One may speculate that these data are reflective of the ‘two-hit vascular hypothesis’ of AD that states a first initial insult or ‘hit’ from cerebrovascular damage, such as chronic hypoperfusion from SVD, is sufficient to initiate neuronal injury, which are subsequently more vulnerable to a second ‘hit’ from independent AD-pathology insults, e.g., accumulation of Aβ and HPτ pathology [39]. The gene discussed is MRS2; the disease is Alzheimer disease.