This weekend I started writing about the differentially expressed gene variants up-regulated and down-regulated in late onset alzheimer's disease (LOAD) and early onset alzheimer's disease (EOAD). My goal is to communicate genetic and environmental risk information to a broader audience. If our communities and eventually societies are well-versed in the science behind diseases--specifically Alzheimer's--we can begin to demand effective allocation of research dollars and governmental intervention for the development of a societal infrastructure to improve social determinants of health.
A 2015 article, Integrated genomic approaches identify major pathways and upstream regulators in late onset Alzheimer's disease, provides complicated science that could get lost if we don't pause and try and understand.
A 2015 article, Integrated genomic approaches identify major pathways and upstream regulators in late onset Alzheimer's disease, provides complicated science that could get lost if we don't pause and try and understand.
Certain mutations in APP, PSEN1 and PSEN2 inevitably lead to early-onset AD (EOAD) at around the age of 50 years in five percent of sufferers. Approximately 50% of the risk of late onset AD (LOAD) can be explained by genetic factors. The apolipoprotein E variant, APOE4, found in 15% of the population, is the major genetic risk factor for LOAD. APOE4 contributes around six percent to the phenotypic variance in AD, and it is estimated that between 40% and 65% of people diagnosed with AD have one or two copies of the variant APOE4 gene--Nature Publishing Group
Here is what you should notice so far. About half of LOAD risk is explained by genetics while the other half is conferred by modifiable risk factors. These risk factors are also implicated in "atherosclerosis, high blood cholesterol, midlife obesity, diabetes, smoking, physical inactivity and western diets." Both genetic and environmental risks share related mechanisms involving inflammation, cerebral blood flow, lipid metabolism and cellular processes although there is still much that we do not know about AD pathogenesis. The figure below is representative of the most significant identified pathways for up-regulated differentially expressed genes (DEGs) (red) and two down-regulated DEGs (green). The blue curve compares the number of DEGs and total number of genes in each of the pathways.
The most relevant data identified 30 DEGs strongly correlated to gene expression and Braak pathological stage or frontal atrophy in patients with AD. Braak pathological stage evaluates neurofibrillary changes that have characteristic distribution patterns differentiated into 6 stages.
Gene set enrichment analysis (GSEA) for NOROS.GSEA confirms that the NOROS gene set containing up-regulated LOAD DEGs is enriched in old people. Microarray data for aging (GSE53890) were analysed using GSEA software to identify significant gene sets (see Methods). The enrichment plot on the left shows the distribution of genes in the set that are correlated with the old or young phenotype. The heatmap on the right shows where gene expression is relatively high (red) or low (blue) for each gene in the indicated sample.
I discuss a bit of the science to contextualize recent findings and create awareness of the limitations of a $300 billion pursuit of a montherapeutic cure. We need to tell stories about the shared mechanisms of AD with chronic diseases associated with aging and the role of prevention. The greatest risk factor for AD is age. Exploring the shared characteristics between AD and normal aging--"the inflammatory pathway is activated, mitochondrial function is suppressed, and regenerative functions are activated". Regenerative functions are often tightly linked to metabolism, and alterations in metabolic state can directly influence activity.
The exciting part about attending the White House Conference on Aging? The ability to measure change and progress in the development of social programs that support our aging society. The conference is held every ten years so there are a lot of successes as well as requested needed interventions to address persistent gaps. I will be traveling the next few weeks to attend a few conferences--2015 National Conference on Health Statistics, Preventing Overdiagnosis meeting being held at the National Institutes of Health and INBOUND 2015, advances in creating a brand that resonates and provides value. Thank you for supporting, Alzheimer's Disease: The Brand. (@alzheimersbrand)
The exciting part about attending the White House Conference on Aging? The ability to measure change and progress in the development of social programs that support our aging society. The conference is held every ten years so there are a lot of successes as well as requested needed interventions to address persistent gaps. I will be traveling the next few weeks to attend a few conferences--2015 National Conference on Health Statistics, Preventing Overdiagnosis meeting being held at the National Institutes of Health and INBOUND 2015, advances in creating a brand that resonates and provides value. Thank you for supporting, Alzheimer's Disease: The Brand. (@alzheimersbrand)
