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Atrial fibrillation and heart failure have both been suggested to increase stroke and dementia risk. However, in observational studies, reversed causation and unmeasured confounding may occur. To mitigate these issues, this study aims to investigate if higher genetic risk for atrial fibrillation and heart failure increases dementia and stroke risk. Data were obtained from the population-based Gothenburg H70 Birth Cohort Studies in Sweden. Participants ( N = 984) were born in 1930 with baseline examinations at age 70, 75, 79 or 85 and follow-ups until age 88-89. Polygenic risk scores at the 5 × 10 -8 , 1 × 10 -5 , 1 × 10 -3 and 1 × 10 -1 thresholds were generated for atrial fibrillation and heart failure. Stroke was diagnosed based on self-reports, close-informant interviews, and the National Patient Register. Dementia was diagnosed based on neuropsychiatric examinations, close-informant interviews, and the National Patient Register. Cox regression analyses were performed, adjusted for sex, age at baseline and the first five principal components to correct for population stratification. Those within the highest atrial fibrillation-polygenic risk score tertile had a 1.5 (95% CI 1.09-2.03) increased risk of dementia (at the 1 × 10 -5 threshold) and a 1.5 (95% CI 1.07-2.03) increased risk of stroke (at the 1 × 10 -3 threshold) compared to the lowest tertile. Those within the highest heart failure-polygenic risk score tertile had a 1.6 (95% CI 1.19-2.27) increased risk of dementia (at the 5 × 10 -8 threshold), but no increased risk of stroke (HR 1.2; 95% CI 0.83-1.60 at the 1 × 10 -5 threshold), compared to the lowest tertile. When analysing the polygenic risk scores as a continuous variable, the associations were in the same direction, although weaker. This study, investigating genetic risk of atrial fibrillation and heart failure in relation to stroke and dementia, supports the increasing body of evidence suggesting that atrial fibrillation is associated with both stroke and dementia risk. Whether heart failure increases dementia risk is less established, but the present study found that genetic risk of heart failure increased dementia risk. The finding that genetic risk for heart failure did not increase stroke risk needs to be interpreted with caution, as it may be due to a lack of statistical power. There are guidelines on how to best treat atrial fibrillation to prevent stroke, but more knowledge is needed on how to treat atrial fibrillation and heart failure to prevent dementia., Competing Interests: S.K. has served at scientific advisory boards, speaker and/or as consultant for Roche, Geras Solutions, Optoceutics, Biogen and Bioarctic. H.Z. has served at scientific advisory boards and/or as a consultant for Abbvie, Acumen, Alector, Alzinova, ALZPath, Amylyx, Annexon, Apellis, Artery Therapeutics, AZTherapies, Cognito Therapeutics, CogRx, Denali, Eisai, Merry Life, Nervgen, Novo Nordisk, Optoceutics, Passage Bio, Pinteon Therapeutics, Prothena, Red Abbey Labs, reMYND, Roche, Samumed, Siemens Healthineers, Triplet Therapeutics, and Wave, has given lectures in symposia sponsored by Alzecure, Biogen, Cellectricon, Fujirebio, Lilly, Novo Nordisk, and Roche, and is a co-founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program (outside submitted work). K.B. has served as a consultant and at advisory boards for AC Immune, Acumen, ALZPath, AriBio, BioArctic, Biogen, Eisai, Lilly, Moleac Pte. Ltd, Novartis, Ono Pharma, Prothena, Roche Diagnostics and Siemens Healthineers; has served at data monitoring committees for Julius Clinical and Novartis; has given lectures, produced educational materials and participated in educational programs for AC Immune, Biogen, Celdara Medical, Eisai and Roche Diagnostics; and is a co-founder of Brain BBS, which is a part of the GU Ventures Incubator Program, outside the work presented in this paper., (© The Author(s) 2025. Published by Oxford University Press on behalf of the Guarantors of Brain.)

The relation between cerebrospinal fluid (CSF) biomarkers of Alzheimer's disease (AD) and magnetic resonance imaging (MRI) measures is poorly understood in cognitively healthy individuals from the general population. Participants' ( n  = 226) mean age was 70.9 years (SD = 0.4). CSF concentrations of amyloid beta (Aβ)1-42, total tau (t-tau), phosphorylated tau (p-tau), neurogranin, and neurofilament light, and volumes of hippocampus, amygdala, total basal forebrain (TBF), and cortical thickness were measured. Linear associations between CSF biomarkers and MRI measures were investigated. In Aβ1-42 positives, higher t-tau and p-tau were associated with smaller hippocampus ( P  = 0.001 and P  = 0.003) and amygdala ( P  = 0.005 and P  = 0.01). In Aβ1-42 negatives, higher t-tau, p-tau, and neurogranin were associated with larger TBF volume ( P  = 0.001, P  = 0.001, and P  = 0.01). No associations were observed between the CSF biomarkers and an AD signature score of cortical thickness. AD-specific biomarkers in cognitively healthy 70-year-olds may be related to TBF, hippocampus, and amygdala. Lack of association with cortical thickness might be due to early stage of disease., Competing Interests: KB has served as a consultant, on advisory boards, or data monitoring committees for Abcam, Axon, BioArctic, Biogen, JOMDD/Shimadzu, Julius Clinical, Lilly, MagQu, Novartis, Ono Pharma, Roche Diagnostics, and Siemens Healthineers, and is a co‐founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program. HZ has served on scientific advisory boards and/or as a consultant for Abbvie, Acumen, Alector, ALZPath, Annexon, Apellis, Artery Therapeutics, AZTherapies, CogRx, Denali, Eisai, Nervgen, Novo Nordisk, Passage Bio, Pinteon Therapeutics, Red Abbey Labs, reMYND, Roche, Samumed, Siemens Healthineers, Triplet Therapeutics, and Wave; has given lectures in symposia sponsored by Cellectricon, Fujirebio, Alzecure, Biogen, and Roche; and is a co‐founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program (outside submitted work). SK has served on scientific advisory boards and/or as a consultant for Geras Solutions, Optoceutics, and Biogen, unrelated to the present study. The authors declare no conflicts of interest. Author disclosures are available in the supporting information., (© 2024 The Authors.Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Introduction: There are few studies investigating genetic factors related to suicidal ideation or behavior in older adult populations. Our aim was to test associations between passive and active suicidal ideation and polygenic risk scores (PRSs) for suicidality and other traits of relevance for suicidality in old age (i.e. depression, neuroticism, loneliness, Alzheimer's disease, cognitive performance, educational attainment, and several specified vascular diseases) in a population-based sample aged 70 years and older., Methods: Participants in the prospective H70 study in Gothenburg, Sweden, took part in a psychiatric examination that included the Paykel questions on active and passive suicidal ideation. Genotyping was performed with the Neurochip (Illumina). After quality control of the genetic data the sample included 3467 participants. PRSs for suicidality and other related traits were calculated based on summary statistics from recent GWASs of relevance. Exclusion of persons with dementia or incomplete data on suicidal ideation yielded 3019 participants, age range 70-101 years. Associations between past year suicidal ideation (any level) and selected PRSs were analysed using general estimation equation (GEE) models, adjusted for sex and age., Results: We observed associations between passive/active suicidal ideation and PRSs for depression (three versions), neuroticism, and general cognitive performance. After excluding individuals with current major depressive disorder (MDD), similar associations were seen with PRS for neuroticism, general cognitive performance and two PRSs for depression. No associations were found between suicidal ideation and PRSs for suicidality, loneliness, Alzheimer's disease, educational attainment, or vascular disease., Discussion: Our results could indicate which types of genetic susceptibility that are of importance for suicidality in old age, and these findings can help to shed light on potential mechanisms that may be involved in passive and active suicidal ideation in late-life, also in those with no current MDD. However, due to the limited sample size, the results need to be interpreted with caution until replicated in larger samples., Competing Interests: SK has been consultant for Geras Solutions, unrelated to the findings in this manuscript. HZ has served at scientific advisory boards for Eisai, Denali, Roche Diagnostics, Wave, Samumed, Siemens Healthineers, Pinteon Therapeutics, Nervgen, AZTherapies, and CogRx, has given lectures in symposia sponsored by Cellectricon, Fujirebio, Alzecure, and Biogen, and is a co-founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program (outside submitted work). KB has served as a consultant, at advisory boards, or at data monitoring committees for Abcam, Axon, Biogen, JOMDD/Shimadzu, Julius Clinical, Lilly, MagQu, Novartis, Roche Diagnostics, and Siemens Healthineers, and is a co-founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program, all outside the submitted work. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Zettergren, Jonson, Mellqvist Fässberg, Najar, Rydberg Sterner, Seidu, Kern, Blennow, Zetterberg, Skoog and Waern.)

Healthy metabolic measures in humans are associated with longevity. Dysregulation leads to metabolic syndrome (MetS) and negative health outcomes. Recent exceptional longevity (EL) genome wide association studies have facilitated estimation of an individual's polygenic risk score (PRS) for EL. We tested the hypothesis that individuals with high ELPRS have a low prevalence of MetS. Participants were from five cohorts of middle-aged to older adults. The primary analyses were performed in the UK Biobank (UKBB) (n = 407,800, 40-69 years). Replication analyses were undertaken using three Australian studies: Hunter Community Study (n = 2122, 55-85 years), Older Australian Twins Study (n = 539, 65-90 years) and Sydney Memory and Ageing Study (n = 925, 70-90 years), as well as the Swedish Gothenburg H70 Birth Cohort Studies (n = 2273, 70-93 years). MetS was defined using established criteria. Regressions and meta-analyses were performed with the ELPRS and MetS and its components. Generally, MetS prevalence (22-30%) was higher in the older cohorts. In the UKBB, high EL polygenic risk was associated with lower MetS prevalence (OR = 0.94, p = 1.84 × 10 -42 ) and its components (p < 2.30 × 10 -8 ). Meta-analyses of the replication cohorts showed nominal associations with MetS (p = 0.028) and 3 MetS components (p < 0.05). This work suggests individuals with a high polygenic risk for EL have a healthy metabolic profile promoting longevity., (© 2022. The Author(s).)

Objectives: To determine the accuracy of 12 previously validated short versions of the Geriatric Depression Scale (GDS) to detect major depressive disorder (MDD) in a high-risk population with and without global cognitive impairment., Design: Cross-sectional study., Setting: Five hospitals, Western Sweden., Participants: Older adults (age ≥70 years, n = 60) assessed at a home visit 1 year after hospital care in connection with suicide attempt., Measurements: Depression symptoms were rated using the established 15-item GDS. Eleven short GDS versions identified by a recent systematic review were derived from this administered version. Receiver operating characteristic curves and area under the curve (AUC) for the identification of MDD diagnosed according to Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, were obtained for each version. The Youden Index optimal criterion was used to determine the appropriate cutoffs. Analyses were repeated after stratification by cognitive status (Mini Mental State Examination score ≤24 and >24) for the best performing GDS short versions and the established 15-item GDS., Results: The 7-item GDS according to Broekman et al . (), with a cutoff 3, was the most accurate among the 12 short versions (AUC 0.90, 95% confidence interval 0.80-1.00), identifying MDD with sensitivity 88% and specificity 81%. The cutoff score remained consistent in the presence of global cognitive impairment, which was not the case for the standardized 15-item GDS., Conclusion: The Broekman 7-item GDS had high accuracy to detect MDD in this prospective clinical cohort at high risk for MDD. Further testing of GDS short versions in diverse settings is required.

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 ɛ4 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.