Apolipoprotein E Levels and Genotype, APP, βA4, MTHFR Genotype, Homocysteine Levels, Cognition and Depression in Older Men in Perth

Leon Flicker¹, Ralph Martins², Jenny Thomas², John Acres², Kevin Taddei², Paul Norman², Konrad Jamrozik³, and Osvaldo Almeida⁴. (1) University of Western Australia, Perth, Australia, (2) University of WA, Perth, Australia, (3) Imperial College, London, United Kingdom, (4) School of Psychiatry and Clinical Sciences, Universi, Perth, Australia

Objective: There is a strong documented association between e4 allele of apolipoprotein E (APOE) and dementia. In addition, plasma levels of APOE, amyloid precursor protein (APP), beta amyloid protein 40 (Aβ40), and homocysteine (HC) have been correlated with the presence of dementia. Mutations in the methyl-tetrahydrofolate reductase enzyme (MTHFR) have been associated with elevated levels of HC. This study explored the associations between APOE levels and genotypes, MTHFR genotypes, HC, APP and Aβ40 levels with cognitive function and depression in 299 men recruited from a large ongoing cohort study.

Design: Cross-sectional survey.

Materials and Methods: The mean age (SD) of these men was 78.9 (2.8) years. Fasting blood plasma was assayed for APOE and APP levels by previously described western blotting procedures. Aβ40 was assayed by ELISA. APOE genotyping, apo E promoter polymorphisms and MTHFR mutations were assayed by standard PCR based procedures. Serum creatinine and HC were measured. Cognitive assessment included MMSE, ADAS-Cog, a digit cancellation test, California Verbal Learning Test (CVLT), and Clock Drawing. Quality of life was measured using the SF36. Depressed mood was measured by the GDS 15 and the Beck Depression Inventory (BDI).

Results: ApoE e4 genotype was found in 13% of alleles. The e 4 allele was associated with increased depressive symptoms as measured by the GDS-15 (Chi Sq = 5.3, p = 0.02) and poorer performance on the Clock Drawing test (Chi Sq = 7.7, p = 0.005). There were no statistically significant associations between the MTHFR polymorphism/mutation and HC on any measure of cognition or depression. Log HC and log Aβ40 were both correlated with calculated GFR, r = -0.35 (p<0.001), r = -0.18 (p<0.001), respectively. Log HC was inversely associated with the physical functioning subscale of the SF36. There was a difference of 1.9 mmol/l (SE: 1.0) between the mean HC levels for the different APOE promoter polymorphisms. After adjusting for GFR, B12 and folate levels, log HC remained positively associated with Aβ40 (p < 0.001).

Conclusion: This study failed to demonstrate previously documented associations between the e 4 allele of APOE and cognition, and MTHFR genotype and HC. There was a positive association between Aβ40 and HC even after adjustment for GFR and this association may help elucidate the link between HC and AD.