By Lisa Mosconi, PhD

Associate Professor of Neuroscience in Neurology; Associate Director, Alzheimer’s Prevention Clinic/Department of Neurology, Weill Cornell Medical College

Dr. Mosconi reports no financial relationships relevant to this field of study.

SYNOPSIS: Apolipoprotein E epsilon 4 (APOE4) genotype, the stronger genetic risk factor for late-onset Alzheimer’s disease, negatively affects cerebrospinal levels of tau protein in a sex-dependent manner, whereby the effect of APOE4 is stronger in women than men.

SOURCE: Hohman TJ, Dumitrescu L, Barnes LL, et al. Sex-specific association of apolipoprotein E with cerebrospinal fluid levels of tau. JAMA Neurol 2018;75:989-998.

It long has been known that the prevalence of Alzheimer’s disease (AD) is higher in women than in men, even accounting for women’s increased longevity relative to men.1 Further, the epsilon 4 variant of the apolipoprotein E gene (APOE4), the strongest genetic risk factor for late-onset AD, increases AD risk in a sex-dependent manner. The strength of the association varies by age, with female APOE4 carriers aged 55-70 years at highest risk.2 To address the gender disparity in AD prevalence, efforts toward understanding sex-specific differences in disease etiology, manifestation, and progression have begun to emerge. Hohman et al conducted a multicohort study that combined data from 10 longitudinal cohort studies of normal aging and AD. The goal of the study was to examine sex-dependent effects of APOE genotype on markers of AD pathology in vivo and ex vivo.

The first set of analyses focused on four in vivo data sets that included cerebrospinal fluid (CSF) levels of beta-amyloid 42, total tau, and hyperphosphorylated tau measures collected from 1,798 patients, 48% of whom were women. The second set of analyses focused on six autopsy data sets leveraging direct measures of AD neuropathology, including Consortium to Establish a Registry for Alzheimer’s Disease (CEDAR) staging for neuritic plaques and Braak staging for neurofibrillary tangles, obtained from 5,109 patients, including 55% women. Of the 1,798 patients in the CSF biomarker cohort, 862 were women, 226 had AD, 1,690 were white, and the mean age was 70 years. Of the 5,109 patients in the autopsy cohort, 2,813 were women, 4,953 were white, and the mean age was 84 years. After correcting for multiple comparisons, the authors found a statistically significant interaction between APOE4 and sex on CSF total tau and phosphorylated tau (P ≤ 0.001). APOE4 showed a stronger association among women than men. On post-hoc analysis, this sex difference was present in amyloid-positive individuals but not amyloid-negative individuals. No interactions between APOE4 and sex were found on postmortem measures.


These findings provide robust evidence of sex differences in the association between APOE4 and CSF tau levels. The authors found the effect of APOE was stronger in women than men. The observed sex difference was driven by amyloid-positive individuals, which suggests that APOE may confer sex-specific risk for downstream neurodegeneration in the presence of enhanced amyloidosis.

These results point to several sex-driven mechanisms that could underline this sex difference in tau, especially hormonal changes that occur during and after menopause, representing the strongest candidate pathway. For example, other researchers have found evidence that lower estrogen levels in women could lead to a more severe downstream response to amyloidosis,3 an effect that could be enhanced among APOE4 carriers. Alternatively, late-life changes in estrogen levels in women directly affect tau. In fact, in female rats, estradiol appears to protect against tau hyperphosphorylation.4

These data are consistent with recent brain imaging studies showing that, among middle-aged women at risk for AD, those at the perimenopausal and postmenopausal stages exhibit emergence and progression of an AD endophenotype characterized by increasing beta-amyloid deposition, declines in glucose metabolism, and smaller brain volumes.5-7 Amyloid deposition was more pronounced in APOE4 carriers than noncarriers.5 No such abnormalities were observed in age-matched men, suggesting that AD-related pathological changes and their downstream effects on neuronal function affect women’s brains earlier than men’s brains.

More research is needed to evaluate the genetic drivers of plaques, tangles, neurodegeneration, and cognitive impairment in a sex-specific manner to identify novel pathways of risk.


  1. Farrer LA, Cupples LA, Haines JL, et al. Effects of age, sex, and ethnicity on the association between apolipoprotein E genotype and Alzheimer disease. A meta-analysis. APOE and Alzheimer Disease Meta-Analysis Consortium. JAMA 1997;278:1349-1356.
  2. Neu SC, Pa J, Kukull W, et al. Apolipoprotein E genotype and sex risk factors for Alzheimer disease: A meta-analysis. JAMA Neurol 2017;74:1178-1189.
  3. Xu H, Gouras GK, Greenfield JP, et al. Estrogen reduces neuronal generation of Alzheimer b-amyloid peptides. Nat Med 1998;4:447-451.
  4. Alvarez-de-la-Rosa M, Silva I, Nilsen J, et al. Estradiol prevents neural tau hyperphosphorylation characteristic of Alzheimer’s disease. Ann N Y Acad Sci 2005;1052:210-224.
  5. Mosconi L, Berti V, Quinn C, et al. Sex differences in Alzheimer risk: Brain imaging of endocrine vs chronologic aging. Neurology 2017;89:1382-1390.
  6. Mosconi L, Berti V, Quinn C, et al. Perimenopause and emergence of an Alzheimer’s bioenergetic phenotype in brain and periphery. PLOS One 2017;12:e0185926.
  7. Mosconi L, Diaz I, Rahman A, et al. The perimenopause to menopause transition influences Alzheimer’s biomarker progression: A 3-year brain imaging study. PLOS One 2018; in press.