Genetically proxied blood pressure, vascular brain injury, and Alzheimer's disease pathology.

INTRODUCTION

Lower blood pressure (BP) is linked to reduced dementia risk, though it is uncertain whether this benefit stems solely from mitigating vascular brain injury (VBI) or also extends to directly influencing Alzheimer's disease (AD) pathology. We leveraged Mendelian randomization (MR) to assess whether lifelong lower BP is causally associated with neuropathological correlates of VBI and AD.

METHODS

We identified genetic proxies for systolic and diastolic BP (n = 1,028,980) and applied them in MR analyses of post mortem neuropathological measures of VBI and AD (n = 6363-7786).

RESULTS

Genetically proxied lower systolic BP associated with reduced risk of all VBI measures, including atherosclerosis, arteriolosclerosis, gross infarcts, and microinfarcts. There was no evidence for associations between systolic BP and AD pathology, including measures of amyloid and tau pathology. Diastolic BP analyses yielded similar results.

DISCUSSION

These findings suggest that BP-lowering protects against dementia by mitigating VBI rather than by directly affecting AD pathology.

HIGHLIGHTS

It is uncertain whether blood pressure impacts dementia risk solely through its effects on blood vessel health, or whether it also impacts Alzheimer's disease (AD) pathology. We performed a Mendelian randomization study using genetic predictors of blood pressure applied to a unique autopsy study of neuropathological correlates of both vascular brain injury and AD pathology. We found evidence that genetically lowered blood pressure solely impacts vascular brain injury, with no effects on AD pathology.