Alzheimer’s disease (AD) is the most common cause of dementia in the elderly and the sixth leading cause of death in the United States. AD is mainly considered a complex disorder with polygenic inheritance. Despite discovering many susceptibility loci, a major proportion of AD genetic variance remains to be explained. We investigated the genetic architecture of AD in four publicly available independent datasets through genome-wide association, transcriptome-wide association, and gene-based and pathway-based analyses. To explore differences in the genetic basis of AD between males and females, analyses were performed on three samples in each dataset: males and females combined, only males, or only females. Our genome-wide association analyses corroborated the associations of several previously detected AD loci and revealed novel significant associations of 35 single-nucleotide polymorphisms (SNPs) outside the chromosome 19q13 region at the suggestive significance level of p < 5E–06. These SNPs were mapped to 21 genes in 19 chromosomal regions. Of these, 17 genes were not associated with AD at genome-wide or suggestive levels of associations by previous genome-wide association studies. Also, the chromosomal regions corresponding to 8 genes did not contain any previously detected AD-associated SNPs with p < 5E–06. Our transcriptome-wide association and gene-based analyses revealed that 26 genes located in 20 chromosomal regions outside chromosome 19q13 had evidence of potential associations with AD at a false discovery rate of 0.05. Of these, 13 genes/regions did not contain any previously AD-associated SNPs at genome-wide or suggestive levels of associations. Most of the newly detected AD-associated SNPs and genes were sex specific, indicating sex disparities in the genetic basis of AD. Also, 7 of 26 pathways that showed evidence of associations with AD in our pathway-bases analyses were significant only in females. Our findings, particularly the newly discovered sex-specific genetic contributors, provide novel insight into the genetic architecture of AD and can advance our understanding of its pathogenesis.

Decline in biological resilience (ability to recover) is a key manifestation of aging that contributes to increase in vulnerability to death with age eventually limiting longevity even in people without major chronic diseases. Understanding the mechanisms of this decline is essential for developing efficient anti-aging and pro-longevity interventions. In this paper we discuss: a) mechanisms of the decline in resilience with age, and aging components that contribute to this decline, including depletion of body reserves, imperfect repair mechanisms, and slowdown of physiological processes and responses with age; b) anti-aging interventions that may improve resilience or attenuate its decline; c) biomarkers of resilience available in human and experimental studies; and d) genetic factors that could influence resilience. There are open questions about optimal anti-aging interventions that would oppose the decline in resilience along with extending longevity limits. However, the area develops quickly, and prospects are exciting.