Having established the association of vitamin B12 insufﬁciency with neurodegenerative disease, the challenge is to discern the direction, if any, of causation.
Most neurological impairments present a slow, progressive course (Josephs et al., 2009) and vitamin B12 levels may take a number of years to deplete (Herbert, 1988). Studies investigating causation would need to continue over an extended period of time.
Low serum vitamin B12 levels may play a role in the pathogenesis of neurodegenerative disease; however, it is equally plausible that neurological impairment may lead to poor nutrition and hence to inadequate dietary intake. Also, any association may simply be coincident or the factors predisposing patients for neurodegenerative disease may simply also expose the patient to a higher risk of vitamin B12 deﬁciency, for example, poor nutrition. Further intervention studies in large samples followed over an extended period of time are required. This will allow for further investigation of the role, if any, of vitamin B12 in the onset or progression of neurodegenerative disease, as well as the latent period of effect of vitamin B12 insufﬁciency before cognitive deﬁcits are evident.