The hypothesis LEMH proposes that progressive dietary shifts across the Homo lineage — from marrow to organ meat to brain tissue to marine resources — drove successive innovations in the APOE allele sequence, enabling hominin brain expansion over approximately 1.5 million years. The modern removal of those ancestral lipid conditions explains the disproportionate neuroinflammatory and neurodegenerative burden carried by APOE4 carriers today.

APOE4's association with Alzheimer's disease appears to be strongly contingent on dietary environment. Populations carrying the allele on ancestral-pattern diets show dramatically attenuated risk compared to those on modern Western diets. LEMH proposes that it is the mismatch, not the allele, that drives pathology — APOE4 is a conditionally expressed adaptive allele, not an intrinsically pathogenic one.

The APOE-Dependent Cascade APOE4 was not merely the first allele in a sequence — it was the necessary prerequisite for all subsequent APOE evolution. APOE4 built the ancestral ketogenic and lipid-transport architecture required for brain expansion. APOE3 introduced metabolic flexibility. APOE2 maximised system efficiency. The cascade is strictly dependent: each allele becomes selectable only within the metabolic context created by its predecessor.

The mismatch mechanism The central claim of LEMH is precise: the metabolic axis that originally drove APOE4 selection is the same axis whose modern activation produces APOE4 pathology. That axis is the uric-acid–fructokinase pathway.

In the ancestral environment, systematic organ-meat consumption delivered extreme purine loads to a lineage that had already lost functional uricase — driving uric acid elevation that provided powerful antioxidant cover for an encephalising brain. This hepatic challenge was the primary selective pressure behind APOE4's emergence. APOE4 raised the metabolic ceiling for organ-meat consumption, and in doing so built the ketogenic architecture that sustained large-brain energetics for over a million years.

The agricultural transition (~10,000 years ago) replaced dietary fat with carbohydrate as the dominant macronutrient, suppressing the ketogenic metabolism the APOE4 architecture was built to sustain. The industrial dietary transition (~150 years ago) introduced chronic fructose exposure — via sucrose, high-fructose corn syrup, and the polyol pathway under high-glycaemic load — that reactivates the same uric-acid–fructokinase axis at intensities far beyond anything the ancestral environment produced, but now without the ketogenic counterbalance that once regulated it.

The selective forge of APOE4 and the mechanism of its modern vulnerability are therefore not separate stories. They are the same metabolic axis, viewed from opposite ends of evolutionary time. Modern APOE4 pathology is, in this reading, retrospective evidence of the original selection pressure.

Cross-cultural evidence The prediction that APOE4 neurodegeneration risk is environmentally contingent is supported across multiple independent populations. Nigerian APOE4 carriers on traditional dietary patterns show substantially attenuated Alzheimer's risk compared to African American APOE4 carriers with identical allele prevalence and shared ancestry. The Tsimane of Bolivia — maintaining a traditional subsistence ecology — show the lowest recorded cardiovascular disease rates of any studied population, despite high APOE4 prevalence. Traditional Inuit populations showed low neurodegeneration on fat-dominant ancestral diets, with rates rising toward Western levels as dietary patterns industrialised. Across four independent populations, the pattern is consistent: APOE4 pathology tracks dietary mismatch, not allele frequency.

The Neurolithic Diet The Neurolithic Diet is an evolutionary dietary concept derived from LEMH — a genotype-stratified framework for restoring the ancestral metabolic conditions under which each APOE variant evolved. Three versions: Littoral (APOE4), Boreal (APOE3), and Pelagic (APOE2), each personalised above genotype baseline using SNP testing and functional biomarker assessment.

Academic status LEMH deposited as a preprint at Preprints.org (MDPI), June 2026 ([DOI]). Not peer-reviewed. In preparation for submission to Evolution, Medicine and Public Health (Oxford University Press). A PROSPERO-registered systematic review of APOE-stratified DHA supplementation response forms the basis of the author's MSc dissertation in Nutrition and Lifestyle Medicine. A PhD research programme in evolutionary paleoanthropology and genomics is proposed for 2027.

Glanville, L. (2026). The Lipid Encephalisation and Mismatch Hypothesis (LEMH): An Evolutionary Framework Linking APOE Allele Evolution, Hominin Encephalisation, and Neuroinflammatory Vulnerability. Preprints.org. [DOI]

The clinical taxonomy underpinning the Neurolithic Diet — proximate medicine and ultimate medicine as complementary categories of clinical action — is developed formally on the Glanville's Classification page.