In human Alzheimer’s disease (AD), and the APPNL-G-F mouse model of AD, cerebral blood flow (CBF) is reduced by amyloid beta evoking pericyte-mediated capillary constriction (Nortley et al., 2019). Vascular dementia can also involve a decrease of cerebral blood flow (CBF) (Anderle et al., 2025). The CBF decrease in AD leads to tissue hypoxia which can be reversed by administering the L-type voltage-gated calcium channel blocker nimodipine to increase blood flow (Korte et al., 2024). In human small vessel disease, giving the repurposed drugs cilostazol and isosorbide mononitrate (which are also expected to relax blood vessels) leads to an improved cognitive state (Wardlaw et al., 2023). Maintaining brain energy supply is thus likely to be a prerequisite for avoiding cogniitive decline.
One possible mediator between reduced energy supply and cognitive impairment is damage to myelinated axons (Anderle et al., 2025). White matter hyperintensities on MRI images, which may reflect myelinated axon damage, correlate with cognitive decline and lower blood flow in small vessel disease, but their origin is poorly understood. We find that either ischaemia or amyloid beta leads to a lengthening of the node of Ranvier in mouse and human myelinated axons, which is then followed by an enzyme-evoked disruption of the paranodal structure leading to myelin loss. We are testing whether blocking the culprit enzyme protects the myelin, and hence cognition.
Targeting the damage to myelinated axons as well as the fall in CBF may offer benefits for treating both vascular dementia and AD.
Animal experiments were conducted under a Home Office licence to David Attwell. Human tissue discarded from neurosurgery was used with ethical approval provided to David Attwell from the NHS REC system.