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.

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.

Women carrying germ-line mutations in BRCA1 are strongly predisposed to developing breast cancers with characteristic features also observed in sporadic basal-like breast cancers. They appear as high-grade tumors with high proliferation rates and pushing borders. On the molecular level, they are negative for hormone receptors and ERBB2, display frequent TP53 mutations, and express basal epithelial markers. To study the role of BRCA1 and P53 loss of function in breast cancer development, we generated conditional mouse models with tissue-specific mutation of Brca1 and/or p53 in basal epithelial cells. Somatic loss of both BRCA1 and p53 resulted in the rapid and efficient formation of highly proliferative, poorly differentiated, estrogen receptor-negative mammary carcinomas with pushing borders and increased expression of basal epithelial markers, reminiscent of human basal-like breast cancer. BRCA1-and p53-deficient mouse mammary tumors exhibit dramatic genomic instability, and their molecular signatures resemble those of human BRCA1-mutated breast cancers. Thus, these tumors display important hallmarks of hereditary breast cancers in BRCA1-mutation carriers.mouse models ͉ conditional knockout G erm-line mutations in the human breast cancer susceptibility gene BRCA1 are responsible for 40% to 50% of hereditary breast cancers and confer increased risk for development of ovarian, colon, and prostate cancers (1, 2). BRCA1 has been implicated in various cellular processes, including maintenance of genome integrity, DNA replication and repair, chromatin remodeling, and transcriptional regulation (3, 4). Although the exact mechanism of mammary tumor suppression by BRCA1 remains largely unknown, cells with dysfunctional BRCA1 show defects in survival and proliferation, increased radiosensitivity, chromosomal abnormalities, G 2 /M checkpoint loss, and impaired homologous recombination repair (5).BRCA1-mutated breast cancers that arise in women with germline mutations in BRCA1 are high-grade, hormone receptornegative breast carcinomas with frequent mutation of TP53 (4, 6). They also possess a basal-like phenotype as defined by the expression of markers that are typical for basal/myoepithelial cells, such as the basal cytokeratins (CKs) CK5/6 and CK14 (7). Indeed, strong molecular similarities are observed between hereditary BRCA1-mutated breast cancers and sporadic basal-like breast carcinomas (8,9). This phenotypic overlap has led to the hypothesis that sporadic basal-like cancers may have defects in BRCA1-related pathways, such as the amplification of EMSY and the methylation of BRCA1 and FANCF (10).Despite the fact that several mouse strains with conventional or conditional mutations in Brca1 have been generated (11), no good mouse model for BRCA1-mutated basal-like breast cancer has been developed so far. Most conventional Brca1 knockouts are embryonic-lethal when bred to homozygosity, yet heterozygous ⌬11 allele, which encodes BRCA1-⌬11, a naturally occurring splice variant of Brca1 (19). Mouse mammary tumor models ba...