Maintaining low levels of low-density lipoprotein cholesterol (LDL-C) is widely recognized for its benefits in reducing cardiovascular events. However, its role in the development or prevention of dementia remains a topic of ongoing debate. A recent study published in the Journal of Neurology, Neurosurgery & Psychiatry sheds light on this issue by investigating the association between LDL-C levels and the risk of dementia, including Alzheimer’s disease-related dementia (ADRD).
Cholesterol and Cognitive Decline: What’s the Connection?
While some earlier observational studies hinted at the possibility that very low LDL-C levels might contribute to cognitive decline, more recent and comprehensive meta-analyses have challenged this perspective. In particular, large-scale clinical trials such as FOURIER and ODYSSEY have demonstrated that significant reductions in LDL-C—even to levels as low as 30 mg/dL (0.8 mmol/L)—do not increase the risk of dementia or impair cognitive performance.
Given these contradictory findings, the scientific community has called for more targeted research to reassess LDL-C guidelines in the context of cognitive health.
Study Overview
The recent observational study aimed to clarify the relationship between LDL-C levels and the risk of developing dementia. Researchers utilized data from two major healthcare networks—the Observational Medical Outcomes Partnership (OMOP) Common Data Model and the Observational Health Data Sciences and Informatics (OHDSI) network.
Participants were adults aged 18 years or older who received outpatient care between November 1986 and December 2020. Individuals with prior diagnoses of ADRD or those appearing in both data sets were excluded to ensure data integrity.
Study Design
Index date: The date on which the patient’s LDL-C level was recorded.
Time-at-risk (TAR): Began one day after the index date and extended until the end of the observation period or 99,999 days.
Bias reduction: A 180-day observation period was enforced to minimize biases such as immortal time bias and duplication.
Key Findings
From an initial pool of over 12 million patients, 903,711 met the inclusion criteria. Among these:
192,213 had LDL-C levels below 70 mg/dL (1.8 mmol/L)
379,006 had LDL-C levels above 130 mg/dL (3.4 mmol/L)
After 1:1 propensity score matching, the final analysis included 108,908 matched pairs.
Main Results
LDL-C <70 mg/dL was linked to a:
26% reduction in all-cause dementia
28% reduction in ADRD risk
LDL-C <55 mg/dL was associated with an 18% reduced risk of both all-cause dementia and ADRD.
Interestingly, LDL-C <30 mg/dL was not associated with a statistically significant reduction in dementia risk.
Impact of Statin Therapy
Among statin users:
LDL-C <70 mg/dL correlated with a:
13% lower risk of all-cause dementia
14% lower risk of ADRD
LDL-C <55 mg/dL and <30 mg/dL did not show a statistically significant benefit compared to levels ≥130 mg/dL.
Statin use in patients with LDL-C ≥130 mg/dL was still beneficial, reducing:
All-cause dementia risk by 7%
ADRD risk by 10%
These effects were observed across both lipophilic and hydrophilic statin types.
Statin Use vs. Non-use
When comparing statin users vs. non-users:
Among those with LDL-C <70 mg/dL, statin users showed:
13% lower risk of all-cause dementia
12% lower risk of ADRD
Among those with high LDL-C (≥130 mg/dL), statin users still benefitted from:
7% lower risk of all-cause dementia
10% lower risk of ADRD
Conclusion
This large-scale observational study suggests that maintaining LDL-C levels below 70 mg/dL—either through lifestyle or pharmacological means—may significantly reduce the risk of developing dementia, including ADRD. Importantly, these protective associations were observed both with and without statin therapy, indicating a potentially broader public health implication.
While the exact biological mechanisms remain to be fully elucidated, these findings align with a growing body of evidence supporting cardiovascular-metabolic health as a pillar of cognitive preservation. Further prospective and interventional studies are needed to solidify these associations and optimize clinical guidelines for cholesterol management in the context of brain health.
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