Genetically predicted telomere length and Alzheimer's disease endophenotypes: a Mendelian randomization study

Area of Science:

• Genetics
• Neuroscience
• Aging Research

Background:

• Telomere length (TL) is a biomarker of biological aging.
• Aging is a primary risk factor for Alzheimer's disease (AD).
• Understanding the link between TL and AD pathogenesis is crucial.

Purpose of the Study:

• To investigate the potential causal relationship between TL and AD endophenotypes.
• To assess TL's role in cognitive performance, brain aging, and cerebrospinal fluid (CSF) biomarkers.
• To explore these associations using Mendelian randomization (MR) in a high-risk cohort.

Main Methods:

• Mendelian randomization (MR) analysis using 20 single nucleotide polymorphisms (SNPs) associated with TL.
• Analysis conducted in the ALFA study cohort (N=2233 for cognition, N=1134 for brain imaging, N=304 for CSF biomarkers).
• Stratified analyses by APOE-ɛ4 status and AD polygenic risk score (PRS).

Main Results:

• Genetically predicted longer TL associated with lower CSF Aβ and higher CSF NfL in APOE-ɛ4 non-carriers.
• Longer TL linked to increased cortical thickness and lower CSF p-tau in individuals with high AD genetic predisposition.
• No significant associations observed in APOE-ɛ4 carriers.

Conclusions:

• Genetically determined TL may causally influence specific AD endophenotypes.
• The effect of TL on AD biomarkers and brain structure appears dependent on genetic factors like APOE-ɛ4 status and AD PRS.
• Further observational studies are needed to confirm these findings.