Exploratory chromosome 14-focused transcriptomic profiling of PSEN1-associated familial Alzheimer's disease across brain regions

Abstract

Familial Alzheimer's disease (FAD) is an inherited form of early-onset Alzheimer's disease associated with pathogenic variants in presenilin 1 (PSEN1). To explore chromosome 14-associated transcriptional patterns in FAD across anatomically distinct brain regions, publicly available RNA sequencing (RNA-Seq) datasets from frontal cortex, temporal cortex, and whole-brain samples were analyzed. Because one FAD sample and one control sample were available for each brain region, expression differences were evaluated descriptively using observed log₂ fold-change values rather than conventional inferential differential-expression statistics. Functional annotation and protein–protein interaction analyses were subsequently used to provide biological context for the observed expression patterns. Distinct regional expression patterns were observed within the chromosome 14-focused dataset. Higher expression was observed for representative genes including FITM1, IFI27, AHSA1, and NFKBIA in the frontal cortex, and DHRS4L2, ESR2, GPR65, EFCAB11, and HOMEZ in the temporal cortex. The observed expression patterns were associated with inflammatory, cellular stress, metabolic, receptor-mediated, proteostatic, and neuronal signaling-related functions. Network analysis was used to contextualize these expression patterns rather than to infer causal regulatory relationships. Five representative proteins—NFKBIA, ESR2, GPR65, AHSA1, and IFI27—were further examined structural information to provide structural context for selected transcriptomic observations. Given the absence of biological replication and the chromosome 14-focused design, these findings should be considered descriptive and hypothesis-generating. Independent replicated cohorts and complementary transcriptomic, proteomic, and functional studies are required to determine the reproducibility and biological relevance of the observed patterns.