or dementia within 17 years and with the blood biomarkers neurofilament light (NfL), phosphorylated tau181 (p-tau181), and glial fibrillary acidic protein (GFAP). Design, Setting, and Participants: In this prospective, population-based cohort study and nested case-control study, 9940 participants in Germany were enrolled between 2000 and 2002 by their general practitioners and followed up for up to 17 years. Participants were included if information on dementia status and creatinine/cystatin C measurements were available. A subsample of participants additionally had measurements of NfL, p-tau181, and GFAP obtained from blood samples. Statistical analysis was performed from January 3 to November 25, 2022. Exposures: Impaired kidney function, based on estimated glomerular filtration rate less than 60 mL/min/1.73 m2 according to the 2021 Chronic Kidney Disease Epidemiology Collaboration creatinine-cystatin C equation. Main Outcomes and Measures: All-cause dementia, AD, and vascular dementia diagnosis, as well as log-transformed levels of NfL, p-tau181, and GFAP in blood. Results: Of 6256 participants (3402 women [54.4%]; mean [SD] age at baseline, 61.7 [6.6] years), 510 received an all-cause dementia diagnosis within 17 years of baseline. The dementia-related blood biomarker nested case-control sample included 766 participants. After adjusting for age and sex, impaired kidney function at baseline was not associated with a higher risk of all-cause dementia (hazard ratio [HR], 0.95; 95% CI, 0.69-1.29), AD (HR, 0.94; 95% CI, 0.55-1.63), or vascular dementia diagnosis (HR, 1.06; 95% CI, 0.65-1.70) within 17 years. In the cross-sectional analysis, after adjusting for age and sex, impaired kidney function was significantly associated with NfL and p-tau181 levels in blood (NfL: ß = 0.47 and P < .001; p-tau181: ß = 0.21 and P = .003). After adjusting for age and sex, significant associations with GFAP levels were evident only among men (men: ß = 0.31 and P = .006; women: ß = -0.12 and P = .11). Conclusions and Relevance: In this population-based study of community-dwelling adults, reduced kidney function was associated with increased levels of dementia-related blood biomarkers but not increased dementia risk. Kidney function might influence the accuracy of dementia-related blood biomarkers and should be considered in clinical translation.

Association of plasma biomarkers, p-tau181, glial fibrillary acidic protein, and neurofilament light, with intermediate and long-term clinical Alzheimer's disease risk: Results from a prospective cohort followed over 17 years.

INTRODUCTION: Blood biomarkers for Alzheimer's disease (AD) are the future of AD risk assessment. The aim of this study was to determine the association between plasma-measured phosphorylated tau (p-tau181), glial fibrillary acidic protein (GFAP), and neurofilament light (NfL) levels and risk of clinical AD incidence with consideration to the impact of cardiovascular health. METHODS: Within a community-based cohort, biomarker levels were measured at baseline using single molecule array technology in 768 participants (aged 50-75) followed over 17 years. Associations among biomarkers and AD, vascular dementia, and mixed dementia incidence were assessed. RESULTS: GFAP was associated with clinical AD incidence even more than a decade before diagnosis (9-17 years), while p-tau181 and NfL were associated with more intermediate AD risk (within 9 years). Significant interaction was detected between cardiovascular health and p-tau181/NfL. DISCUSSION: GFAP may be an early AD biomarker increasing before p-tau181 and NfL and the effect modifying role of cardiovascular health should be considered in biomarker risk stratification.

HSP70-HSP90 Chaperone Networking in Protein-Misfolding Disease.

Molecular chaperones and their associated co-chaperones are essential in health and disease as they are key facilitators of protein-folding, quality control and function. In particular, the heat-shock protein (HSP) 70 and HSP90 molecular chaperone networks have been associated with neurodegenerative diseases caused by aberrant protein-folding. The pathogenesis of these disorders usually includes the formation of deposits of misfolded, aggregated protein. HSP70 and HSP90, plus their co-chaperones, have been recognised as potent modulators of misfolded protein toxicity, inclusion formation and cell survival in cellular and animal models of neurodegenerative disease. Moreover, these chaperone machines function not only in folding but also in proteasome-mediated degradation of neurodegenerative disease proteins. This chapter gives an overview of the HSP70 and HSP90 chaperones, and their respective regulatory co-chaperones, and explores how the HSP70 and HSP90 chaperone systems form a larger functional network and its relevance to counteracting neurodegenerative disease associated with misfolded proteins and disruption of proteostasis.

The interplay of family history of depression and early trauma: associations with lifetime and current depression in the German national cohort (NAKO).

Introduction: Family history of depression and childhood maltreatment are established risk factors for depression. However, how these factors are interrelated and jointly influence depression risk is not well understood. The present study investigated (i) if childhood maltreatment is associated with a family history of depression (ii) if family history and childhood maltreatment are associated with increased lifetime and current depression, and whether both factors interact beyond their main effects, and (iii) if family history affects lifetime and current depression via childhood maltreatment. Methods: Analyses were based on a subgroup of the first 100,000 participants of the German National Cohort (NAKO), with complete information (58,703 participants, mean age = 51.2 years, 53% female). Parental family history of depression was assessed via self-report, childhood maltreatment with the Childhood Trauma Screener (CTS), lifetime depression with self-reported physician's diagnosis and the Mini-International Neuropsychiatric Interview (MINI), and current depressive symptoms with the depression scale of the Patient Health Questionnaire (PHQ-9). Generalized linear models were used to test main and interaction effects. Mediation was tested using causal mediation analyses. Results: Higher frequencies of the childhood maltreatment measures were found in subjects reporting a positive family history of depression. Family history and childhood maltreatment were independently associated with increased depression. No statistical interactions of family history and childhood maltreatment were found for the lifetime depression measures. For current depressive symptoms (PHQ-9 sum score), an interaction was found, with stronger associations of childhood maltreatment and depression in subjects with a positive family history. Childhood maltreatment was estimated to mediate 7%-12% of the effect of family history on depression, with higher mediated proportions in subjects whose parents had a depression onset below 40 years. Abuse showed stronger associations with family history and depression, and higher mediated proportions of family history effects on depression than neglect. Discussion: The present study confirms the association of childhood maltreatment and family history with depression in a large population-based cohort. While analyses provide little evidence for the joint effects of both risk factors on depression beyond their individual effects, results are consistent with family history affecting depression via childhood maltreatment to a small extent.

Multi-omic profiling reveals the ataxia protein sacsin is required for integrin trafficking and synaptic organization.

Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is a childhood-onset cerebellar ataxia caused by mutations in SACS, which encodes the protein sacsin. Cellular ARSACS phenotypes include mitochondrial dysfunction, intermediate filament disorganization, and progressive death of cerebellar Purkinje neurons. It is unclear why the loss of sacsin causes these deficits or why they manifest as cerebellar ataxia. Here, we perform multi-omic profiling in sacsin knockout (KO) cells and identify alterations in microtubule dynamics and mislocalization of focal adhesion (FA) proteins, including multiple integrins. Deficits in FA structure, signaling, and function can be rescued by targeting PTEN, a negative regulator of FA signaling. ARSACS mice possess mislocalization of ITGA1 in Purkinje neurons and synaptic disorganization in the deep cerebellar nucleus (DCN). The sacsin interactome reveals that sacsin regulates interactions between cytoskeletal and synaptic adhesion proteins. Our findings suggest that disrupted trafficking of synaptic adhesion proteins is a causal molecular deficit in ARSACS.

Association of the inflammation-related proteome with dementia development at older age: results from a large, prospective, population-based cohort study.

BACKGROUND: Chronic inflammation is a central feature of several forms of dementia. However, few details on the associations of blood-based inflammation-related proteins with dementia incidence have been explored yet. METHODS: The Olink Target 96 Inflammation panel was measured in baseline serum samples (collected 07/2000-06/2002) of 1782 older adults from a German, population-based cohort study in a case-cohort design. Logistic regression models were used to assess the associations of biomarkers with all-cause dementia, Alzheimer's disease, and vascular dementia incidence. RESULTS: During 17 years of follow-up, 504 participants were diagnosed with dementia, including 163 Alzheimer's disease and 195 vascular dementia cases. After correction for multiple testing, 58 out of 72 tested (80.6%) biomarkers were statistically significantly associated with all-cause dementia, 22 with Alzheimer's disease, and 33 with vascular dementia incidence. We identified four biomarker clusters, among which the strongest representatives, CX3CL1, EN-RAGE, LAP TGF-beta-1, and VEGF-A, were significantly associated with dementia endpoints independently from other inflammation-related proteins. CX3CL1 (odds ratio [95% confidence interval] per 1 standard deviation increase: 1.41 [1.24-1.60]) and EN-RAGE (1.41 [1.25-1.60]) were associated with all-cause dementia incidence, EN-RAGE (1.51 [1.25-1.83]) and LAP TGF-beta-1 (1.46 [1.21-1.76]) with Alzheimer's disease incidence, and VEGF-A (1.43 [1.20-1.70]) with vascular dementia incidence. All named associations were stronger among APOE ε4-negative subjects. CONCLUSION: With this large, population-based cohort study, we show for the first time that the majority of inflammation-related proteins measured in blood samples are associated with total dementia incidence. Future studies should concentrate not only on single biomarkers but also on the complex relationships in biomarker clusters.

Subjective short-term memory difficulties at ages 50-75 predict dementia risk in a community-based cohort followed over 17 years.

INTRODUCTION: Subjective cognitive decline (SCD) is an established precursor of dementia. However, the relationship between SCD and dementia has been mostly studied among people aged 65+. We aimed to assess the association between subjective memory difficulties at ages 50-75 with all-cause dementia and dementia-subtypes in a community-based cohort with long-term follow-up. METHODS: 6,190 individuals (51% female) aged 50-75 years (median age, 62) attending a general health examination (by a total of 684 general practitioners) in Saarland, Germany, in 2000-2002 were recruited for a community-based cohort study. Subjective difficulties regarding short-term and long-term memory were assessed at baseline with two simple yes/no questions. Associations with dementia (-subtypes) diagnoses during 17 years of follow-up were estimated by Cox proportional hazards models. RESULTS: 492 participants were diagnosed with dementia during 17 years of follow-up. Participants with short-term memory difficulties were at higher risk to receive incident all-cause dementia and vascular dementia diagnoses both within 0-9 years (age and sex adjusted hazard ratios (aHR), 1.80 and 2.00, respectively) and within 0-17 years (aHR 1.55 and 1.78, respectively) from recruitment (P < 0.05 in all cases). For clinical Alzheimer's disease, a significant association was only seen within the initial 6 years. There were no associations of long-term memory difficulties with any type of dementia. CONCLUSIONS: Subjective difficulties in short-term memory predict both intermediate and long-term risk of vascular and all-cause dementia even among late middle-age adults. These results underline the importance of cardiovascular disease prevention efforts well before old age for maintaining cognitive health.

The association between supportive social ties and autonomic nervous system function-differences between family ties and friendship ties in a cohort of older adults.

Supportive family and friendship ties can serve different functions and thus might show different associations with an individual's health. Particularly, older adults might show varying health benefits of different types of supportive ties depending on their marital and retirement status. Our aim is to analyze relationships between different types of supportive social ties and autonomic nervous system (ANS) function, a physiological indicator of health that can help to establish the biological plausibility of the association-measured by heart rate variability (HRV). We present cross-sectional linear regression analyses of a German cohort of community-dwelling older adults (2008-2010; n = 1,548; mean age = 68.7 years). Our findings indicate that supportive friendship ties show significant positive associations (i.e., higher HRV) in individuals that are either not married or above retirement age. Supportive family ties show significant positive associations in individuals below retirement age. Significant results vanish or are reduced after accounting for behavioral/physical and psychological/cognitive indicators. We conclude that programs supporting the development or maintenance of friendship ties might be especially beneficial in unmarried older adults and adults above retirement age. Supplementary Information: The online version contains supplementary material available at 10.1007/s10433-021-00638-2.

Type 2 diabetes mellitus and cognitive decline in older adults in Germany - results from a population-based cohort.

BACKGROUND: A large body of evidence supports a link between type 2 diabetes mellitus (T2DM) and cognitive function, including dementia. However, longitudinal studies on the association between T2DM and decline of cognitive function are scarce and reported mixed results, and we hence set out to investigate the cross-sectional and longitudinal association between T2DM and global as well as domain-specific cognitive performance. METHODS: We used multivariable regression models to assess associations of T2DM with cognitive performance and cognitive decline in a subsample of a population-based prospective cohort study (ESTHER). This subsample (n = 732) was aged 70 years and older and had participated in telephone-based cognitive function assessment (COGTEL) measuring global and domain-specific cognitive performance during the 5- and 8-year follow-up. RESULTS: Total COGTEL scores of patients with prevalent T2DM were 27.4 ± 8.3 and 29.4 ± 8.7 at the 5- and 8-year measurements, respectively, and were roughly two points lower than those of T2DM-free participants after adjustment for age and sex. In cross-sectional models, after adjustment for several potential confounders, performance in verbal short-term and long-term memory tasks was statistically significantly lower in participants with T2DM, but the association was attenuated after further adjustment for vascular risk factors. The difference in total COGTEL scores reflecting global cognitive function by T2DM status after full adjustment for confounders and vascular risk factors was equivalent to a decrement in global cognitive function associated with a four-year age difference. In longitudinal models, a statistically significantly stronger cognitive decline in patients with T2DM was observed for working memory. CONCLUSIONS: In this sample of older individuals, T2DM was associated with worse performance and stronger decline in a cognitive function test. Memory-related domains were found to be particularly sensitive to T2DM. Further large-scale prospective studies are needed to clarify potential T2DM-related predictors of cognitive decline and possible consequences on the abilities to perform patient self-management tasks in diabetes care.

How Welfare Regimes Moderate the Associations Between Cognitive Aging, Education, and Occupation.

OBJECTIVES: Previous studies have shown the importance of individual markers of cognitive reserve, such as education and occupation, for cognitive health in old age. However, there has been only little investigation so far on how this relationship varies across contexts. METHODS: We analyzed data from the Survey of Health, Ageing, and Retirement in Europe, using second-order latent growth models, to assess the moderating role of welfare regimes on the relationship between education and occupation skill level in explaining overall cognitive functioning and decline in old age. Our sample includes 13 European countries using data from 5 regular waves of the survey (2004-2007 and 2011-2015) and 2 retrospective ones (2008-2009 and 2017). Cognitive functioning was modeled as a latent variable measured by immediate and delayed recall, verbal fluency, and numeracy. RESULTS: 74,193 participants were included from the survey. Our analysis showed that the association of education with cognition was weaker overall in Scandinavian countries, but stronger in Southern European countries, relative to Bismarckian ones. However, educational differences in the decline of cognition were more pronounced only in Scandinavian compared to Bismarckian countries. Additionally, higher-skilled occupations in Scandinavian countries had better overall functioning compared to the same occupations in Bismarckian countries, but there was no difference in the decline in cognitive functioning. DISCUSSION: Our findings indicate that the associations of cognitive functioning and its decline with individuals' cognitive reserve markers (education and occupational skill level) vary according to welfare regimes, showing the importance of contextual factors in cognitive aging processes.

Risk of Late-Onset Depression and Cognitive Decline: Results From Inflammatory Proteome Analyses in a Prospective Population-Based Cohort Study.

OBJECTIVE: Research suggests that inflammation is linked to both late-onset depression (LOD) and cognitive decline, and that LOD might have biological underpinnings differentiating it from recurrent depression. Evidence from inflammatory proteome analyses in large prospective cohorts is scarce. The aim of this study was to assess whether and which inflammation-related biomarkers are associated with LOD, recurrent depression, and cognitive decline due to vascular pathology (vascular dementia). DESIGN: Ongoing population-based cohort study of older adults followed for up to 17 years with regard to clinical diagnosis of various age-related diseases (ESTHER study, n = 9,940). SETTING: Longitudinal cohort started in 2000-2002 in a community setting in Saarland, a southwestern German state. PARTICIPANTS: Subgroup of randomly selected participants of the ESTHER study (n = 1,665). MEASUREMENTS: Inflammatory biomarkers were measured with the Olink Target 96 in baseline samples. RESULTS: Out of 78 biomarkers interleukin 10 (IL-10) and C-C chemokine ligand 4 (CCL4) were associated with significantly increased risk of LOD after multiple testing correction. Hazard ratios (95-confidence interval) per 1 standard deviation increase were 1.37 (1.15-1.63) for IL-10 and 1.34 (1.13-1.59) for CCL4. None of the inflammatory markers was associated with recurrent depression. The dose-response analysis showed a similar monotonic risk increase for LOD and vascular dementia with increasing IL-10 levels. CONCLUSION: These results suggest that inflammatory markers are involved in the etiology of LOD, but not of recurrent depression and that LOD and vascular dementia might share common inflammatory etiology with respect to IL-10.

AlphaFold predicted structure of the Hsp90-like domains of the neurodegeneration linked protein sacsin reveals key residues for ATPase activity.

The ataxia-linked protein sacsin has three regions of partial homology to Hsp90's N-terminal ATP binding domain. Although a crystal structure for this Hsp90-like domain has been reported the precise molecular interactions required for ATP-binding and hydrolysis are unclear and it is debatable whether ATP biding is compatible with these domains. Furthermore, the Identification of a sacsin domain(s) equivalent to the middle domain of Hsp90 has been elusive. Here we present the superimposition of an AlphaFold structure of sacsin with yeast Hsp90, which provides novel insights into sacsin's structure. We identify residues within the sacsin Hsp90-like domains that are required for ATP binding and hydrolysis, including the putative catalytic arginine residues equivalent to that of the Hsp90 middle domain. Importantly, our analysis allows comparison of the Hsp90 middle domain with corresponding sacsin regions and identifies a shorter lid segment, in the sacsin ATP-binding domains, than the one found in the N-terminal domain of Hsp90. Our results show how a realignment of residues in the lid segment of sacsin that are involved in ATP binding can better match equivalent residues seen in Hsp90, which we then corroborated using molecular dynamic simulations. We speculate, from a structural viewpoint, why some ATP competitive inhibitors of Hsp90 may not bind sacsin, while others would. Together our analysis supports the hypothesis that sacsin's function is ATP-driven and would be consistent with it having a role as a super molecular chaperone. We propose that the SR1 regions of sacsin be renamed as HSP-NRD (Hsp90 N-Terminal Repeat Domain; residues 84-324) and the fragment immediately after as HSP-MRD (Hsp90 Middle Repeat Domain; residues 325-518).

Aß misfolding in blood plasma is inversely associated with body mass index even in middle adulthood.

BACKGROUND: To understand the potential for early intervention and prevention measures in Alzheimer's disease, the association between risk factors and early pathological change needs to be assessed. Hence, the aim of this study was to determine whether risk factors of Alzheimer's clinical syndrome (clinical AD), such as body mass index (BMI), are associated with Aß misfolding in blood, a strong risk marker for AD among older adults. METHODS: Information on risk factors and blood samples were collected at baseline in the ESTHER study, a population-based cohort study of older adults (age 50-75 years) in Germany. Aß misfolding in blood plasma was analyzed using an immuno-infrared-sensor in a total of 872 participants in a nested case-control design among incident dementia cases and matched controls. Associations between risk factors and Aß misfolding were assessed by multiple logistic regression. For comparison, the association between the risk factors and AD incidence during 17 years of follow-up was investigated in parallel among 5987 cohort participants. RESULTS: An inverse association with Aß misfolding was seen for BMI at age 50 based on reported weight history (aOR 0.64, 95% CI 0.43-0.96, p = 0.03). Similar but not statistically significant associations were seen for BMI at baseline (i.e., mean age 68) and at age 40. No statistically significant associations with Aß misfolding were found for other risk factors, such as diabetes, smoking, and physical activity. On the other hand, low physical activity was associated with a significantly reduced risk of developing clinical AD compared to physical inactivity. CONCLUSIONS: Our results support that AD pathology may be detectable and associated with reduced weight even in middle adulthood, many years before clinical diagnosis of AD. Physical activity might reduce the risk of onset of AD symptoms.

Genetic predisposition, Aß misfolding in blood plasma, and Alzheimer's disease.

Alzheimer's disease is highly heritable and characterized by amyloid plaques and tau tangles in the brain. The aim of this study was to investigate the association between genetic predisposition, Aß misfolding in blood plasma, a unique marker of Alzheimer associated neuropathological changes, and Alzheimer's disease occurrence within 14 years. Within a German community-based cohort, two polygenic risk scores (clinical Alzheimer's disease and Aß42 based) were calculated, APOE genotype was determined, and Aß misfolding in blood plasma was measured by immuno-infrared sensor in 59 participants diagnosed with Alzheimer's disease during 14 years of follow-up and 581 participants without dementia diagnosis. Associations between each genetic marker and Aß misfolding were assessed through logistic regression and the ability of each genetic marker and Aß misfolding to predict Alzheimer's disease was determined. The Alzheimer's disease polygenic risk score and APOE ε4 presence were associated to Aß misfolding (odds ratio, 95% confidence interval: per standard deviation increase of score: 1.25, 1.03-1.51; APOE ε4 presence: 1.61, 1.04-2.49). No association was evident for the Aß polygenic risk score. All genetic markers were predictive of Alzheimer's disease diagnosis albeit much less so than Aß misfolding (areas under the curve: Aß polygenic risk score: 0.55; AD polygenic risk score: 0.59; APOE ε4: 0.63; Aß misfolding: 0.84). Clinical Alzheimer's genetic risk was associated to early pathological changes (Aß misfolding) measured in blood, however, predicted Alzheimer's disease less accurately than Aß misfolding itself. Genetic predisposition may provide information regarding disease initiation, while Aß misfolding could be important in clinical risk prediction.

Aß misfolding in blood plasma measured by immuno-infrared-sensor as an age-independent risk marker of Alzheimer's disease.

INTRODUCTION: Determining potential risk factors of amyloid beta (Aß) misfolding in blood, a risk marker for clinical Alzheimer's disease (AD), could have important implications for its utility in future research and clinical settings. METHODS: Participants aged 50 to 75 years attending a general health examination were recruited for a prospective community-based cohort study in Saarland, Germany, in 2000 to 2002. For these analyses, participants with available Aß misfolding measurements and clinical AD information at 17-year follow-up were included (n = 444). RESULTS: Age did not show any association with Aß misfolding in plasma; however, a strong association of both age and Aß misfolding with the incidence of clinical AD was evident. Education and cardiovascular diseases were likewise not associated with Aß misfolding. DISCUSSION: Structural measurement of Aß misfolding in blood plasma is an age-independent risk marker of clinical AD among older adults, supporting that risk of clinical AD is already largely determined before older adulthood.