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.

Memory is an essential element to adaptive behavior since it allows consolidation of past experience guiding the subject to consider them in future experiences. Among the endogenous molecules that participate in the consolidation of memory, including the drug-seeking reward, considered as a form of learning, is dopamine. This neurotransmitter modulates the activity of specific brain nucleus such as nuclei accumbens, putamen, ventral tegmental area (VTA), among others and synchronizes the activity of these nuclei to establish the neurobiological mechanism to set the hedonic element of learning. We review the experimental evidence that highlights the activity of different brain nuclei modulating the mechanisms whereby dopamine biases memory towards events that are of motivational significance.

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.

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.