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)ε4 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-ß (Aß). 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 ε4 status, CSF Aß 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 Aß on CSF p-tau levels (ß = 0·18, p = 0·04). Specifically, there was a stronger association between APOE status and CSF Aß42 on CSF p-tau in males compared to females. Further, in females with high Aß levels (reflecting less cortical deposition), ε4 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 ε4 carriers and non-carriers with high Aß (W = 23523, p = 0·64). INTERPRETATION: An interaction between sex and cerebrospinal fluid Aß may mediate the relationship between APOE status and CSF p-tau. These data suggest tau accumulation may be independent of Aß in females, but not males. FUNDING: Innovative Medicines Initiative, Swedish Research Council, Alzheimer Drug Discovery Foundation, Swedish Alzheimer Foundation, the Swedish state under the agreement between the Swedish government and the County Councils the ALF-agreement, and the Alzheimer's Association 2021 Zenith Award.