Shared genetic etiology underlying Alzheimer’s disease and major depressive disorder

Abstract

Patients with late-onset Alzheimer's disease (LOAD) frequently manifest comorbid neuropsychiatric symptoms with depression and anxiety being most frequent, and individuals with major depressive disorder (MDD) have an increased prevalence of LOAD. This suggests shared etiologies and intersecting pathways between LOAD and MDD. We performed pleiotropy analyses using LOAD and MDD GWAS data sets from the International Genomics of Alzheimer's Project (IGAP) and the Psychiatric Genomics Consortium (PGC), respectively. We found a moderate enrichment for SNPs associated with LOAD across increasingly stringent levels of significance with the MDD GWAS association (LOAD| MDD), of maximum four and eightfolds, including and excluding the APOE-region, respectively. Association analysis excluding the APOE-region identified numerous SNPs corresponding to 40 genes, 9 of which are known LOAD-risk loci primarily in chromosome 11 regions that contain the SPI1 gene and MS4A genes cluster, and others were novel pleiotropic risk-loci for LOAD conditional with MDD. The most significant associated SNPs on chromosome 11 overlapped with eQTLs found in whole-blood and monocytes, suggesting functional roles in gene regulation. The reverse conditional association analysis (MDD|LOAD) showed a moderate level,~sevenfold, of polygenic overlap, however, no SNP showed significant association. Pathway analyses replicated previously reported LOAD biological pathways related to immune response and regulation of endocytosis. In conclusion, we provide insights into the overlapping genetic signatures underpinning the common phenotypic manifestations and inter-relationship between LOAD and MDD. This knowledge is crucial to the development of actionable targets for novel therapies to treat depression preceding dementia, in an effort to delay or ultimately prevent the onset of LOAD.

Single-cell mass cytometry of microglia in major depressive disorder reveals a non-inflammatory phenotype with increased homeostatic marker expression

“…Interestingly, the brains of individuals resilient to dementia despite robust Alzheimer’s neuropathology (amyloid plaques and neurofibrillary tangles) displayed lower numbers of CD68 + microglia in the temporal lobe and higher levels of the cytokines IL-6, IL-1β, IL-10 73 . Recent evidence from genome-wide association studies suggests shared genetic architecture between MDD and late-onset Alzheimer’s disease 74 , 75 , and some of the identified genes were highly expressed in monocytes/macrophages and involved in immune response and endocytosis. However, the findings of our high-dimensional single-cell analysis of microglia in MDD do not lend support to neuroinflammatory changes in any of the examined cortical and subcortical brain regions.…”

Cell-type Specific Expression Quantitative Trait Loci Associated with Alzheimer Disease in Blood and Brain Tissue

“…Expression of RPL9 is downregulated in severe AD 66 and significantly differs by sex among persons with the APOE □4 allele 67 . Significant evidence of association with a TRIM49B SNP was found in a genome-wide pleiotropy GWAS of AD and major depressive disorder (MDD) 68 .…”

Gene-Editing Technologies Paired With Viral Vectors for Translational Research Into Neurodegenerative Diseases

“…Importantly, many of these therapeutics very effectively cleared beta-amyloid plaques from the brain, yet patients saw no improvements, nor delays in disease progression. If the mechanisms underlying these diseases can be fully elucidated, the potential for prevention or reversal of progression and pathophysiology will increase considerably (Gottschalk et al, 2016 ; Tagliafierro and Chiba-Falek, 2016 ; Kampmann, 2017 ; Lutz et al, 2020 ).…”