Psychotic Alzheimer's disease is associated with gender-specific tau phosphorylation abnormalities

Abstract

Converging evidence suggests that psychotic Alzheimer's disease (AD + P) is associated with an acceleration of frontal degeneration, with tau pathology playing a primary role. Previous histopathologic and biomarker studies have specifically implicated tau pathology in this condition. To precisely quantify tau abnormalities in the frontal cortex in AD + P, we used a sensitive biochemical assay of total tau and 4 epitopes of phospho-tau relevant in AD pathology in a postmortem sample of AD + P and AD - P. Samples of superior frontal gyrus from 26 AD subjects without psychosis and 45 AD + P subjects with psychosis were analyzed. Results of enzyme-linked immunosorbent assay demonstrate that AD + P females, but not males, had significantly higher levels of phosphorylated tau in the frontal cortex. In males, but not females, AD + P was associated with the presence of α-synuclein pathology. These results support a gender dissociation of pathology in AD + P. The design of future studies aimed at the elucidation of cognitive and/or functional outcomes; regional brain metabolic deficits; or genetic correlates of AD + P should take gender into consideration.

Keywords: Alpha-synuclein; Alzheimer's disease; Dementia with Lewy bodies; Neurofibrillary tangles; Psychosis; Tau.

Figure 1

Mean levels of total tau (a.) and hyperphosphorylated tau: PHF1 (pSer396/404), CP13 (pSer202), RZ3 (pThr231) and AT8 (pSer199/p202/pThr205) (b.–e.) in superior frontal gyri of subjects with AD without psychosis (AD−P, N=26) compared with AD and psychosis (AD+P, N=45), 95% confidence intervals are represented.

Figure 2

Mean levels of total tau (a.) and hyperphosphorylated tau: PHF1 (pSer396/404), CP13 (pSer202), RZ3 (pThr231) and AT8 (pSer199/p202/pThr205) (b.–e.) in superior frontal gyri of females without psychosis (AD−P, N=13) compared with AD and psychosis (AD+P, N=23). 95% confidence intervals are represented and significant individual differences (p<0.05) are highlighted.

Figure 3

Mean levels of total tau (a.) and hyperphosphorylated tau: PHF1 (pSer396/404), CP13 (pSer202), RZ3 (pThr231) and AT8 (pSer199/p202/pThr205 (b.–e.) in superior frontal gyri of males with AD without psychosis (AD−P, N=13) compared with AD and psychosis (AD+P, N=22). 95% confidence intervals are represented and significant individual differences (p<0.05) are highlighted.