GSE203206
Transcriptomic profiling of sporadic Alzheimer's disease patients
Alzheimer's disease (AD) manifested before age 65 is commonly referred to as early-onset AD (EOAD). While the majority (>?90%) of EOAD cases are not caused by autosomal-dominant mutations in PSEN1, PSEN2, and APP, they do have a higher heritability (92–100%) than sporadic late-onset AD (LOAD, 70%). Although the endpoint clinicopathological changes, i.e., Aß plaques, tau tangles, and cognitive decline, are common across EOAD and LOAD, the disease progression is highly heterogeneous. This heterogeneity, leading to temporally distinct age at onset (AAO) and stages of cognitive decline, may be caused by myriad combinations of distinct disease-associated molecular mechanisms. We and others have used transcriptome profiling in AD patient-derived neuron models of autosomal-dominant EOAD and sporadic LOAD to identify disease endotypes. Further, analyses of large postmortem brain cohorts demonstrate that only one-third of AD patients show hallmark disease endotypes like increased inflammation and decreased synaptic signaling. Areas of the brain less affected by AD pathology at early disease stages—such as the primary visual cortex—exhibit similar transcriptomic dysregulation as those regions traditionally affected and, therefore, may offer a view into the molecular mechanisms of AD without the associated inflammatory changes and gliosis induced by pathology. To this end, we analyzed AD patient samples from the primary visual cortex (19 EOAD, 20 LOAD) using transcriptomic signatures to identify patient clusters and disease endotypes. Interestingly, although the clusters showed distinct combinations and severity of endotypes, each patient cluster contained both EOAD and LOAD cases, suggesting that AAO may not directly correlate with the identity and severity of AD endotypes. Overall design: Alzheimer's disease (AD) and healthy, non-demented control (NDC) samples were obtained from brain bank of samples preserved at the UC San Diego Shiley-Marcos Alzheimer's Disease Research Center (UCSD ADRC), extracting tissue from the occipital lobe (primary visual cortex, Brodmann Area 17, Bm-17) in accordance with UC San Diego IRB approval. A total of 48 samples were selected: 8 NDC and 40 AD patient samples. The 40 AD samples were selected based on their lack of alternative diagnosis (e.g. Lewy Body Dementia, hippocampal sclerosis) and stratified into two groups based on the age of onset of AD: early-onset, i.e. those with an age of onset less than 60 years (n=19), and late-onset, i.e. those with an age of onset between 70 and 80 years (n=21)