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Higher apolipoprotein E (APOE) levels in high-density lipoprotein (HDL) were linked to lower dementia risk, but only when HDL did not contain apolipoprotein C3 (APOC3), researchers reported.

Higher APOE levels in whole plasma and in HDL were linked to better cognitive function on the (whole plasma β coefficient −0.15; 95% CI −0.24 to −0.06; HDL β coefficient −0.20; 95% CI −0.30 to −0.10) but not to dementia or Alzheimer's disease risk, said Manja Koch, PhD, of Harvard T.H. Chan School of Public Health in Boston, and co-authors, they reported in .

The presence of APOC3 appeared to modulate the association between APOE levels in HDL and dementia. Higher APOE levels in HDL that lacked APOC3 were tied to better cognitive function and lower dementia risk:

• ADAS-Cog: per SD β coefficient −0.17; 95% CI −0.27 to −0.07
• score: per SD β coefficient 0.25; 95% CI 0.07 to 0.42
• Dementia risk: HR per SD 0.86; 95% CI 0.76-0.99

APOE levels in HDL that contained APOC3 were unassociated with any of these outcomes.

Koch said these findings extend the beneficial associations of the novel APOE–positive, APOC3–negative lipoprotein from cardiovascular disease to dementia.

"Lower apolipoprotein E in plasma is a risk factor for dementia, but the underlying biological mechanisms are not fully understood," Koch told 番茄社区app.

The ε4 allele of the APOE gene is the most important known single genetic risk factor for late-onset Alzheimer's disease, though how it increases Alzheimer's risk is unclear. In the general population, low protein are associated with higher risk of dementia and Alzheimer's disease, independent of ε2/ε3/ε4 APOE genotype.

Higher APOE levels in plasma HDL previously were found to be associated with lower risk, but the coexistence of APOC3 modified this lower risk.

In their analysis, Koch and collaborators looked at data from a subset of the that included 1,351 community-dwelling participants with a median age of 78; 47% were women. GEMS aimed to study the effect of and Alzheimer's disease and was conducted from 2000 to 2008.

A total of 995 participants were dementia-free at baseline, and 521 people were diagnosed with incident dementia during a median follow-up of 5.9 years.

The findings "raise the possibility that composition of the HDL-associated proteome may be a key determinant of APOE-associated risk of Alzheimer's disease and all-cause dementia," wrote Madhav Thambisetty, MD, PhD, of the National Institute on Aging in Baltimore, in an .

They also may have important clinical translational implications, he said.

"As multiple clinical trials have demonstrated the limitations of increasing plasma HDL levels as a therapeutic strategy against coronary artery disease, the potential clinical utility of such as APOC3 has received increasing attention," he noted.

"These approaches may also be relevant to developing novel disease-modifying treatments for Alzheimer's disease including APOE-based therapeutics targeting the complex interactions of these pleiotropic lipid mediators," he added.

This analysis was limited to older participants and findings may not apply to younger populations, Koch and colleagues acknowledged. Cognitive testing was systematic but stopped in GEMS when dementia occurred, they noted. In addition, mild cognitive impairment was not a trial outcome.

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