Box 1 Unanswered questions for future research regarding hypercholesterolaemia in VaD

FOURIER, Further Cardiovascular OUtcomes Research with PCSK-9 Inhibition in Subjects with Elevated Risk.

What is the relationship between dementia onset and cholesterol level?As cholesterol level increases is the relationship with disease onset linear?
Does lowering of ‘normal’ cholesterol levels influence the timing of dementia onset?If so, when should this be done–middle age, late age? Is there an age cut-off above which cholesterol should not be lowered?
Does (the degree of) lowering of cholesterol levels influence the severity or progression of dementia in a pre-symptomatic population?Does the concept of over excessive cholesterol lowering exist i.e. can ‘too low’ be detrimental?
Does timing of lipid-lowering therapy influence dementia onset or severity?Does treatment started in midlife have a benefit over starting later in life?
Does targeting ideal CVH in midlife influence onset/severity of dementia [189]?Further data are needed. A large RCT could answer this question but would be potentially prohibitively expensive.
Treatment of existing dementia
Are statins of benefit in the treatment of VaD?In order to accurately test efficacy, should people with mild cognitive impairment (at worst) be recruited to future trials?
Does targeting ideal CVH in an at-risk population in later life influence severity/progression of dementia?FINGER showed that a multi-domain intervention can prevent deterioration in cognitive functioning over 2 years in those in later life [191]. Whether this effect is maintained, is unclear.
Lipid-lowering therapy
Cholesterol level target versus class of lipid-lowering therapyIs target lipid-lowering more or less effective than the choice of lipid-lowering agent?
Lipophilic versus hydrophilic statinsLipophilic statins can cross the BBB, whilst hydrophilic statins cannot. Some authors advocate that lipophilic statins should be assessed above other statins in preventing/treating dementia due to this property [131].
Are PCSK-9 inhibitors safe and efficacious at reducing stroke in primary and/or secondary stroke prevention?Concern surrounds the safety of PCSK-9 inhibitors in this population given their reported neurocognitive adverse effects. Although a recent press release stated that evolocumab was non-inferior to placebo regarding effects on cognition in a study involving FOURIER participants [197]. Further monitoring and trials are required to answer these questions.