Lower LDL of ‘Critical Importance’ in Reducing Dementia Risk

A low-density lipoprotein cholesterol (LDL-C) level below 70 mg/dL was associated with a 26% reduced risk of all-cause dementia and a 28% lower risk of Alzheimer’s disease-related dementia (ADRD), with statin use further decreasing that risk, a new study suggests.

While earlier research had suggested lower LDL levels may offer a protective advantage against dementia, these findings provide a specific target number, which investigators said could prove helpful in clinical practice. 

“These findings emphasize the importance of targeted LDL-C management as part of dementia prevention strategies, with potential integration into clinical guidelines,” lead investigator Minwoo Lee, MD, PhD, Department of Neurology, Hallym University Sacred Heart Hospital, Hallym University College of Medicine, Anyang, South Korea, and colleagues wrote.

“The results support the use of statin therapy within specific LDL-C ranges for both cardiovascular and cognitive health benefits.”

The study was published online April 1 in the Journal of Neurology, Neurosurgery & Psychiatry.

LDL-Dementia Link Poorly Understood

The relationship between LDL-C levels and cognitive outcomes is not well understood, and prior research has yielded conflicting results. 

Early studies raised concerns that very low levels were linked to cognitive decline, but those findings have been mitigated by more recent evidence showing a significant reduction in LDL-C does not raise the risk of dementia. 

Level fluctuations have also been shown to carry an increased risk of cognitive decline, and the Lancet Commission on dementia prevention, intervention, and care recently added high cholesterol to its list of modifiable risk factors associated with dementia.

To the study the issue further, investigators led a retrospective analysis of patients in 11 university hospitals in South Korea that included 108,980 patients with LDL-C levels < 70 mg/dL and a propensity score matched group of 108,980 patients with levels > 130 mg/dL.

Researchers assessed the prevalence of all-cause dementia as a primary outcome and ADRD as a secondary outcome and performed secondary analyses of patients with LDL-C levels below 55 mg/dL and patients who used statins.

LDL of ‘Critical Importance’

Compared with patients who had LDL-C levels of ≥ 130 mg/dL, investigators found a 26% reduction in all-cause dementia among patients with LDL-C levels < 70 mg/dL (hazard ratio [HR], 0.74; 95% CI, 0.70-0.78) and a 28% reduction in ADRD (HR, 0.72; 95% CI, 0.67-0.77).

Among patients with LDL-C levels < 55 mg/dL, researchers noted an 18% reduction, each, in the risk for all-cause dementia (HR, 0.82; 95% CI, 0.77-0.88) and ADRD (HR, 0.82; 95% CI, 0.76-0.89). There was no significant reduction in dementia risk in those with levels < 30 mg/dL compared with patients with LDL-C levels of ≥ 130 mg/dL.

The use of statins in patients with LDL-C < 70 mg/dL was also associated with a 13% lower risk of all-cause dementia (HR, 0.87; 95% CI, 0.80-0.94) and a 12% decrease in ADRD risk (HR, 0.86; 95% CI, 0.78-0.94) compared with patients who did not use statins. There was no link between lower risk and statin use among those with LDL-C levels < 55 mg/dL.

“The primary findings of this study highlight the critical importance of LDL-C levels in dementia risk, emphasizing the critical importance of these levels irrespective of statin use,” the investigators wrote. “Lower LDL-C levels are directly associated with reduced dementia incidence, supporting cholesterol management as fundamental in preventing dementia.”

‘Evidence-Based Benchmark’

Balancing LDL-C for cardiovascular benefits while being cognizant of potential neurocognitive impacts is “something we deal with constantly in clinical practice,” Shaheen Lakhan, MD, PhD, a neurologist and researcher based in Miami, Florida, told Medscape Medical News.

“Until now, it’s been hard to say what level is ‘safe’ or even beneficial for the brain,” said Lakhan, who was not part of the new research. “The study’s identification of <70 mg/dL as a target that significantly reduces risk of both all-cause and Alzheimer’s-related dementia is incredibly helpful. It gives us a concrete, evidence-based benchmark we can share with patients — especially those at high vascular and cognitive risk.”

The finding that there is a potential floor to the benefits of lowering LDL-C also runs counter to the idea that a lower LDL-C level is always better, Lakhan added. 

“It’s a strong argument for individualized targets rather than pushing every patient to extreme lows, particularly in those with cognitive concerns,” he said.

For Lakhan, the evidence that statins have neuroprotective effects and that those benefits extend beyond lowering cholesterol are the most important findings for clinical care. 

“It gives clinicians a strong rationale to continue statins in older adults and those at risk for dementia, not just for their hearts, but for their brains as well,” he said.

While the results do not establish causality due to the study’s retrospective nature, overall, Lakhan said the study’s “size, consistency, and methodologic rigor make this a valuable contribution that should absolutely inform clinical decision-making and future guidelines.”

Several experts also weighed in on the results in a statement from the independent, nonprofit UK Science Media Center.

The results of the study “give a convincing argument for researchers to consider LDL cholesterol in addition to the classic approaches,” said Francesco Tamagnini, PhD, a neurophysiologist with the University of Reading. 

“Amyloid beta and hyperphosphorylated tau have, so far, been assumed to be the main cause of Alzheimer’s but that is an opinion that is now likely to fade,” he added.

Julia Dudley, head of research at Alzheimer’s Research UK, said it is difficult to know whether there is a direct link between LDL-C and reduced dementia risk. 

“Clinical trials will be key to understand what effects statins might be having on disease processes in the brain,” she said.

This study was supported by the National Research Foundation of Korea and the Korean Neurological Association. Study authors, Lakhan, and Tamagnini reported no relevant financial relationships. Medscape could not confirm Dudley’s financial disclosures at the time of reporting.