High-density lipoprotein cholesterol (HDL-C), long known as “good cholesterol,” may not be entirely good. A new study published in Archives of Medical Science reveals that while higher HDL-C levels reduce the risk of diabetes (T2D) by about 9%, they simultaneously increase the risk of mild cognitive impairment (MCI) by 5%.
Their analysis integrated data from 6,356 T2D cases and 1,138 MCI cases using Mendelian randomization and transcriptomic mapping. Nuclear factor I A (NFIA) emerged as a central regulator of HDL metabolism and inflammatory pathways. Laboratory assays confirmed that NFIA overexpression raised intracellular HDL-C and suppressed NF-κB signaling, while NFIA knockdown reduced APOA1 and APOE expression.

The study also evaluated modified fasting therapy (MFT) in 17 T2D patients and 23 controls. Short-term MFT lowered fasting glucose, body mass index, and HDL-C, while improving cognitive scores, particularly in patients with T2D-MCI. NFIA expression increased after therapy, and HDL-C levels rebounded at six months, suggesting a dynamic response.

These findings highlight the paradoxical effects of HDL-C on metabolic and cognitive health. NFIA represents a potential therapeutic target, and MFT may offer a feasible strategy to enhance glucose regulation and cognition while addressing long-term lipid balance.

These findings highlight the paradoxical effects of HDL-C on metabolic and cognitive health. NFIA represents a potential therapeutic target, and MFT may offer a feasible strategy to enhance glucose regulation and cognition while addressing long-term lipid balance.