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.

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.

Application of biological age as a measure of an individual´s health status offers new perspectives into extension of both lifespan and healthspan. While algorithms predicting mortality and most aging-related morbidities have been reported, the major shortcoming has been an inability to predict dementia. We present a community-based cohort study of 1930 participants with a mean age of 72 years and a follow-up period of over 7 years, using two variants of a phenotypic blood-based algorithm that either excludes (BioAge1) or includes (BioAge2) neurofilament light chain (NfL) as a neurodegenerative marker. BioAge1 and BioAge2 predict dementia equally well, as well as lifespan and healthspan. Each one-year increase in BioAge1/2 was associated with 11% elevated risk (HR 1.11; 95%CI 1.08–1.14) of mortality and 7% elevated risk (HR 1.07; 95%CI 1.05–1.09) of first morbidities. We additionally tested the association of microRNAs with age and identified 263 microRNAs significantly associated with biological and chronological age alike. Top differentially expressed microRNAs based on biological age had a higher significance level than those based on chronological age, suggesting that biological age captures aspects of aging signals at the epigenetic level. We conclude that accelerated biological age for a given age is a predictor of major age-related morbidity, including dementia, among healthy elderly.

Background and purpose This study was undertaken to compare risk factors, neuroimaging characteristics and prognosis between two clinical prodromes of dementia, namely, the motoric cognitive risk syndrome (MCRS) and mild cognitive impairment (MCI). Methods Between 2009 and 2015, dementia‐free participants of the population‐based Rotterdam Study were classified with a dementia prodrome if they had subjective cognitive complaints and scored >1 SD below the population mean of gait speed (MCRS) or >1.5 SD below the population mean of cognitive test scores (MCI). Using multinomial logistic regression models, we determined cross‐sectional associations of risk factors and structural neuroimaging markers with MCRS and MCI, followed by subdistribution hazard models, to determine risk of incident dementia until 2016. Results Of 3025 included participants (mean age = 70.4 years, 54.7% women), 231 had MCRS (7.6%), 132 had MCI (4.4%), and 62 (2.0%) fulfilled criteria for both. Although many risk factors were shared, a higher body mass index predisposed to MCRS, whereas male sex and hypercholesterolemia were associated with MCI only. Gray matter volumes, hippocampal volumes, white matter hyperintensities, and structural white matter integrity were worse in both MCRS and MCI. During a mean follow‐up of 3.9 years, 71 individuals developed dementia and 200 died. Five‐year cumulative risk of dementia was 7.0% (2.5%–11.5%) for individuals with MCRS, versus 13.3% (5.8%–20.8%) with MCI and only 2.3% (1.5%–3.1%) in unaffected individuals. Conclusions MCRS is associated with imaging markers of neurodegeneration and risk of dementia, even in the absence of MCI, highlighting the potential of motor function assessment in early risk stratification for dementia.