The etiological effect of a new low-frequency

Area of Science:

• Neurogenetics
• Metabolic Disorders
• Alzheimer's Disease Pathogenesis

Background:

• Genetic variations in cholesterol metabolism genes are understudied in mild cognitive impairment (MCI) and late-onset Alzheimer's disease (AD).
• Understanding these genetic factors is crucial for elucidating disease mechanisms and developing targeted therapies.

Purpose of the Study:

• To identify genetic variants associated with cholesterol metabolism that contribute to MCI and late-onset AD.
• To investigate the role of the novel risk variant ESR1 rs9340803 in the pathogenesis of MCI and late-onset AD.

Main Methods:

• Targeted sequencing of 12 nuclear receptor genes and APOE involved in cholesterol modulation.
• Validation of the ESR1 rs9340803 variant in three independent Chinese cohorts (854 MCI, 1059 AD, 1254 controls).
• In vitro functional assays and analysis of serum/plasma biomarkers (Aβ1-40, total cholesterol).

Main Results:

• The ESR1 rs9340803 variant significantly increases the risk for both MCI (OR=3.08) and late-onset AD (OR=3.30).
• This low-frequency variant showed decreased ESR1 expression in vitro.
• Variant carriers exhibited higher serum Aβ1-40 and lower plasma total cholesterol in AD patients.

Conclusions:

• ESR1 rs9340803 is identified as a susceptible genetic variant for MCI and late-onset AD.
• This variant may influence disease development through altered cholesterol metabolism and ESR1 expression.
• The findings provide novel insights into AD etiology and potential therapeutic strategies.