Does lowering cholesterol increase the risk of developing dementia?

Lowering Cholesterol Does Not Increase Dementia Risk

Based on the highest quality evidence from multiple major medical societies and randomized controlled trials, lowering cholesterol does not increase the risk of developing dementia and should not be avoided due to cognitive concerns. 1

Evidence from Randomized Controlled Trials

The most definitive evidence comes from large randomized trials that directly tested cognitive function:

• Three major randomized trials comparing statins to placebo performed specific cognitive testing and found no differences in cognitive function between groups 1
• The EBBINGHAUS sub-study of FOURIER specifically evaluated evolocumab (achieving LDL-C levels as low as <25 mg/dL) and found no difference in cognitive function at 19 months, with the primary endpoint of spatial working memory showing noninferiority (p<0.001) 1
• Studies adding ezetimibe or PCSK9 inhibitors to statin therapy showed no cognitive decline, even among patients achieving very low LDL cholesterol levels 1

Guideline Consensus

Multiple authoritative guidelines explicitly address this concern:

• The 2013 ACC/AHA Cholesterol Guideline states that RCT evidence does not support an adverse effect of statins on cognitive changes or risk of dementia 1
• The 2019 and 2023 ADA Standards of Care conclude that concerns about statins causing cognitive dysfunction or dementia are not supported by evidence and should not deter their use in high-risk individuals 1
• The 2023 American Heart Association Scientific Statement found that the preponderance of observational studies and randomized trial data do not support a link between aggressive LDL-C lowering and cognitive impairment or dementia 2

Understanding the Biological Context

The lack of association makes biological sense:

• Brain cholesterol regulation depends primarily on local de novo synthesis within the brain rather than circulating plasma cholesterol levels 1
• This explains why lowering blood cholesterol does not impair brain function, as the brain maintains its own cholesterol homeostasis independently 1

Addressing Reported Neurocognitive Events

While some observational data raised initial concerns, these have not been substantiated:

• The OSLER study showed statistically more neurocognitive events with evolocumab/statin (0.9%) versus statin alone (0.3%), but the risk did not vary between patients achieving very low LDL-C and those who did not 1
• The FDA's systematic review of postmarketing surveillance databases, randomized trials, and observational studies found no adverse effect of statins on cognition 1

Age-Related Considerations

The relationship between cholesterol and cognition is age-dependent, but this does not support avoiding cholesterol lowering:

• High cholesterol in midlife (not late life) is associated with increased dementia risk later 3, 4
• When cholesterol is measured in late life, high levels show no association or even inverse relationships with cognitive decline 3, 5, 4
• However, randomized trials show no beneficial effect of statin treatment on late-life cognitive function, meaning the observational inverse relationship does not translate to harm from lowering cholesterol 3, 4
• The 2024 ADA Standards note that control of blood pressure and cholesterol lowering with statins are associated with reduced risk of incident dementia in older adults 1

Clinical Management Algorithm

When patients express concerns about cholesterol lowering and dementia:

1. Reassure patients that high-quality randomized trial evidence shows no increased dementia risk from cholesterol lowering 1
2. Emphasize that cardiovascular benefits far outweigh any theoretical cognitive concerns 1
3. If cognitive symptoms develop on statin therapy, evaluate for non-statin causes (other medications, systemic conditions, neuropsychiatric causes) before attributing to the statin 6
4. For patients >75 years with clinical ASCVD, consider moderate-intensity rather than high-intensity statins for safety reasons related to comorbidities, not cognitive concerns 1

Important Caveats

• The EBBINGHAUS study had limitations including short follow-up (19 months), relatively young participants (mean age 63), and exclusion of patients with known dementia, so long-term monitoring in high-risk patients remains prudent 1
• However, these limitations do not justify withholding proven cardiovascular therapy based on unsubstantiated cognitive concerns 1