Correction:Comprehensive genetic screening of early-onset dementia patients in an Austrian cohort-suggesting new disease-contributing genes (Human Genomics, (2023), 17, 1, (55), 10.1186/s40246-023-00499-z)

Following publication of the original article [1], the authors reported an error in Table 1. The correct Table 1 has been provided in this Correction. (Table presented.) Basic clinical and genetic characteristics of all 60 EOD patients ID Diagnosis AAO (years) Sex FH APOE Gene Variant Position Transcript CADD ClinVar Significance for disease EOD-1 EOD-2 c.184G &gt; A; p.R62C chr6:41129208-41129208 NM_001271821.1 25.5 n.r Risk modifier Risk modifier EOD-3 AD 45 f 2 E3/E3 EOD-4 AD 51 f 4 E4/E3 Risk modifier EOD-5 nfPPA 58 f 2 E3/E2 EOD-6 AD 56 f 3 E3/E3 EOD-7 AD/PCA 56 f 4 E3/E3 EOD-8 bvFTD 56 m 4 E3/E3 c.1427T &gt; C; p.M476T chr11:117160361-117160361 NM_012104.3 26.4 n.r Unknown c.9757A &gt; G; p.S3253G chr15:62173781-62173781 NM_020821.2 29.5 n.r Unknown EOD-9 AD 55 f 3,5 E4/E3 Risk modifier EOD-10 AD 58 f 3,5 E3/E3 EOD-11 AD 63 m 4 E3/E3 EOD-12 mixed dementia (AD + VD) 55 m 3,5 E4/E3 Risk modifier EOD-13 AD 61 m 4,5 E3/E3 EOD-14 AD/lpPPA 61 m 4 E4/E3 Risk modifier c.4300C &gt; T; p.V1434I chr15:62244179-62244179 NM_020821.2 24.8 n.r Unknown EOD-15 nfPPA 64 m 2 E3/E3 c.2218C &gt; T; p.E740K chr2:74594514-74594514 NM_004082.4 24.0 n.r Unknown EOD-16 AD 56 f 4 E3/E3 EOD-17 AD (PD) 60 m 1 E4/E3 Risk modifier g.chr16:1816528 A &gt; G; c.2817-2A &gt; G chr16:1816528-1816528 NM_015133.3 22.3 n.r Unknown EOD-18a c.2914C &gt; T; p.P972S chr19:1051537-1051537 NM_019112.3 25.3 n.r Potential risk modifier EOD-19 EOD-19 (2)b EOD-20 AD 57 m 4,5 E3/E3 c.7397T &gt; A; p.L2466H chr12:40760814-40760814 NM_198578.3 25.7 VUS Unknown EOD-21 EOD-22 EOD-23 EOD-24 EOD-25 EOD-26 AD 56 f 4 E3/E3 c.2980G &gt; C; p.P994A chr2:74590268-74590268 NM_023019.3 17.3 VUS Unknown c.2087G &gt; A; p.R696H chr16:1814180-1814180 NM_015133.3 31.0 n.r Unknown EOD-27 AD 57 f 4 E4/E3 Risk modifier EOD-28 AD 54 m 4 E3/E3 EOD-29 AD 54 m 4 E3/E3 EOD-30 AD 64 m 4 E3/E3 EOD-31 mixed dementia (AD + VD) 58 m 3,5 E3/E3 EOD-32 FTD/svPPA 61 m 4 E3/E3 EOD-33 AD 62 f 4,5 E4/E3 Risk modifier c.521G &gt; A; p.S174L chr2:74598788-74598788 NM_004082.4 24.4 VUS Unknown EOD-34 AD 59 f 2 E4/E3 Risk modifier EOD-35 AD 55 m 3,5 E4/E3 Risk modifier EOD-36c AD 64 m 2 E4/E3 c.140G &gt; A; p.R47H chr6:41129252-41129252 NM_018965.3 9.7 LB Risk modifier Risk modifier EOD-37 AD 52 f 3,5 E3/E3 c.7397T &gt; A; p.L2466H chr12:40760814-40760814 NM_198578.3 25.7 VUS Unknown EOD-38 AD 52 f 3,5 E4/E3 Risk modifier EOD-39 AD 63 f 3 E4/E3 Risk modifier EOD-40 AD 55 f 4 E4/E3 Risk modifier EOD-41 AD 58 m 3,5 E3/E3 EOD-42 AD 39 m 4 E3/E2 EOD-43 AD 63 m 4 E3/E3 c.3148A &gt; G; p.I1050V chr15:62256964-62256964 NM_020821.2 0.001 VUS Unknown EOD-44 AD/lpPPA 58 f 3,5 E3/E3 c.3014T &gt; G; p.M1005R chr11:121430331-121430331 NM_003105.5 27.9 n.r Potential risk modifier EOD-45 AD 65 m 4 E3/E3 EOD-46 CBS + AD 51 f 3,5 E3/E3 c.4606G &gt; A; p.G1536S chr11:121474988-121474988 NM_003105.5 25.2 B Risk modifier EOD-47 AD 54 f 4 E3/E3 EOD-48 bvFTD 57 m 4 E3/E3 EOD-49 FTD/nfPPA + ALS 58 m 4 E3/E3 c.986T &gt; C; p.L276P chr12:64875636-64875636 NM_013254.3 n.r Potential risk modifier c.7436T &gt; C; p.I2429T chr15:62212307-62212307 NM_020821.2 n.r Unknown EOD-50 Risk modifier EOD-51 FTD/svPPA 62 f 4 E3/E3 EOD-52 AD 57 m 4 E4/E3 Risk modifier EOD-53 c.7377G &gt; A; p.M2459I chr12:40758839-40758839 NM_198578.3 17.7 n.r Unknown EOD-54 AD 59 m 1 E4/E3 Risk modifier EOD-55 AD 49 m 4 E3/E3 EOD-56 AD 61 m 3,5 E3/E3 EOD-57 AD/lpPPA 57 f 4 E3/E3 EOD-58 AD + VD 64 f 3 E3/E3 c.823C &gt; T; p.R141C chr2:74598126-74598126 NM_004082.3 29.3 VUS Unknown EOD-59 bvFTD 52 m 4 E4/E3 Risk modifier EOD-60 a, EOD-18: The APP duplication of was confirmed to be 'de novo'. Both parents did not show this duplication b, EOD-19 (2) is the brother of EOD19. He was also affected by AD and carrier of the same duplication. EOD 19 (2) was not included in the analyses of AAO and FH c, EOD-36: ClinVar assessment of TREM2 p.R47H of LB (likely benign) refers to Nasu-Hakola disease. However, p.R47H is an established risk variant for dementia (Ref. 15) The original article [1] has been corrected.</p

Mapping genomic loci implicates genes and synaptic biology in schizophrenia

Schizophrenia has a heritability of 60-80%1, much of which is attributable to common risk alleles. Here, in a two-stage genome-wide association study of up to 76,755 individuals with schizophrenia and 243,649 control individuals, we report common variant associations at 287 distinct genomic loci. Associations were concentrated in genes that are expressed in excitatory and inhibitory neurons of the central nervous system, but not in other tissues or cell types. Using fine-mapping and functional genomic data, we identify 120 genes (106 protein-coding) that are likely to underpin associations at some of these loci, including 16 genes with credible causal non-synonymous or untranslated region variation. We also implicate fundamental processes related to neuronal function, including synaptic organization, differentiation and transmission. Fine-mapped candidates were enriched for genes associated with rare disruptive coding variants in people with schizophrenia, including the glutamate receptor subunit GRIN2A and transcription factor SP4, and were also enriched for genes implicated by such variants in neurodevelopmental disorders. We identify biological processes relevant to schizophrenia pathophysiology; show convergence of common and rare variant associations in schizophrenia and neurodevelopmental disorders; and provide a resource of prioritized genes and variants to advance mechanistic studies

Analysis of shared heritability in common disorders of the brain

ience, this issue p. eaap8757 Structured Abstract INTRODUCTION Brain disorders may exhibit shared symptoms and substantial epidemiological comorbidity, inciting debate about their etiologic overlap. However, detailed study of phenotypes with different ages of onset, severity, and presentation poses a considerable challenge. Recently developed heritability methods allow us to accurately measure correlation of genome-wide common variant risk between two phenotypes from pools of different individuals and assess how connected they, or at least their genetic risks, are on the genomic level. We used genome-wide association data for 265,218 patients and 784,643 control participants, as well as 17 phenotypes from a total of 1,191,588 individuals, to quantify the degree of overlap for genetic risk factors of 25 common brain disorders. RATIONALE Over the past century, the classification of brain disorders has evolved to reflect the medical and scientific communities' assessments of the presumed root causes of clinical phenomena such as behavioral change, loss of motor function, or alterations of consciousness. Directly observable phenomena (such as the presence of emboli, protein tangles, or unusual electrical activity patterns) generally define and separate neurological disorders from psychiatric disorders. Understanding the genetic underpinnings and categorical distinctions for brain disorders and related phenotypes may inform the search for their biological mechanisms. RESULTS Common variant risk for psychiatric disorders was shown to correlate significantly, especially among attention deficit hyperactivity disorder (ADHD), bipolar disorder, major depressive disorder (MDD), and schizophrenia. By contrast, neurological disorders appear more distinct from one another and from the psychiatric disorders, except for migraine, which was significantly correlated to ADHD, MDD, and Tourette syndrome. We demonstrate that, in the general population, the personality trait neuroticism is significantly correlated with almost every psychiatric disorder and migraine. We also identify significant genetic sharing between disorders and early life cognitive measures (e.g., years of education and college attainment) in the general population, demonstrating positive correlation with several psychiatric disorders (e.g., anorexia nervosa and bipolar disorder) and negative correlation with several neurological phenotypes (e.g., Alzheimer's disease and ischemic stroke), even though the latter are considered to result from specific processes that occur later in life. Extensive simulations were also performed to inform how statistical power, diagnostic misclassification, and phenotypic heterogeneity influence genetic correlations. CONCLUSION The high degree of genetic correlation among many of the psychiatric disorders adds further evidence that their current clinical boundaries do not reflect distinct underlying pathogenic processes, at least on the genetic level. This suggests a deeply interconnected nature for psychiatric disorders, in contrast to neurological disorders, and underscores the need to refine psychiatric diagnostics. Genetically informed analyses may provide important "scaffolding" to support such restructuring of psychiatric nosology, which likely requires incorporating many levels of information. By contrast, we find limited evidence for widespread common genetic risk sharing among neurological disorders or across neurological and psychiatric disorders. We show that both psychiatric and neurological disorders have robust correlations with cognitive and personality measures. Further study is needed to evaluate whether overlapping genetic contributions to psychiatric pathology may influence treatment choices. Ultimately, such developments may pave the way toward reduced heterogeneity and improved diagnosis and treatment of psychiatric disorders

Differences regarding the five-factor personality model in patients with subjective cognitive decline and mild cognitive impairment

Persönlichkeitsveränderung und Demenz sind miteinander assoziiert. Wissen über Persönlichkeitsveränderungen bei prodromalen Stadien der Demenz könnte hilfreich sein, um Demenz früher zu erkennen. Anhand einer Querschnittsstudie wurden Persönlichkeitsunterschiede zwischen drei kognitiv beeinträchtigten Gruppen anhand der Selbsteinschätzung von Persönlichkeitsmerkmalen untersucht. Des Weiteren wurden Zusammenhänge zwischen Persönlichkeit und kognitiver Funktion untersucht. Die Stichprobe bestand aus kognitiv beeinträchtigten Patienten (N=133) im Alter von 50 Jahren und älter, die aufgrund kognitiver Beschwerden eine Gedächtnisklinik aufsuchten. Die Untersuchung umfasste ein kognitives Screening, die Neuropsychologische Testbatterie Wien (NTBV) und das Big Five Plus One Persönlichkeitsinventar (B5PO). Während sich Patienten mit subjektivem kognitivem Abbau (SCD) nicht von denen mit nicht-amnestischer leichter kognitiver Beeinträchtigung (naMCI) bezüglich der verschiedenen Persönlichkeitsmerkmale unterschieden, zeigten Patienten mit amnestischer leichter kognitiver Beeinträchtigung (aMCI) signifikant niedrigere Werte für Extraversion (p<0,05), Offenheit (p<0,001) und Empathie (p<0,001) als Patienten mit SCD sowie Patienten mit naMCI. Kognitiv beeinträchtigte Gruppen unterschieden sich hinsichtlich Persönlichkeitseigenschaften in Abhängigkeit davon, ob Gedächtnisbeeinträchtigungen vorlagen oder nicht.Personality and dementia are connected in different ways. A broad knowledge about personality and prodromal stages of dementia might be helpful to identify dementia as early as possible. Hence, personality differences between three cognitively impaired groups on the basis of patients self-assessments of personality traits and connections between personality and cognitive functioning were examined via a cross-sectional study. The sample consisted of cognitively impaired patients (N=133), aged 50 and older, who came to a memory clinic due to cognitive complaints. The test procedure encompassed a cognitive screening, the Neuropsychological Test Battery Vienna (NTBV), and self-assessment questionnaires such as the Big Five Plus One Persönlichkeitsinventar (B5PO). While patients with subjective cognitive decline (SCD) did not differ from those with non-amnestic mild cognitive impairment (naMCI) concerning the different personality traits, patients with amnestic mild cognitive impairment (aMCI) showed significantly lower scores for extraversion (p<0.05), openness (p<0.001), and empathy (p<0.001) than patients with SCD as well as patients with naMCI. Thus, cognitively impaired groups mainly differ concerning personality traits depending on whether they do show memory decline or not.(VLID)365859

Volkskrankheit Alzheimer: Handlungsbedarf und mögliche Lösungsansätze für die Zukunft

Die Gesellschaft wird immer älter - und damit nehmen auch Krankheiten wie zb Alzheimer zu. In Österreich leben derzeit rund 139.000 Menschen mit einer Demenz und etwa zwei Drittel davon, sind von der Alzheimer-Erkrankung betroffen. Nach aktuellen Schätzungen wird die Gesamtzahl der Betroffenen bis zum Jahr 2050 dramatisch ansteigen. Alzheimer ist damit eine der größten Herausforderungen für unser Gesundheitswesen und Gegenstand intensiver Forschungen. Die Krankheit stellt dabei nicht nur die Betroffenen selbst, sondern auch die Angehörigen, das soziale Umfeld und die gesamte Gesellschaft vor enorme Aufgaben

AI-Based Predictive Modelling of the Onset and Progression of Dementia

Dementia, the most severe expression of cognitive impairment, is among the main causes of disability in older adults and currently affects over 55 million individuals. Dementia prevention is a global public health priority, and recent studies have shown that dementia risk can be reduced through non-pharmacological interventions targeting different lifestyle areas. The FINnish GERiatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER) has shown a positive effect on cognition in older adults at risk of dementia through a 2-year multidomain intervention targeting lifestyle and vascular risk factors. The LETHE project builds on these findings and will provide a digital-enabled FINGER intervention model for delaying or preventing the onset of cognitive decline. An individualised ICT-based multidomain, preventive lifestyle intervention program will be implemented utilising behaviour and intervention data through passive and active data collection. Artificial intelligence and machine learning methods will be used for data-driven risk factor prediction models. An initial model based on large multinational datasets will be validated and integrated into an 18-month trial integrating digital biomarkers to further improve the model. Furthermore, the LETHE project will investigate the concept of federated learning to, on the one hand, protect the privacy of the health and behaviour data and, on the other hand, to provide the opportunity to enhance the data model easily by integrating additional clinical centres

AI-Based Predictive Modelling of the Onset and Progression of Dementia

Dementia, the most severe expression of cognitive impairment, is among the main causes of disability in older adults and currently affects over 55 million individuals. Dementia prevention is a global public health priority, and recent studies have shown that dementia risk can be reduced through non-pharmacological interventions targeting different lifestyle areas. The FINnish GERiatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER) has shown a positive effect on cognition in older adults at risk of dementia through a 2-year multidomain intervention targeting lifestyle and vascular risk factors. The LETHE project builds on these findings and will provide a digital-enabled FINGER intervention model for delaying or preventing the onset of cognitive decline. An individualised ICT-based multidomain, preventive lifestyle intervention program will be implemented utilising behaviour and intervention data through passive and active data collection. Artificial intelligence and machine learning methods will be used for data-driven risk factor prediction models. An initial model based on large multinational datasets will be validated and integrated into an 18-month trial integrating digital biomarkers to further improve the model. Furthermore, the LETHE project will investigate the concept of federated learning to, on the one hand, protect the privacy of the health and behaviour data and, on the other hand, to provide the opportunity to enhance the data model easily by integrating additional clinical centres

Self-reported and informant-reported memory functioning and awareness in patients with mild cognitive impairment and Alzheimers disease

Grundlagen Die Einsicht (Awareness) hinsichtlich der Erinnerungsleistung ist ein wichtiger Faktor für eine angemessene Behandlung von Patienten mit leichter kognitiver Beeinträchtigung (MCI) und Alzheimer-Krankheit (AD). Ziel der vorliegenden Studie war herauszufinden (i) ob subjektive Gedächtnisleistung und objektive Gedächtnisleistung assoziiert sind, (ii) ob sich die Einsicht (Awareness) hinsichtlich der Erinnerungsleistung mit der Zeit verändert und (iii) ob die Einsicht (Awareness) hinsichtlich der Erinnerungsleistung ein Prädiktor für die Entwicklung einer Demenz ist. Methodik Vierunddreißig Patienten mit MCI, die Hilfe in einer universitären Gedächtnisambulanz suchten, wurden in die Studie eingeschlossen. Alle Teilnehmer wurden einer ausführlichen neuropsychologischen Untersuchung unterzogen. Die Einsicht (Awareness) hinsichtlich der Erinnerungsleistung wurde durch Berechnung der Differenzwerte zwischen Patient und Informant Bewertung auf einem 16-Punkt-Fragebogen hinsichtlich Gedächtnisbeschwerden im täglichen Leben erhalten. Eine Kontrolluntersuchung wurde nach einer mittleren Nachbeobachtungszeit von 24 Monaten durchgeführt. Ergebnisse Die Analyse zeigte, dass die Einsicht (Awareness) hinsichtlich der Erinnerungsleistung relativ stabil über die Zeit blieb. Selbst berichtete Gedächtnisbeschwerden korrelierten mit der episodischen Gedächtnisleistung zu Beginn der Studie und mit der Leistung bei einer Sprachaufgabe bei der Nachuntersuchung. Wiederholungsprüfungen angezeigt Rückgang des Bewusstseins. Der prädiktive Wert der Einsicht (Awareness) hinsichtlich der Erinnerungsleistung in Bezug auf die Demenzentwicklung war gering. Schlussfolgerungen Einsicht (Awareness) hinsichtlich der Erinnerungsleistung ist mit episodischer Gedächtnis-Funktion verknüpft und nimmt mit Abnahme der kognitiven Fähigkeiten ab. Weitere Studien zur Vorhersagekraft der Einsicht (Awareness) hinsichtlich der Erinnerungsleistung sollten eine größere Patientenstichprobe umfassen.Awareness of subjective memory is an important factor for adequate treatment of patients with mild cognitive impairment (MCI) and Alzheimers disease (AD). This study served to find out whether awareness of subjective memory complies with objective performance, if differences in awareness are observed longitudinally and whether decrease of awareness can serve as a predictor of AD in MCI patients. Methods Thirty-four patients with MCI seeking help in a memory outpatient clinic were included. All participants underwent thorough neuropsychological examination. Awareness of subjective memory was obtained by calculating difference scores between patient and informant ratings on a 16-item questionnaire concerning complaints about loss of memory in every-day life. Retesting was performed after a mean follow-up period of 24 months. Results Whole group analyses showed that awareness remained relatively stable across time. Self-reported memory complaints correlated with episodic memory at baseline and with performance on a language task at follow-up. Retests displayed decrease of awareness. At group level differences in awareness between both times of assessment were not significant for MCI and MCI patients converting to mild AD at follow-up. The predictive value of awareness was low. Conclusions Awareness of subjective memory deficit is linked to episodic memory function and decreases with decline of cognitive ability. Further studies evaluating predictive power of awareness of subjective memory should include a larger patient sample.(VLID)347208