The Coastal Hypothesis: Evolutionary Dietary Mismatch as a Unifying Mechanistic Explanation for the Aetiology and Geographic Distribution of Multiple Sclerosis

Multiple Sclerosis (MS) is a chronic, immune-mediated demyelinating disease affecting approximately 2.8 million individuals worldwide.[1] Current disease-modifying therapies remain limited to attenuating relapse frequency and do not address the structural vulnerability of the myelin sheath or promote remyelination.[2,3] No unified mechanistic framework has integrated the known genetic, nutritional, and geographic risk factors within a coherent evolutionary model. We present the Coastal Adaptation Hypothesis of MS aetiology, proposing that MS is a predictable metabolic mismatch disease arising in populations of coastal evolutionary ancestry who carry loss-of-function variants in the FADS gene cluster (FADS1, FADS2, FADS3) and elongase gene ELOVL2. These variants, enriched to 60–70% carrier frequency in Northern European populations, severely compromise endogenous synthesis of docosahexaenoic acid (DHA; 22:6n-3) and eicosapentaenoic acid (EPA; 20:5n-3).[6,7] We hypothesise that these alleles were positively selected over the past several thousand years — in parallel with Neolithic dietary transitions — in populations subsisting on marine-rich diets providing pre-formed DHA and EPA in quantities far exceeding the brain's daily structural requirement, rendering endogenous synthesis biologically redundant. In the modern dietary environment—characterised by elimination of marine fat intake and displacement of cellular phospholipid membranes by omega-6 linoleic acid from seed oils—FADS-variant individuals face a state of functional DHA and EPA insufficiency that is simultaneously structurally and immunologically catastrophic.[6,9,10] DHA constitutes 25–40% of myelin phospholipid fatty acid content.[11] In DHA deficiency, omega-6-derived fatty acids substitute into the myelin sheath, producing a rigid, oxidation-prone membrane whose degraded fragments are recognised as non-self by a hypervigilant HLA-DRB1*15:01 immune system. EPA deficiency simultaneously eliminates the E-series resolvins and protectins that terminate neuroinflammation.[13] Vitamin D deficiency, itself produced by loss of the ancestral marine dietary source, abrogates regulatory T-cell suppression of the autoreactive cascade.[14,15] The hypothesis integrates the disease's geographic distribution, population genetics, and known CNS biochemistry into a unified causal architecture, and generates specific falsifiable predictions amenable to clinical trial investigation.