New insights into the genetic etiology of Alzheimer's disease and related dementias

Characterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele

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

Across multiancestry groups, we analyzed Human Leukocyte Antigen (HLA) associations in over 176,000 individuals with Parkinson’s disease (PD) and Alzheimer’s 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 Aβ42. 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

Early intervention in eating disorders: introducing the chronopathogram

Abstract Eating disorders (EDs) pose significant challenges to mental and physical health, particularly among adolescents and young adults, with the COVID-19 pandemic exacerbating risk factors. Despite advancements in psychosocial and pharmacological treatments, improvements remain limited. Early intervention in EDs, inspired by the model developed for psychosis, emphasizes the importance of timely identification and treatment initiation to improve prognosis. Challenges in identifying prodromal phases and measuring the duration of untreated illness highlight the complexity of early intervention efforts in EDs. Current research focuses on reducing the duration of untreated eating disorder (DUED) and understanding the cognitive and behavioral symptoms preceding ED onset. However, current early intervention programs for EDs showed mixed results, necessitating further investigation. We introduce here the chronopathogram, a tool that may aid in precisely investigating the role of development in EDs. A chronopathogram is a graphical representation of pathological events as they unfold over time. Understanding the neurodevelopmental aspects of EDs and utilizing tools like the chronopathogram can aid in tracking the unfolding of symptoms over time, facilitating early detection and intervention efforts. Overall, addressing the key factors influencing the onset and course of EDs is essential for effective early intervention in these conditions. Level of evidence: Level V narrative review

The Nepean Belief Scale (NBS) as a tool to investigate the intensity of beliefs in anorexia nervosa: psychometric properties of the Italian version

Abstract Background People with anorexia nervosa (AN) show a peculiar impairment of insight regarding their condition, often manifesting a denial of extreme emaciation and sometimes hiding or underreporting socially undesirable abnormal eating patterns. Sometimes the intensity of the beliefs held by patients with AN reach a delusional intensity. Objectives In this study, the Italian version of the Nepean Belief Scale was applied to a sample of patients diagnosed with AN to investigate the intensity of their beliefs and convictions and its clinical correlates. Methods The Nepean Belief Scale (NBS) was translated and adapted to Italian and applied to a sample of patients diagnosed with AN based on the Structured Clinical Interview for DSM-5 (SCID-5). Results The Italian version of the 5-item NBS showed excellent reliability. Convergent validity was proved by negative association with levels of insight measured with the Schedule for the Assessment of Insight in Eating Disorders. Beliefs of delusional intensity were reported by 10% of participants. Those with a greater intensity of beliefs, either overvalued or delusional ideas, were more likely to report poorer general cognitive performances on the Montreal Cognitive Assessment. No association was observed between NBS score and age, body mass index, symptoms of eating disorders, body dissatisfaction, or levels of depression. Fear of weight gain and control seeking were the most often reported themes at the NBS. Conclusions The Italian version of the NBS is a reasonably reliable, valid, and usable tool for the multidimensional assessment of insight in AN. Level of evidence Level III, Evidence obtained from well-designed cohort or case–control analytic studies

Classification of Healthy Subjects and Alzheimer's Disease Patients with Dementia from Cortical Sources of Resting State EEG Rhythms: A Study Using Artificial Neural Networks

Previous evidence showed a 75.5% best accuracy in the classification of 120 Alzheimer's disease (AD) patients with dementia and 100 matched normal elderly (Nold) subjects based on cortical source current density and linear lagged connectivity estimated by eLORETA freeware from resting state eyes-closed electroencephalographic (rsEEG) rhythms (Babiloni et al., 2016a). Specifically, that accuracy was reached using the ratio between occipital delta and alpha1 current density for a linear univariate classifier (receiver operating characteristic curves). Here we tested an innovative approach based on an artificial neural network (ANN) classifier from the same database of rsEEG markers. Frequency bands of interest were delta (2-4 Hz), theta (4-8 Hz Hz), alpha1 (8-10.5 Hz), and alpha2 (10.5-13 Hz). ANN classification showed an accuracy of 77% using the most 4 discriminative rsEEG markers of source current density (parietal theta/alpha 1, temporal theta/alpha 1, occipital theta/alpha 1, and occipital delta/alpha 1). It also showed an accuracy of 72% using the most 4 discriminative rsEEG markers of source lagged linear connectivity (inter-hemispherical occipital delta/alpha 2, intra-hemispherical right parietal-limbic alpha 1, intra-hemispherical left occipital-temporal theta/alpha 1, intra-hemispherical right occipital-temporal theta/alpha 1). With these 8 markers combined, an accuracy of at least 76% was reached. Interestingly, this accuracy based on 8 (linear) rsEEG markers as inputs to ANN was similar to that obtained with a single rsEEG marker (Babiloni et al., 2016a), thus unveiling their information redundancy for classification purposes. In future AD studies, inputs to ANNs should include other classes of independent linear (i.e., directed transfer function) and non-linear (i.e., entropy) rsEEG markers to improve the classification

Common variants in Alzheimer’s disease and risk stratification by polygenic risk scores

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

Common variants in Alzheimer’s disease and risk stratification by polygenic risk scores

AbstractGenetic 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.</jats:p