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.

IMPORTANCE Emerging yet contrasting evidence associates air pollution with incident dementia, and the potential role of cardiovascular disease (CVD) in this association is unclear. OBJECTIVE To investigate the association between long-term exposure to air pollution and dementia and to assess the role of CVD in that association. DESIGN, SETTING, AND PARTICIPANTS Data for this cohort study were extracted from the ongoing Swedish National Study on Aging and Care in Kungsholmen (SNAC-K), a longitudinal population-based study with baseline assessments from March 21, 2001, through August 30, 2004. Of the 5111 randomly selected residents in the Kungsholmen district of Stockholm 60 years or older and living at home or in institutions, 521 were not eligible (eg, due to death before the start of the study or no contact information). Among the remaining 4590 individuals, 3363 (73.3%) were assessed. For the current analysis, 2927 participants who did not have dementia at baseline were examined, with follow-up to 2013 (mean [SD] follow-up time, 6.01 [2.56] years). Follow-up was completed

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Deciphering the genetic landscape of Alzheimer disease (AD) is essential to define the pathophysiological pathways involved and to successfully translate genomics to potential tailored medical care. To generate the most complete knowledge of the AD genetics, we developed through the European Alzheimer Disease BioBank (EADB) consortium a discovery meta-analysis of genome-wide association studies (GWAS) based on a new large case-control study and previous GWAS (in total 39,106 clinically diagnosed cases, 46,828 proxy-AD cases and 401,577 controls) with the most promising signals followed-up in independent samples (18,063 cases and 23,207 controls). In addition to 34 known AD loci, we report here the genome-wide significant association of 31 new loci with the risk of AD. Pathway-enrichment analyses strongly indicated the involvement of gene sets related to amyloid and Tau, but also highlighted microglia, in which increased gene expression corresponds to more significant AD risk. In addition, we successfully prioritized candidate genes in the majority of our new loci, with nine being primarily expressed in microglia. Finally, we observed that a polygenic risk score generated from this new genetic landscape was strongly associated with the risk of progression from mild cognitive impairment (MCI) to dementia (4,609 MCI cases of whom 1,532 converted to dementia), independently of age and the APOE e4 allele.

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.

Introduction We investigate dementia risk in older adults with different disease patterns and explore the role of inflammation and apolipoprotein E (APOE) genotype. Methods A total of 2,478 dementia‐free participants with two or more chronic diseases (ie, multimorbidity) part of the Swedish National study on Aging and Care in Kungsholmen (SNAC‐K) were grouped according to their multimorbidity patterns and followed to detect clinical dementia. The potential modifier effect of C‐reactive protein (CRP) and apolipoprotein E (APOE) genotype was tested through stratified analyses. Results People with neuropsychiatric, cardiovascular, and sensory impairment/cancer multimorbidity had increased hazards for dementia compared to the unspecific (Hazard ration (HR) 1.66, 95% confidence interval [CI] 1.13‐2.42; 1.61, 95% CI 1.17‐2.29; 1.32, 95% CI 1.10‐1.71, respectively). Despite the lack of statistically significant interaction, high CRP increased dementia risk within these patterns, and being APOE ε4 carriers heightened dementia risk for neuropsychiatric and cardiovascular multimorbidity. Discussion Individuals with neuropsychiatric, cardiovascular, and sensory impairment/cancer patterns are at increased risk for dementia and APOE ε4, and inflammation may further increase the risk. Identifying such high‐risk groups might allow tailored interventions for dementia prevention.

Introduction: Delirium is a frequent condition in hospitalized older patients and it usually has a negative prognostic value. A direct effect of SARS-COV-2 on the central nervous system (CNS) has been hypothesized. Objective: To evaluate the presence of delirium in older patients admitted for a suspected diagnosis of COVID-19 and its impact on in-hospital mortality. Setting and subjects: 91 patients, aged 70-years and older, admitted to an acute geriatric ward in Northern Italy from March 8th to April 17th, 2020. Methods: COVID-19 cases were confirmed by reverse transcriptase-polymerase chain reaction assay for SARS-Cov-2 RNA from nasal and pharyngeal swabs. Delirium was diagnosed by two geriatricians according to the DSM-V criteria. The number of chronic diseases was calculated among a pre-defined list of 60. The pre-disease Clinical Frailty Scale (CFS) was assessed at hospital admission. Results: Of the total sample, 39 patients died, 49 were discharged and 3 were transferred to ICU. Twenty-five patients (27.5%) had delirium. Seventy-two percent of patients with delirium died during hospitalization compared to 31.8% of those without delirium. In a multivariate logistic regression model adjusted for potential confounders, patients with delirium were four times more likely to die during hospital stay compared to those without delirium (OR = 3.98;95%CI = 1.05–17.28; p = 0.047). Conclusions: Delirium is common in older patients with COVID-19 and strongly associated with in-hospital mortality. Regardless of causation, either due to a direct effect of SARS-COV-2 on the CNS or to a multifactorial cause, delirium should be interpreted as an alarming prognostic indicator in older people.

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