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.

Genetic discoveries of Alzheimer’s disease are the drivers of our understanding, and together with polygenetic risk stratification can contribute towards planning of feasible and efficient preventive and curative clinical trials. We first perform a large genetic association study by merging all available case-control datasets and by-proxy study results (discovery n = 409,435 and validation size n = 58,190). Here, we add six variants associated with Alzheimer’s disease risk (near APP, CHRNE, PRKD3/NDUFAF7, PLCG2 and two exonic variants in the SHARPIN gene). Assessment of the polygenic risk score and stratifying by APOE reveal a 4 to 5.5 years difference in median age at onset of Alzheimer’s disease patients in APOE ɛ4 carriers. Because of this study, the underlying mechanisms of APP can be studied to refine the amyloid cascade and the polygenic risk score provides a tool to select individuals at high risk of Alzheimer’s disease.

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.

ObjectiveIn a multi-center cohort of probable dementia with Lewy bodies (DLB), we tested the hypothesis that amyloid-β and tau biomarker positivity increases with age, which is modified by APOE genotype and sex, and that there are isolated and synergistic associations with the clinical phenotype.MethodsWe included 417 DLB patients (45–93 years, 31% women). Positivity on amyloid-β (A+) and tau (T+) biomarkers was determined by cerebrospinal fluid amyloid-β 1-42 and phosphorylated tau in the European cohort, and Pittsburgh compound-B and AV-1451 positron emission tomography in the Mayo Clinic cohort. Patients were stratified into 4 groups: A-T-, A+T-, A-T+, A+T+.ResultsA-T- was the largest group (39%), followed by A+T- (32%), A+T+ (15%), and A-T+ (13%). The percentage of A-T- decreased with age and A+ and T+ increased with age both in women and men. A+ increased more in APOE ε4 carriers with age than in non-carriers. A+ was the main predictor of lower cognitive performance when considered together with T+. T+ was associated with a lower frequency of parkinsonism and probable rapid eye movement sleep behavior disorder. There were no significant interactions between A+ and T+ in relation to the clinical phenotype.ConclusionsAlzheimer's disease pathologic changes are common in DLB and are associated with the clinical phenotype. Amyloid-β is associated with cognitive impairment and tau pathology is associated with lower frequency of clinical features of DLB. These findings have important implications for diagnosis, prognosis, and disease monitoring, as well as for clinical trials targeting disease-specific proteins in DLB.Classification of evidenceThis study provides Class II evidence that in patients with probable DLB, amyloid-β is associated with lower cognitive performance and tau pathology is associated with lower frequency of clinical features of DLB.

Introduction: Large variability among Alzheimer's disease (AD) cases might impact genetic discoveries and complicate dissection of underlying biological pathways. Methods: Genome Research at Fundacio ACE (GR@ACE) is a genome-wide study of dementia and its clinical endophenotypes, defined based on AD's clinical certainty and vascular burden. We assessed the impact of known AD loci across endophenotypes to generate loci categories. We incorporated gene coexpression data and conducted pathway analysis per category. Finally, to evaluate the effect of heterogeneity in genetic studies, GR@ACE series were meta-analyzed with additional genome-wide association study data sets. Results: We classified known AD loci into three categories, which might reflect the disease clinical heterogeneity. Vascular processes were only detected as a causal mechanism in probable AD. The meta-analysis strategy revealed the ANKRD31-rs4704171 and NDUFAF6-rs10098778 and confirmed SCIMP-rs7225151 and CD33-rs3865444. Discussion: The regulation of vasculature is a prominent causal component of probable AD. GR@ACE meta-analysis revealed novel AD genetic signals, strongly driven by the presence of clinical heterogeneity in the AD series.

The use of optical coherence tomography (OCT) has been suggested as a potential biomarker for Alzheimer’s Disease based on previously reported thinning of the retinal nerve fiber layer (RNFL) in Alzheimer’s disease’s (AD) and Mild Cognitive Impairment (MCI). However, other studies have not shown such results. 930 individuals (414 cognitively healthy individuals, 192 probable amnestic MCI and 324 probable AD) attending a memory clinic were consecutively included and underwent spectral domain OCT (Maestro, Topcon) examinations to assess differences in peripapillary RNFL thickness, using a design of high ecological validity. Adjustment by age, education, sex and OCT image quality was performed. We found a non-significant decrease in mean RNFL thickness as follows: control group: 100,20 ± 14,60 µm, MCI group: 98,54 ± 14,43 µm and AD group: 96,61 ± 15,27 µm. The multivariate adjusted analysis revealed no significant differences in mean overall (p = 0.352), temporal (p = 0,119), nasal (p = 0,151), superior (p = 0,435) or inferior (p = 0,825) quadrants between AD, MCI and control groups. These results do not support the usefulness of peripapillary RNFL analysis as a marker of cognitive impairment or in discriminating between cognitive groups. The analysis of other OCT measurements in other retinal areas and layers as biomarkers for AD should be tested further.

Background & Objective The aim of this study was to describe the rate and clinical predictors of cognitive decline in dementia with Lewy bodies (DLB), and compare the findings with Alzheimer’s disease (AD) and Parkinson’s disease dementia (PDD) patients. Methods Longitudinal scores for the Mini-Mental State Examination (MMSE) in 1290 patients (835 DLB, 198 PDD and 257 AD) were available from 18 centers with up to three years longitudinal data. Linear mixed effects analyses with appropriate covariates to model MMSE decline over time. Several subgroup analyses were performed, defined were run by anti-dementia medication use, baseline MMSE score, and DLB core features. Results The mean annual decline in MMSE score was 2.1 points in DLB, compared to 1.6 in AD (p=0.07 compared to DLB) and 1.8 in PDD (p=0.19). Rates of decline were significantly higher in DLB compared to AD and PDD when baseline MMSE score was included as a covariate, and when only those DLB patients with an abnormal dopamine transporter SPECT scan were included. Decline was not predicted by sex, baseline MMSE score, or presence of specific DLB core features. Conclusions The average annual decline in MMSE score in DLB is approximately two points. Although in the overall analyses there were no differences in the rate of decline between the three neurodegenerative disorders, there were indications of a more rapid decline in DLB than in AD and PDD. Further studies are needed to understand the predictors and mechanisms of cognitive decline in DLB.

Reduced levels of CSF amyloid beta 1-42 were associated with more rapid cognitive decline in Lewy body dementia patients. Future prospective studies should include larger samples, centralized CSF analyses, longer follow-up, and biomarker-pathology correlation. © 2016 International Parkinson and Movement Disorder Society.