New insights into the genetic etiology of Alzheimer's disease and related dementias

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

External validation of the KORA S4/F4 prediction models for the risk of developing type 2 diabetes in older adults: the PREVEND study

Recently, prediction models for type 2 diabetes mellitus (T2DM) in older adults (aged >/=55 year) were developed in the KORA S4/F4 study, Augsburg, Germany. We aimed to externally validate the KORA models in a Dutch population. We used data on both older adults (n = 2,050; aged >/=55 year) and total non-diabetic population (n = 6,317; aged 28-75 year) for this validation. We assessed performance of base model (model 1: age, sex, BMI, smoking, parental diabetes and hypertension) and two clinical models: model 1 plus fasting glucose (model 2); and model 2 plus uric acid (model 3). For 7-year risk of T2DM, we calculated C-statistic, Hosmer-Lemeshow chi(2)-statistic, and integrated discrimination improvement (IDI) as measures of discrimination, calibration and reclassification, respectively. After a median follow-up of 7.7 years, 199 (9.7%) and 374 (5.9%) incident cases of T2DM were ascertained in the older and total population, respectively. In the older adults, C-statistic was 0.66 for model 1. This was improved for model 2 and model 3 (C-statistic = 0.81) with significant IDI. In the total population, these respective C-statistics were 0.77, 0.85 and 0.85. All models showed poor calibration (P < 0.001). After adjustment for the intercept and slope of each model, we observed good calibration for most models in both older and total populations. We validated the KORA clinical models for prediction of T2DM in an older Dutch population, with discrimination similar to the development cohort. However, the models need to be corrected for intercept and slope to acquire good calibration for application in a different setting

New insights into the genetic etiology of Alzheimer’s disease and related dementias

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. © 2022, The Author(s)