Interactions between apolipoprotein E, sex, and amyloid‐beta on cerebrospinal fluid p‐tau levels in the European Prevention of Alzheimer’s Dementia Longitudinal Cohort Study (EPAD LCS)

Abstract

Background Alzheimer's Disease, the leading cause of dementia, is over-represented in females. The apolipoprotein E (APOE) e4 allele is the strongest genetic risk factor for late-onset AD and is associated with aberrant cerebrospinal fluid levels (CSF) of total tau (t-tau), phosphorylated tau (p-tau), and amyloid-b (Ab). There is some evidence that sex may mediate the relationship between APOE status and CSF tau, however, evidence is mixed.Methods We aimed to examine the interaction between sex, APOE e4 status, CSF Ab on t-tau and p-tau in 1599 mid-to-late life individuals without a diagnosis of dementia in the European Prevention of Alzheimer's Dementia (EPAD) longitudinal cohort study.Findings We found a significant interaction between APOE status, sex, and CSF Ab on CSF p-tau levels (b = 0¢18, p = 0¢04). Specifically, there was a stronger association between APOE status and CSF Ab 42 on CSF p-tau in males compared to females. Further, in females with high Ab levels (reflecting less cortical deposition), e4 carriers had significantly elevated p-tau levels relative to non-carriers (W = 39663, p = 0¢01). However, there were no significant differences in p-tau between male e4 carriers and non-carriers with high Ab (W = 23523, p = 0¢64).Interpretation An interaction between sex and cerebrospinal fluid Ab may mediate the relationship between APOE status and CSF p-tau. These data suggest tau accumulation may be independent of Ab in females, but not males.

Large-scale cerebrospinal fluid proteomic analysis in Alzheimer’s disease patients reveals five molecular subtypes with distinct genetic risk profiles

“…These measures were not included in clustering, but used as independent markers to compare between AD subtypes. Genetic data APOE genotyping was performed in blood as previously described 16,17,135,136 . A subset of 560 individuals we had genotyping data available (Illumina Global Screening Array, GSA).…”