Aging-focused transcriptome-wide association study reveals opposing PI3K–AKT–mTOR and PGC-1α architectures in ALS and frontotemporal dementia

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) share clinical, pathological, and genetic features, but they differ in their main clinical presentations and in the structure of their genetic risk. To examine whether aging-related pathways are engaged differently in these disorders, we performed a transcriptome-wide association study using S-PrediXcan across 42 curated gene sets covering NAD metabolism, mitochondrial biogenesis, mTOR and AMPK signaling, senescence, apoptosis, synaptic function, and glial biology. Summary statistics were drawn from large ALS and sporadic FTD genome-wide association studies (Manzoni et al., 2024; van Rheenen et al., 2021). Five gene set by disease combinations met permutation significance. In ALS, PI3K–AKT–mTOR signaling showed positive enrichment, whereas oxidative phosphorylation showed negative enrichment. In FTD, the strongest negative signals involved PGC-1α-related mitochondrial biogenesis and PI3K–AKT–mTOR, along with a SIRT1-linked metabolic set. Direct comparison between diseases identified MOOTHA PGC and PI3K–AKT–mTOR as the clearest differentiating pathways, with opposite directions of genetically predicted expression. Together, these findings support a two-axis model in which ALS is marked by TBK1-centered mTOR and autophagy stress together with mitochondrial energy deficit, whereas FTD is characterized by failure of PGC-1α-driven biogenesis and RIPK1 and MAPK stress signaling. These results point to pathway-state-specific biomarkers and therapeutic hypotheses for more precise approaches across the ALS–FTD spectrum.