Biomarkers.

Area of Science:

• Neuroscience
• Genetics
• Cardiovascular Science

Background:

• The MTHFR gene's 677T and 1298C alleles are linked to homocysteine processing and increased risks for Alzheimer's disease (AD) and cardiovascular disease.
• Vascular factors play a role in AD pathogenesis.
• Investigating gene-environment interactions is crucial for understanding AD risk.

Purpose of the Study:

• To examine the association between MTHFR allele interactions (677T, 1298C) with APOE e4 and white matter hyperintensity volume (WMHV) and amyloid-positivity.
• To identify potential genetic and vascular risk factors for amyloid accumulation in cognitively unimpaired older adults.

Main Methods:

• Analysis of 341 cognitively unimpaired (CU) subjects from the Alzheimer's Disease Neuroimaging Initiative (ADNI).
• Amyloid-PET SUVR was used to determine amyloid positivity.
• Logistic regression models assessed MTHFR allele contributions and interactions with APOE e4 status and WMHV, adjusting for age and sex.

Main Results:

• Neither MTHFR 1298C nor 677T alleles showed significant main effects on amyloid positivity.
• MTHFR 1298C allele interactions with APOE e4 and WMHV were not associated with amyloid positivity.
• A significant interaction was found between the MTHFR 677T allele and APOE e4 carrier status (OR=4.53, p=0.04) regarding amyloid positivity.

Conclusions:

• Cognitively unimpaired individuals carrying both the APOE e4 and MTHFR 677T alleles are more likely to be amyloid-positive.
• Targeting vascular-related pathways involving APOE e4 and MTHFR 677T may offer therapeutic strategies for mitigating amyloid pathology in AD.