Sex-Specific Cross Tissue Meta-Analysis Identifies Immune Dysregulation in Women with Alzheimer’s Disease

Abstract

In spite of evidence of females having a greater lifetime risk of developing Alzheimer's Disease (AD) and greater apolipoprotein E4-related (apoE4) AD risk compared to males, molecular signatures underlying these findings remain elusive. We took a meta-analysis approach to study gene expression in the brains of 1,084 AD patients and age-matched controls and whole blood from 645 AD patients and age-matched controls. Gene-expression, network-based analysis and cell type deconvolution approaches revealed a consistent immune signature in the brain and blood of female AD patients that was absent in males. Machine learning-based classification of AD using gene expression from whole blood in addition to clinical features revealed an improvement in classification accuracy upon stratifying by sex, achieving an AUROC of 0.91 for females and 0.80 for males. These results help identify sex and apoE4 genotype-specific transcriptomic signatures of AD and underscore the importance of considering sex in the development of biomarkers and therapeutic strategies for AD.Alzheimer's disease (AD) is a progressive neurodegenerative disorder and the most common cause of dementia 1,2 . It is pathologically characterized by the deposition of extracellular amyloid β (Aβ) and intracellular tau, otherwise referred to as plaques and neurofibrillary tangles, respectively 3-5 . AD is also marked by neuronal loss, impaired neurotransmitter signaling, neuroinflammation, and dysregulation of neuronal metabolism and immune response in the central nervous system 6-8 . AD prevalence increases dramatically with age, where the majority of cases are in individuals above the age of 65 1,9 . Although AD was identified more than a century ago 10 , its cause and pathophysiology are not fully understood, and there are no available treatments that aid in halting or reversing the disease 11 . Accordingly, it is of high priority to tackle AD, as it is projected to triple in incidence by 2050 as a consequence of population aging 6,8,12 and, to date, has no disease-modifying therapies.While the exact cause and pathophysiology remain unknown, a number of mutations and genetic risk factors have been identified as associated with AD. Apolipoprotein E (apoE) is the most common genetic risk factor for late onset AD 8,13-18 . ApoE is a lipid binding protein, that plays a central role in lipid transport and metabolism. It is highly expressed in the brain, and is important for maintaining neuronal membranes during inflammation and damage. In humans, apoE has three isoforms, apoE2, apoE3, and apoE4, which are encoded by the three alleles, ε2, ε3, and ε4, of the apoE gene, respectively. The ε2 isoform has been shown to be protective against AD, while the ε4 isoform (apoE4) is associated with increasing the risk and lowering the age of onset for developing late onset AD in a gene dose-dependent manner 19,20 . Specifically, one copy of the ε4 isoform confers a 3 to 4-fold increased risk and 7 year decrease in age of onset, while two copies confers a 12 to 15-fold increased r...

Sex-stratified single-cell RNA-Seq analysis identifies sex-specific and cell type-specific transcriptional responses in Alzheimer’s disease across two brain regions.

“…We also observed more shared DEGs in AD case versus control female signatures versus male signatures across the cell types (Fig. 2a), which is consistent with previous bulk tissue analysis 34 . Some of the differentially expressed genes include LINGO1, a negative regulator of myelination 38,39 , which we found upregulated in all AD compared to control female cell types; SLC1A3, which encodes excitatory amino acid transporter 1 that transports glutamate in the synaptic cleft 40 and was perturbed in all female AD compared to control cell types except oligodendrocytes and OPCs; and SPP1, a protein involved in neuroinflammation also known as Osteopontin 41 that we observed to be upregulated in AD versus control samples of both female and male excitatory neurons and microglia, as well as female astrocytes and inhibitory neurons.…”

Association of sex and APOE ε4 with brain tau deposition and atrophy in older adults with Alzheimer's disease

“…Recent metabolic and transcriptomic data add potential mechanistic explanations to the findings of this study 34 - 37 . For example, prior work has found that specific metabolic effects were limited to FACs.…”

“…This provides an additional line of support for the findings drawn in this work. Moreover, in-vitro and transcriptomic data has suggested that sex modulates neuroinflammation, another risk factor for AD, with inflammatory dysregulation being stronger in females with AD 37 , 38 . APOE ε4 also triggers neuroinflammatory cascades that cause neurovascular dysfunction resulting in leakage of blood derived toxic proteins into the brain 39 .…”

Deep clinical phenotyping of Alzheimer’s Disease Patients Leveraging Electronic Medical Records Data Identifies Sex-Specific Clinical Associations

“…Recent studies in mice demonstrate that a second X chromosome may contribute to AD resilience 4 . Further sex-specific studies in AD also show sex modification of AD risk 8 , progression 9 , and molecular phenotype 9–12 . As such, sex is an important factor to consider in studying and phenotyping AD.…”

“…However, how sex modultes AD complexity and heterogeneity has still not been fully explored. Prior big data approaches to AD have examined genotype-phenotype associations 20, 21 and molecular analyses 12, 22, 23 to characterize AD disease and sex differences 10, 11 . Other work on phenotyping AD patients using clinical data has examined neuroimaging 24 , neuropsychiatric phenotype 25 , chart reviews 26 , and billing records independently.…”