Alterations in erythrocyte fatty acid composition in preclinical Alzheimer's disease

Abstract

Brain and blood fatty acids (FA) are altered in Alzheimer's disease and cognitively impaired individuals, however, FA alterations in the preclinical phase, prior to cognitive impairment have not been investigated previously. The current study therefore evaluated erythrocyte FA in cognitively normal elderly participants aged 65-90 years via trans-methylation followed by gas chromatography. The neocortical beta-amyloid load (NAL) measured via positron emission tomography (PET) using ligand ¹⁸F-Florbetaben, was employed to categorise participants as low NAL (standard uptake value ratio; SUVR < 1.35, N = 65) and high NAL or preclinical AD (SUVR ≥ 1.35, N = 35) wherein, linear models were employed to compare FA compositions between the two groups. Increased arachidonic acid (AA, p < 0.05) and decreased docosapentaenoic acid (DPA, p < 0.05) were observed in high NAL. To differentiate low from high NAL, the area under the curve (AUC) generated from a 'base model' comprising age, gender, APOEε4 and education (AUC = 0.794) was outperformed by base model + AA:DPA (AUC = 0.836). Our findings suggest that specific alterations in erythrocyte FA composition occur very early in the disease pathogenic trajectory, prior to cognitive impairment. As erythrocyte FA levels are reflective of tissue FA, these alterations may provide insight into the pathogenic mechanism(s) of the disease and may highlight potential early diagnostic markers and therapeutic targets.

Figure 1

Altered fatty acid levels in cognitively normal individuals with low and high NAL. Elevated erythrocyte arachidonic acid levels and decreased docosapentaenoic acid (n-3) levels were observed in individuals with high NAL (N = 35) compared to those with low NAL (N = 65), based on standard uptake value ratio cut off score of 1.35. Fatty acid concentrations were measured in arbitrary units (AU). ‘*’ represents p < 0.05, adjusted for covariates age, gender, years of education and APOE ε4 status; NAL: neocortical amyloid load measured via positron emission tomography, using ligand ¹⁸F-Florbetaben. The error bars represent SE.

Figure 2

Receiver operating characteristic curves for the prediction of high neocortical amyloid load. Receiver operating characteristic curves of logistic regression modelling shows that the specificity of the ‘base’ model comprising major risk factors age and APOE ε4 allele status, and gender and education (a) was enhanced by adding the ratio of AA:DPA i.e. ‘base + AA:DPA’ model (b) at 80% sensitivity. AUC: area under the curve; AA: arachidonic acid, DPA: Docosapentaenoic acid n-3.