Alzheimer's disease (AD) is highly heritable and recent studies have identified over 20 diseaseassociated genomic loci. Yet these only explain a small proportion of the genetic variance, indicating that undiscovered loci remain. Here, we performed the largest genome-wide association study of clinically diagnosed AD and AD-by-proxy (71,880 cases, 383,378 controls). AD-by-proxy, based on parental diagnoses, showed strong genetic correlation with AD (rg=0.81). Meta-analysis identified 29 risk loci, implicating 215 potential causative genes. Associated genes are strongly expressed in immune-related tissues and cell types (spleen, liver and microglia). Gene-set analyses indicate biological mechanisms involved in lipid-related processes and degradation of amyloid precursor proteins. We show strong genetic correlations with multiple health-related outcomes, and Mendelian randomisation results suggest a protective effect of cognitive ability on AD risk. These results are a step forward in identifying the genetic factors that contribute to AD risk and add novel insights into the neurobiology of AD.

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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.

Bakgrunn: Hoftebrudd er en viktig årsak til sykdom og død med 1.3 millioner brudd årlig i verden og en fortsatt stigende insidens. Risikofaktorer er høy alder, osteoporose og skrøpelighet, og de fleste bruddene skyldes lav energitraumer på grunn av fall. Høy alder, nedsatt funksjon før bruddet og mannlig kjønn øker risiko for et uheldig resultat, mens fall utendørs er prognostisk gunstig.Utvikling av såkalt ortogeriatriske behandlingsmodeller for hoftebrudd som bruker teknikker og prinsipper utviklet i geriatrien er en måte å bedre prognosen for pasientene. Det er utviklet flere modeller:1. Konsultasjonsmodeller der pasienten på vanlig måte behandles i en ortopedisk avdeling, men får tilsyn og vurdering av geriater eller et geriatrisk team under oppholdet, og der teamet deretter foreslår tiltak til ortoped. 2. Modeller med felles ansvar der geriater og ortoped inngår i et team som utreder og behandler pasienten og legger en felles plan for videre oppfølging. 3. Geriatrisk team modeller der utredning og behandling (med unntak av selve kirurgien)foregår i en geriatrisk avdeling tilpasset bruddbehandling, og der ortopeder ansvarlig for operasjon, men ellers kun konsulteres ved behov. Målsetninger for studien: Overordnet mål for studien var å undersøke om bred geriatrisk utredning og behandling (CGC) ga en tilleggsgevinst sammenlignet med tradisjonell ortopedisk behandling (OC).Målsetninger for denne avhandlingen er:1. Å beskrive bakgrunn, utvikling og prinsippene bak de orthogeriatriske modellen og hvordan den skiller seg fra vanlig behandling (Artikkel I). 2. Å presentere kliniske resultat (Artikkel II): a. Mobilitet fire måneder etter bruddet (primaert endepunkt) b. Sekundaere endepunkt: i. Mobilitet etter en og 12 måneder, og p-i-ADL, kognisjon, frykt for å falle, stemningsleie og livskvalitet en, fire og 12 måneder etter bruddet, ii. Bruk av helsetjenester første året etter bruddet 3. Finne ut om effekten på mobilitet, p-og-i-ADL og kognisjon var avhengig av alder, kjønn, bruddtype og funksjon før bruddet (Artikkel III).Metode: Hoftebruddsstudien i Trondheim er en randomisert kontrollert studie basert på ortogeriatrimodell 3 ovenfor. Studien sammenligner standard ortopedisk behandling (OC) med ortogeriatrisk behandling i en egen enhet (CGC). Hjemmeboende pasienter 70 år eller eldre som klarer å gå minst 10m og som har et lavenergibrudd kunne inkluderes, mens pasienter fra sykehjem, høy-energi brudd, patologisk fraktur eller annen sykdom med forventede leveutsikter på mindre enn 3 måneder ble ekskludert. Behandlingen er basert på bred geriatrisk utredning (CGA) og gjennomføres av et tverrfaglig team bestående av geriater (overlege eller lege i spesialisering), sykepleier, fysioterapeut og ergoterapeut; teamet har regelmessige møter der det lages individuelle behandlingsplaner og settes mål for opphold og klargjør videre behov etter utreise samt behandlingsmål. Behandlingen er helhetlig og fokuserer på tidlig mobilisering, gjennomgang av den enkelte pasient med tanke på bakenforliggende sykdom, medisingjennomgang...

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BackgroundDelirium is a common complication in patients with hip fractures and is associated with an increased risk of subsequent dementia. The aim of this trial was to evaluate the effect of a pre- and postoperative orthogeriatric service on the prevention of delirium and longer-term cognitive decline.MethodsThis was a single-center, prospective, randomized controlled trial in which patients with hip fracture were randomized to treatment in an acute geriatric ward or standard orthopedic ward. Inclusion and randomization took place in the Emergency Department at Oslo University hospital. The key intervention in the acute geriatric ward was Comprehensive Geriatric Assessment including daily interdisciplinary meetings. Primary outcome was cognitive function four months after surgery measured using a composite outcome incorporating the Clinical Dementia Rating Scale (CDR) and the 10 words learning and recalls tasks from the Consortium to Establish a Registry for Alzheimer’s Disease battery (CERAD). Secondary outcomes were pre- and postoperative delirium, delirium severity and duration, mortality and mobility (measured by the Short Physical Performance Battery (SPPB)). Patients were assessed four and twelve months after surgery by evaluators blind to allocation.ResultsA total of 329 patients were included. There was no significant difference in cognitive function four months after surgery between patients treated in the acute geriatric and the orthopedic wards (mean 54.7 versus 52.9, 95% confidence interval for the difference -5.9 to 9.5; P = 0.65). There was also no significant difference in delirium rates (49% versus 53%, P = 0.51) or four month mortality (17% versus 15%, P = 0.50) between the intervention and the control group. In a pre-planned sub-group analysis, participants living in their own home at baseline who were randomized to orthogeriatric care had better mobility four months after surgery compared with patients randomized to the orthopedic ward, measured with SPPB (median 6 versus 4, 95% confidence interval for the median difference 0 to 2; P = 0.04).ConclusionsPre- and postoperative orthogeriatric care given in an acute geriatric ward was not effective in reducing delirium or long-term cognitive impairment in patients with hip fracture. The intervention had, however, a positive effect on mobility in patients not admitted from nursing homes.Trial registrationClinicalTrials.gov NCT01009268 Registered November 5, 2009

BackgroundGeriatric patients recently discharged from hospital experience increased chance of unplanned readmissions and admission to nursing homes. Several studies have shown that medication-related discrepancies are common. Few studies report unwanted incidents by other factors than medications. In 2002 an ambulatory team (AT) was established within the Department of Geriatrics, St. Olavs University Hospital HF, Trondheim, Norway. The AT monitored the transition of the patients from hospital to home and four weeks after discharge in order to reveal unwanted incidents.The aim of the present study was to describe unwanted incidents registered by the AT among patients discharged from a geriatric evaluation and management unit (GEMU) by character, frequency and stage in the transitional process. Only unwanted incidents with a severity making contact with the primary health care (PHC) necessary were registered.MethodsA prospective observational study with patients treated in the GEMU and followed by the AT was performed. Current practice included comprehensive geriatric assessment and management including discharge planning in the GEMU and collaboration with the primary health care on appointments on assistance to be provided after discharge from hospital. Unwanted incidents severe enough to induce contact with the primary health care were registered during the transitional phase and after discharge.Results118 patients (65% female), with mean age 83.2 ± 6.4 years participated. Median Barthel Index at discharge was 18 (interquartile range 16-19) and median Mini Mental Status Examination 24 (interquartile range 21-26). A total of 146 unwanted incidents were registered in 70 (59%) of the patients. Most frequent were unwanted incidents related to drug prescription regime (32%), exchange of information in and between the GEMU and the primary health care (25%) and service or help provided from the PHC (17%).ConclusionsDespite a seemingly well-organised system for transition of patients from the GEMU to their homes, one or more unwanted incidents occurred in most patients during discharge or four weeks post discharge. The study has revealed areas of importance for improving transitional care of geriatric patients.

Treatment of acutely sick, frail, older patients in a GEMU substantially reduced mortality.