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.

EN-US" style="color: black;">In this seminar the main developments in the field of Alzheimer’s Disease (AD) are highlighted. Most recent data estimate a doubling of dementia prevalence in Europe by 2050. When prevalence estimates of AD are made on a biological, rather than a clinical definition of AD, the prevalence of biologically defined AD is three times higher than that of clinically defined AD. The biological definition based on biomarkers of Aβ and tau has been suggested for research and may enter the clinic in due course. The earliest, cellular, phase of AD includes alterations in neurons, microglia and astroglia. Neuro-inflammation,¹ alterations in the vessels, aging, dysfunction of the glymphatic system act upstream or in parallel to accumulating Aβ in this cellular disease landscape.  Aβ induces the spreading of tau pathology, which is associated with the appearance of necroptosis markers in neurons displaying granulo-vacuolar degeneration. Risk of AD depends for 60-80% on heritable factors. Causative genes include PSEN 1, PSEN2, APP and Sorl1. Risk genes include one or two alleles of APOE4. GWAS studies have identified another 40 risk genes. Protective genes include APOE2, and mutations in the PLCG2 , KLOTHO and the Icelandic APP A673T genes.

Next to the established CSF markers, novel biomarkers include plasma assays for Aβ and p-tau which show great promise for clinical use. Amyloid PET is now making its way into the clinical arena, while tau-PET is established in research.  Multidomain lifestyle-based prevention trials suggest cognitive benefits in subpopulations of participants with increased risk of dementia. Lifestyle factors do not directly impact AD pathology, but can still contribute to a positive outcome in individuals with AD. Promising pharmacological treatments are poised at advanced stages of testing in clinical trials and include anti-abeta, anti tau, anti-inflammatory strategies.

A growing awareness about brain health and Alzheimer's disease in the general population is leading to an increasing number of cognitively unimpaired individuals, who are concerned that they have reduced cognitive function, to approach the medical system for help. The term subjective cognitive decline (SCD) was conceived in 2014 to describe this condition. Epidemiological data provide evidence that the risk for mild cognitive impairment and dementia is increased in individuals with SCD. However, the majority of individuals with SCD will not show progressive cognitive decline. An individually tailored diagnostic process might be reasonable to identify or exclude underlying medical conditions in an individual with SCD who actively seeks medical help. An increasing number of studies are investigating the link between SCD and the very early stages of Alzheimer's disease and other neurodegenerative diseases.