Alzheimer's disease (AD) develops over decades but the early, initiating pathological stresses are undefined. We report the first detailed molecular analysis of young adult, pre-AD histopathology brains from a heterozygous, endogenous fAD PRESENILIN (PSEN) mutation model (i.e. closely modeling the human fAD genetic state rather than attempting to phenocopy late-stage AD pathology). fAD mutation K115Efs truncates the coding sequence of PSEN2 to resemble the hypoxia- and cholesterol-inducible PSEN2 isoform PS2V. We modeled this mutation in zebrafish (K97Gfs in psen1). Heterozygous K97Gfs brains show a reduced unfolded protein response (UPR) despite the existence of a brain-specific homeostatic mechanism that upregulates transcripts from the non-mutant allele to maintain normal gene expression. Large, highly statistically significant differences are observed between the brain transcriptomes/proteomes of young adult heterozygous fAD-like mutant and non-mutant fish. Changes in behaviour and gene expression are observable in very young heterozygous mutant zebrafish larvae (facilitating future exploitation in unbiased drug screens). Systems biology analyses indicate that RNA/protein expression changes driven by the mutation might make the brain more susceptible to initiation of neuroinflammatory, metabolic and phosphorylation-state responses that would then be self-reinforcing. Our results support a model of early onset fAD whereby PSEN fAD mutations force changes in cellular state that prematurely occupy a proportion of cells' homeostatic capacity thereby lowering the threshold at which that homeostatic capacity is overwhelmed by cellular stressors such as hypoxia. Self-reinforcing pathological loops then drive the brain into a neurodegenerative state.