Abstract
Aging is a major risk factor for late-onset Alzheimer’s disease (LOAD). How aging contributes to the development of LOAD remains elusive. In this study, we examined multiple large-scale transcriptomic datasets from both normal aging and LOAD brains to understand the molecular interconnection between aging and LOAD. We found that shared gene expression changes between aging and LOAD are mostly seen in the hippocampal and several cortical regions. In the hippocampus, the expression of phosphoprotein, alternative splicing and cytoskeleton genes are commonly changed in both aging and AD, while synapse, ion transport, and synaptic vesicle genes are commonly down-regulated. Aging-specific changes are associated with acetylation and methylation, while LOAD-specific changes are more related to glycoprotein (both up- and down-regulations), inflammatory response (up-regulation), myelin sheath and lipoprotein (down-regulation). We also found that normal aging brain transcriptomes from relatively young donors (45–70 years old) clustered into several subgroups and some subgroups showed gene expression changes highly similar to those seen in LOAD brains. Using brain transcriptomic datasets from another cohort of older individuals (>70 years), we found that samples from cognitively normal older individuals clustered with the “healthy aging” subgroup while AD samples mainly clustered with the “AD similar” subgroups. This may imply that individuals in the healthy aging subgroup will likely remain cognitively normal when they become older and vice versa. In summary, our results suggest that on the transcriptome level, aging and LOAD have strong interconnections in some brain regions in a subpopulation of cognitively normal aging individuals. This supports the theory that the initiation of LOAD occurs decades earlier than the manifestation of clinical phenotype and it may be essential to closely study the “normal brain aging” to identify the very early molecular events that may lead to LOAD development.
Highlights
Alzheimer’s disease (AD) is the most common cause of dementia and about 6.2 million Americans live with the disease based on the Alzheimer’s Association 2021 report (2021)
Genes differentially expressed between AD and normal control samples were extracted from previously published work
These AD signatures are MS AD sets from Mount Sinai Medical Center Brain Bank (MSBB) AD cohort (Wang et al, 2016), and “Other” AD sets included AMP-AD knowledge portal data (Hodes and Buckholtz, 2016), Jager gene lists from the dorsal lateral prefrontal cortex (DLPFC) region (Mostafavi et al, 2018), Annese2018 DEG list from hippocampal (HIPP) CA1 (Annese et al, 2018) and Rooij2019 DEG list in HIPP
Summary
Alzheimer’s disease (AD) is the most common cause of dementia and about 6.2 million Americans live with the disease based on the Alzheimer’s Association 2021 report (2021). A study analyzing 1,246 subjects aged 30–95 years found that the risk of developing AD dramatically increases in APOE ε4 carriers who are 70 years or older (Jack et al, 2015) It has been well-recognized that normal brain aging and LOAD share multiple common features, e.g., aging brains often manifest certain degrees of cognitive impairment, memory loss, metabolic disturbances, bioenergetic deficits, and inflammation. Even though aging increases the risk of AD and the two processes share similarities in multiple aspects, a detailed brain-regionspecific view of their interconnection at the molecular level is not fully available It is unclear which aging mechanisms are playing major contributions to AD development and why some individuals may age without major cognitive deficits while others develop AD (Koivisto et al, 1995; Herrup, 2010).
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