Alzheimer's disease (AD) is characterized by neuronal loss and astrocytosis in the cerebral cortex. However, the effects of brain cellular composition are often ignored in high-throughput molecular studies. We developed and optimized a cell-type specific expression reference panel and employed digital deconvolution methods to determine brain cellular distribution in three independent transcriptomic studies. We found that neuronal and astrocyte proportions differ between healthy and diseased brains and also among AD cases that carry specific genetic risk variants. Brain carriers of pathogenic mutations in APP, PSEN1 or PSEN2 presented lower neurons and higher astrocytes proportions compared to sporadic AD. Similarly, the APOE ε4 allele also showed decreased neurons and increased astrocytes compared to AD non-carriers. On the contrary, carriers of variants in TREM2 risk showed a lower degree of neuronal loss than matched AD cases in multiple independent studies. These findings suggest that genetic risk factors associated with AD etiology have a specific imprinting in the cellular composition of AD brains. Our digital deconvolution reference panel provides an enhanced understanding of the fundamental molecular mechanisms underlying neurodegeneration, enabling the analysis of large bulk RNA-seq studies for cell composition, and suggests that correcting for the cellular structure when performing transcriptomic analysis will lead to novel insights of AD.
KeywordsDigital deconvolution, Alzheimer's disease, cellular composition, bulk RNA-seq, autosomal dominant AD, TREM2.. CC-BY-NC-ND 4.0 International license It is made available under a (which was not peer-reviewed) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.The copyright holder for this preprint . http://dx.doi.org/10.1101/266296 doi: bioRxiv preprint first posted online Feb. 15, 2018; 3
IntroductionAlzheimer's Disease (AD) is a neurodegenerative disorder characterized clinically by gradual and progressive memory loss and pathologically by the presence of senile plaques (Aβ deposits) and neurofibrillary tangles (NFTs, Tau deposits) in the brain [41]. AD has a substantial but heterogeneous genetic component. Mutations in the amyloid-beta precursor protein (APP) and Presenilin genes (PSEN1 and PSEN2) [21, 59] cause autosomal dominant AD (ADAD) which is typically associated with early-onset (<65 years). In contrast, the most common manifestation of AD presents late-onset (LOAD) and accounts for the majority of the cases (90-95%). Despite appearing sporadic in nature, a complex genetic architecture underlies LOAD risk. APOE ε4 is the most common genetic risk factor, increasing the risk in 3-to 8-fold [19]. In addition, recent whole genome and whole exome analysis have identified rare coding variants in TREM2 [9,32], PLD3 [20], ABCA7 [22,63] and SORL1 [26,56] that are associated with AD and confer risk comparable to that of carrying one APOE ε4 allele. Besides age at onset, the clinical presentations of LOAD a...