254 research outputs found

    Multiancestry analysis of the HLA locus in Alzheimer’s and Parkinson’s diseases uncovers a shared adaptive immune response mediated by HLA-DRB1*04 subtypes

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    Across multiancestry groups, we analyzed Human Leukocyte Antigen (HLA) associations in over 176,000 individuals with Parkinson‚Äôs disease (PD) and Alzheimer‚Äôs disease (AD) versus controls. We demonstrate that the two diseases share the same protective association at the HLA locus. HLA-specific fine-mapping showed that hierarchical protective effects of HLA-DRB1*04 subtypes best accounted for the association, strongest with HLA-DRB1*04:04 and HLA-DRB1*04:07, and intermediary with HLA-DRB1*04:01 and HLA-DRB1*04:03. The same signal was associated with decreased neurofibrillary tangles in postmortem brains and was associated with reduced tau levels in cerebrospinal fluid and to a lower extent with increased Aő≤42. Protective HLA-DRB1*04 subtypes strongly bound the aggregation-prone tau PHF6 sequence, however only when acetylated at a lysine (K311), a common posttranslational modification central to tau aggregation. An HLA-DRB1*04-mediated adaptive immune response decreases PD and AD risks, potentially by acting against tau, offering the possibility of therapeutic avenues

    Associations between dietary patterns and dementia-related neuroimaging markers

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    BACKGROUND: The exploration of associations between dietary patterns and dementia-related neuroimaging markers can provide insights on food combinations that may impact brain integrity. METHODS: Data were derived from the Swedish Gothenburg H70 Birth Cohort Study (n = 610). Three dietary patterns were obtained using principal component analysis. Magnetic resonance imaging markers included cortical thickness, an Alzheimer's disease (AD) signature score, small vessel disease, and white matter microstructural integrity. Adjusted linear/ordinal regression analyses were performed. RESULTS: A high-protein and alcohol dietary pattern was negatively associated with cortical thickness in the whole brain (Beta: ‚ąí0.011; 95% confidence interval [CI]: ‚ąí0.018 to ‚ąí0.003), and with an Alzheimer's disease cortical thickness signature score (Beta: ‚ąí0.013; 95% CI: ‚ąí0.024 to ‚ąí0.001). A positive association was found between a Mediterranean-like dietary pattern and white matter microstructural integrity (Beta: 0.078; 95% CI: 0.002‚Äď0.154). No associations were found with a Western-like dietary pattern. DISCUSSION: Dietary patterns may impact brain integrity through neurodegenerative and vascular pathways. Highlights: Certain dietary patterns were associated with dementia-related neuroimaging markers. A Mediterranean dietary pattern was positively associated with white matter microstructure. A high-protein and alcohol pattern was negatively associated with cortical thickness

    Screening for Mild Cognitive Impairment Using a Machine Learning Classifier and the Remote Speech Biomarker for Cognition:Evidence from Two Clinically Relevant Cohorts

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    BACKGROUND: Modern prodromal Alzheimer's disease (AD) clinical trials might extend outreach to a general population, causing high screen-out rates and thereby increasing study time and costs. Thus, screening tools that cost-effectively detect mild cognitive impairment (MCI) at scale are needed.OBJECTIVE: Develop a screening algorithm that can differentiate between healthy and MCI participants in different clinically relevant populations.METHODS: Two screening algorithms based on the remote ki:e speech biomarker for cognition (ki:e SB-C) were designed on a Dutch memory clinic cohort (N‚Ää=‚Ää121) and a Swedish birth cohort (N‚Ää=‚Ää404). MCI classification was each evaluated on the training cohort as well as across on the unrelated validation cohort.RESULTS: The algorithms achieved a performance of AUC 0.73 and AUC 0.77 in the respective training cohorts and AUC 0.81 in the unseen validation cohort.CONCLUSION: The results indicate that a ki:e SB-C based algorithm robustly detects MCI across different cohorts and languages, which has the potential to make current trials more efficient and improve future primary health care.</p

    Longstanding smoking associated with frontal brain lobe atrophy: a 32-year follow-up study in women

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    Objective To examine the association between midlife tobacco smoking and late-life brain atrophy and white matter lesions.Methods The study includes 369‚ÄČwomen from the Prospective Population Study of Women in Gothenburg, Sweden. Cigarette smoking was reported at baseline 1968 (mean age=44 years) and at follow-up in 1974‚Äď1975 and 1980‚Äď1981. CT of the brain was conducted 32 years after baseline examination (mean age=76 years) to evaluate cortical atrophy and white matter lesions. Multiple logistic regressions estimated associations between midlife smoking and late-life brain lesions. The final analyses were adjusted for alcohol consumption and several other covariates.Results Smoking in 1968‚Äď1969 (adjusted OR 1.85; 95%‚ÄČCI 1.12 to 3.04), in 1974‚Äď1975 (OR 2.37; 95%‚ÄČCI 1.39 to 4.04) and in 1980‚Äď1981 (OR 2.47; 95%‚ÄČCI 1.41 to 4.33) were associated with late-life frontal lobe atrophy (2000‚Äď2001). The strongest association was observed in women who reported smoking at all three midlife examinations (OR 2.63; 95%‚ÄČCI 1.44 to 4.78) and in those with more frequent alcohol consumption (OR 6.02; 95%‚ÄČCI 1.74 to 20.84). Smoking in 1980‚Äď1981 was also associated with late-life parietal lobe atrophy (OR 1.99; 95% CI 1.10 to 3.58). There were no associations between smoking and atrophy in the temporal or occipital lobe, or with white matter lesions.Conclusion Longstanding tobacco smoking was mainly associated with atrophy in the frontal lobe cortex. A long-term stimulation of nicotine receptors in the frontal neural pathway might be harmful for targeted brain cell

    Social connections and risk of incident mild cognitive impairment, dementia, and mortality in 13 longitudinal cohort studies of ageing.

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    International audienceIntroduction: Previous meta-analyses have linked social connections and mild cognitive impairment, dementia, and mortality. However, these used aggregate data from North America and Europe and examined a limited number of social connection markers. Methods: We used individual participant data (N = 39271, M age = 70.67 (40-102), 58.86% female, M education = 8.43 years, M follow-up = 3.22 years) from 13 longitudinal ageing studies. A two-stage meta-analysis of Cox regression models examined the association between social connection markers with our primary outcomes. Results: We found associations between good social connections structure and quality and lower risk of incident mild cognitive impairment (MCI); between social structure and function and lower risk of incident dementia and mortality. Only in Asian cohorts, being married/in a relationship was associated with reduced risk of dementia, and having a confidante was associated with reduced risk of dementia and mortality. Discussion: Different aspects of social connections-structure, function, and qualityare associated with benefits for healthy aging internationally

    Neurofilament light oligomers in neurodegenerative diseases: quantification by homogeneous immunoassay in cerebrospinal fluid

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    BACKGROUND: Neurofilament light (NfL) is a widely used biomarker for neurodegeneration. NfL is prone to oligomerisation, but available assays do not reveal the exact molecular nature of the protein variant measured. The objective of this study was to develop a homogeneous ELISA capable of quantifying oligomeric NfL (oNfL) in cerebrospinal fluid (CSF). METHODS: A homogeneous ELISA, based on the same capture and detection antibody (NfL21), was developed and used to quantify oNfL in samples from patients with behavioural variant frontotemporal dementia (bvFTD, n=28), non-fluent variant primary progressive aphasia (nfvPPA, n=23), semantic variant PPA (svPPA, n=10), Alzheimer's disease (AD, n=20) and healthy controls (n=20). The nature of NfL in CSF, and the recombinant protein calibrator, was also characterised by size exclusion chromatography (SEC). RESULTS: CSF concentration of oNfL was significantly higher in nfvPPA (p<0.0001) and svPPA patients (p<0.05) compared with controls. CSF oNfL concentration was also significantly higher in nfvPPA compared with bvFTD (p<0.001) and AD (p<0.01) patients. SEC data showed a peak fraction compatible with a full-length dimer (~135 kDa) in the in-house calibrator. For CSF, the peak was found in a fraction of lower molecular weight (~53 kDa), suggesting dimerisation of NfL fragments. CONCLUSIONS: The homogeneous ELISA and SEC data suggest that most of the NfL in both the calibrator and human CSF is present as a dimer. In CSF, the dimer appears to be truncated. Further studies are needed to determine its precise molecular composition

    Nat Commun

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    Genetic discoveries of Alzheimer's disease are the drivers of our understanding, and together with polygenetic risk stratification can contribute towards planning of feasible and efficient preventive and curative clinical trials. We first perform a large genetic association study by merging all available case-control datasets and by-proxy study results (discovery n = 409,435 and validation size n = 58,190). Here, we add six variants associated with Alzheimer's disease risk (near APP, CHRNE, PRKD3/NDUFAF7, PLCG2 and two exonic variants in the SHARPIN gene). Assessment of the polygenic risk score and stratifying by APOE reveal a 4 to 5.5 years difference in median age at onset of Alzheimer's disease patients in APOE …õ4 carriers. Because of this study, the underlying mechanisms of APP can be studied to refine the amyloid cascade and the polygenic risk score provides a tool to select individuals at high risk of Alzheimer's disease

    Biomarkers of Alzheimer’s disease and cerebrovascular disease in relation to depressive symptomatology in individuals with subjective cognitive decline

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    Background: Subjective cognitive decline (SCD) has gained recent interest as a potential harbinger of neurodegenerative diseases such as Alzheimer‚Äôs disease (AD) and cerebrovascular disease (CVD). In addition, SCD can be related to depressive symptomatology. However, the association between AD and CVD biomarkers, depressive symptomatology, and SCD is still unclear. We investigated the association of AD and CVD biomarkers and depressive symptomatology with SCD in individuals with subjective memory complaints (SCD-memory group) and individuals with subjective concentration complaints (SCD-concentration group).// Methods: We recruited a population-based cohort of 217 individuals (all aged 70 years, 53% female, 119 SCD-memory individuals, 23 SCD-concentration individuals, 89 controls). AD and CVD were assessed through cerebrospinal fluid levels of the Aő≤42/40 ratio and phosphorylated tau, and white matter signal abnormalities on magnetic resonance imaging, respectively. Associations between biomarkers, depressive symptomatology, and SCD were tested via logistic regression and correlation analyses.// Results: We found a significant association of depressive symptomatology with SCD-memory and SCD-concentration. Depressive symptomatology was not associated with AD and CVD biomarkers. Both the phosphorylated tau biomarker and depressive symptomatology predicted SCD-memory, and the Aő≤42/40 ratio and depressive symptomatology predicted SCD-concentration.// Conclusions: The role of depressive symptomatology in SCD may differ depending on the stage within the spectrum of preclinical AD (as determined by amyloid-beta and tau positivity), and does not seem to reflect AD pathology. Our findings contribute to the emerging field of subclinical depressive symptomatology in SCD, and clarify the association of different types of subjective complaints with distinct syndromic and biomarker profiles
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