Abstract
Across the population, individuals exhibit a wide variation of susceptibility or resilience to developing Alzheimer’s disease (AD). Identifying specific factors that promote resilience would provide insight into disease mechanisms and nominate potential targets for therapeutic intervention. Here, we use transcriptome profiling to identify gene networks present in the pre-symptomatic AD mouse brain relating to neuroinflammation, brain vasculature, extracellular matrix organization, and synaptic signaling that predict cognitive performance at an advanced age. We highlight putative drivers of these observed relationships, including Itgb2, Fcgr2b, Slc6a14, and Gper1, which represent prime targets through which to promote resilience prior to overt symptom onset. In addition, we identify a genomic region on chromosome 2 containing variants that directly modulate resilience network expression. Overall, work here highlights new potential drivers of resilience to AD and contributes significantly to our understanding of early, potentially causal, disease mechanisms.
Highlights
Alzheimer’s disease (AD) is the most common neurodegenerative disease, characterized by a combination of severe memory impairment and two classical neuropathologies, extracellular amyloid plaques and intracellular neurofibrillary tangles (Selkoe, 1991)
Using gene set enrichment analysis (GSEA), a slight but significant upregulation of genes enriched for immune-related functions was observed (Figure 2A), suggesting neuroinflammation increases with age in the AD-BXDs
As expected based on Gene Ontology (GO) term enrichments, down-regulated genes that show celltype specificity in their expression profiles showed enrichment for neuronal localization (Figure 2D, hypergeometric test, p < 0.0001), reminiscent of neurodegeneration observed in the classical 5XFAD model (Oakley et al, 2006) and human AD patients (Crews and Masliah, 2010)
Summary
Alzheimer’s disease (AD) is the most common neurodegenerative disease, characterized by a combination of severe memory impairment and two classical neuropathologies, extracellular amyloid plaques and intracellular neurofibrillary tangles (Selkoe, 1991). Many imaging and post-mortem studies of human brains have shown that substantial amounts of AD pathology, plaque pathology, can be present in the brains of cognitively intact individuals (Morris et al, 1996; Negash et al, 2013) These individuals, who often meet the criteria for a pathological diagnosis of AD but remain asymptomatic, represent a clinically interesting subset of the population that exhibit a certain degree of resilience to what are typically highly deleterious neuropathologies. While FAD is typically thought to be a severe form of the disease with an age of onset before 65, there is a wide range in the age at first symptom onset (Ryman et al, 2014) In both sporadic late-onset AD (LOAD) and FAD, disease onset is highly heritable (Gatz et al, 1997), indicating genetic factors likely play a large role in determining individual susceptibility or resilience. Identifying these specific genetic factors, those that promote resilience, would provide key insight into disease mechanisms and nominate putative targets for therapeutic intervention, as strategies that delay disease onset even by a few years would provide much needed disease modifying therapies
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