The Lipid Encephalisation and Mismatch Hypothesis (LEMH): An Evolutionary Framework Linking APOE Allele Evolution, Hominin Encephalisation, and Neuroinflammatory Vulnerability

APOE4 carriers exhibit a disproportionately high burden of neuroinflammatory and neurodegenerative disease, yet no comprehensive framework has previously linked APOE allele evolution to modern neurological vulnerability. The Lipid Encephalisation and Mismatch Hypothesis (LEMH) proposes an evolutionary system rooted in Miocene hominoid genomics (~15 Ma) and extending across ~3.3 million years of increasingly lipid-dense foraging ecologies that shaped successive APOE variants. Within this model, the APOE-Dependent Cascade is introduced: APOE4 established the ancestral lipid-transport and ketogenic architecture required for encephalisation; APOE3 introduced metabolic flexibility; and APOE2 further optimised system efficiency. In modern nutritional environments characterised by reduced reliance on ancestral lipid substrates and altered metabolic signalling APOE variants, particularly APOE4, are expressed under conditions that diverge sharply from those in which their functional roles evolved. LEMH identifies this discordance as a two-hit evolutionary mismatch, providing a mechanistic explanation for elevated neuroinflammatory and neurodegenerative phenotypes in APOE4 carriers. Within this framework, Alzheimer’s disease risk is not attributed to intrinsic pathogenicity of APOE4, but to its operation in a dietary milieu that disrupts the metabolic context required for normative APOE-mediated lipid transport and neural homeostasis. The hypothesis introduces five theoretical contributions: the integrative LEMH framework; the APOE4 Hepatic Selection-Pressure Forge; the APOE-Dependent Cascade; the Phylogenetic Mismatch Model — which identifies the uric acid–fructokinase axis as both the ancestral selective forge of APOE4 and the primary mechanism of its modern pathological expression; and a Four-Domain Co-evolutionary Convergence argument spanning archaeology, morphology, dietary ecology, and genomics. LEMH further distinguishes proximate from ultimate clinical interventions, positioning the Neurolithic Diet as an explicitly ultimate-level theoretical concept aimed at restoring the ancestral metabolic conditions under which APOE4 was adaptive. The framework generates six falsifiable predictions testable across existing biobank resources, cross-cultural cohort comparisons, and archaeological skeletal collections, including near-term analyses executable within UK Biobank infrastructure without new data collection.