Motor neurone disease (MND) is a neurodegenerative condition characterised by loss of motor neurons, leading to paralysis and eventual death. There is no known cure for MND, and new therapeutics remain desperately needed. Repurposing existing drugs for MND may represent a path to expedite translation. We recently leveraged the polygenic genetic architecture (common and rare variants) of MND to prioritize drug repurposing candidates. This integrative approach revealed several tractable candidates, including an enrichment of rare genetic variation amongst B-vitamin targets. These findings are timely and exciting given recent promising clinical trial evidence and regulatory approval in Japan of an ultra-high dose vitamin B12 formulation (methylcobalamin) to slow MND disease progression. However, more work is needed to build the evidence base to justify wider clinical uptake. To address this, we assembled matched genetics and longitudinally captured clinical data (up to 5 years) from two MND biobanks (N > 1500 MND cases). We then proxied long-term changes in methylcobalamin using a circulating vitamin B12 polygenic score (B12 PGS). Our preliminary data suggests the B12 PGS was associated in the early phases of disease with a decoupling between traditional functional clinical progression measures (ALSFRS-R) and a biological marker of neuronal damage (serum neurofilament light). This may further support a neuroprotective effect of B12 in MND which requires additional examination. Moreover, using transcriptomic data from stem-cell derived motor neurons that carry a series of well-established large-effect size ALS rare variants, we found that B-vitamin targets demonstrate particularly strong dysregulation in SOD1 rare-variant carriers, which may refine opportunities for precision medicine with methylcobalamin. We are now testing methylcobalamin in vitro in combination with other candidate MND therapeutics, potentially revealing therapeutic synergies. In summary, we leveraged genetics to provide further support to the clinical tractability of methylcobalamin as therapy to slow disease progression in MND.