Genetic variants and functional pathways associated with resilience to Alzheimer's disease.

Approximately 30% of older adults exhibit the neuropathological features of Alzheimer's disease without signs of cognitive impairment. Yet, little is known about the genetic factors that allow these potentially resilient individuals to remain cognitively unimpaired in the face of substantial neuropathology. We performed a large, genome-wide association study (GWAS) of two previously validated metrics of cognitive resilience quantified using a latent variable modelling approach and representing better-than-predicted cognitive performance for a given level of neuropathology. Data were harmonized across 5108 participants from a clinical trial of Alzheimer's disease and three longitudinal cohort studies of cognitive ageing. All analyses were run across all participants and repeated restricting the sample to individuals with unimpaired cognition to identify variants at the earliest stages of disease. As expected, all resilience metrics were genetically correlated with cognitive performance and education attainment traits (P-values < 2.5 × 10-20), and we observed novel correlations with neuropsychiatric conditions (P-values < 7.9 × 10-4). Notably, neither resilience metric was genetically correlated with clinical Alzheimer's disease (P-values > 0.42) nor associated with APOE (P-values > 0.13). In single variant analyses, we observed a genome-wide significant locus among participants with unimpaired cognition on chromosome 18 upstream of ATP8B1 (index single nucleotide polymorphism rs2571244, minor allele frequency = 0.08, P = 2.3 × 10-8). The top variant at this locus (rs2571244) was significantly associated with methylation in prefrontal cortex tissue at multiple CpG sites, including one just upstream of ATPB81 (cg19596477; P = 2 × 10-13). Overall, this comprehensive genetic analysis of resilience implicates a putative role of vascular risk, metabolism, and mental health in protection from the cognitive consequences of neuropathology, while also providing evidence for a novel resilience gene along the bile acid metabolism pathway. Furthermore, the genetic architecture of resilience appears to be distinct from that of clinical Alzheimer's disease, suggesting that a shift in focus to molecular contributors to resilience may identify novel pathways for therapeutic targets.

Profiles of Depressive Symptoms and Anger in Men: Associations With Postpartum Family Functioning.

Background: Evidence suggests that men commonly experience depression as feelings of anger; yet, research has not investigated what this means for the manifestation of depressive symptoms in the early years of fatherhood and for key indicators of family functioning. Methods: Using data from a longitudinal cohort study of men at the normative age for entering fatherhood (28-32 years), we conducted latent class analyses to identify patterns of depressive symptoms and 3 sub-types of state anger (feeling; verbal; physical). We then assessed whether class membership was associated with paternity status (n = 535). In a subsample of fathers of infants aged up to 18 months (n = 162), we prospectively assessed associations with paternal-infant bonding, co-parenting, perceived social support, paternal involvement in childcare and alcohol use up to 2 years later. Results: Five classes emerged that differentiated men by anger and depressive symptom severity and by the degree to which men endorsed the feeling of wanting to express anger physically. Compared to the reference class with minimal symptoms, fathers had a higher probability of being in either the mild or most severe symptom classes. Men in symptomatic classes were at higher risk of lower levels of social support, co-parenting problems, and paternal-infant bonds. Class membership was not associated with alcohol use or paternal involvement in childcare. Conclusions: Our results reveal patterns of co-existing symptoms of depression and anger in fathers of infants that will be relevant to men's own need for support, their family safety, partner mental health and child developmental outcomes.