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Hohman TJ, Dumitrescu L, Barnes LL, Thambisetty M, Beecham G, Kunkle B, Gifford KA, Bush WS, Chibnik LB, Mukherjee S, De Jager PL, Kukull W, Crane PK, Resnick SM, Keene CD, Montine TJ, Schellenberg GD, Haines JL, Zetterberg H, Blennow K, Larson EB, Johnson SC, Albert M, Bennett DA, Schneider JA, Jefferson AL, Alzheimer’s Disease Genetics Consortium and the Alzheimer’s Disease Neuroimaging Initiative. Sex-Specific Association of Apolipoprotein E With Cerebrospinal Fluid Levels of Tau. JAMA Neurol. 2018 Aug 1;75(8):989-998. PubMed.
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The paper by Hohman et al. provides compelling evidence of a positive interaction between female sex and APOE4 on levels of tau in CSF. The significance of this work lies in its definition of biological endpoints that underlie the established relationship between sex and APOE4. Although we have known of the significant female bias in the AD risk associated with APOE4 since the report of Payami et al., our understanding of how this risk is manifested in terms of AD pathogenesis has remained poorly defined (Payami et al., 1994). The Hohman et al. paper is not the first to document a link among sex, APOE4, and tau, but its combined analyses of several data sets that include broad ranges of age and diagnoses and both biomarker and autopsy measures is the most complete investigation of the issue to date.
It is interesting to note that the interaction between sex and APOE4 applied specifically to CSF tau (in the presence of amyloid positivity) but not to CSF Abeta42. This may suggest a greater vulnerability of female APOE4 carriers to Abeta-related neurodegenerative changes but perhaps not to their increased susceptibility to APOE4-associated risk of developing AD. Also interesting is that the sex X APOE4 interaction was not observed in autopsy samples, a finding that may suggest sex modulates APOE4 effects in early rather than late stages of pathogenesis. In this context, it is interesting to note prior work with our colleagues on EFAD mice (contain human APOE and AD transgenes) demonstrating that APOE4 accelerates AD-related pathology, a relationship that is significantly stronger in females (Cacciottolo et al., 2016).
There remain numerous unanswered questions. For example, it is unclear whether the findings indicate an inherent vulnerability of the female brain to the deleterious effects of apoE4 or perhaps instead reflect the consequences of estrogen depletion in aging women and loss of protective estrogen pathways. Also, while the findings provide important definition to the relationships between sex and APOE4, there remains a significant void in our understanding of the underlying mechanism(s). A combination of complementary human and animal model studies are needed to address this knowledge gap.
References:
Payami H, Montee KR, Kaye JA, Bird TD, Yu CE, Wijsman EM, Schellenberg GD. Alzheimer's disease, apolipoprotein E4, and gender. JAMA. 1994 May 4;271(17):1316-7. PubMed.
Cacciottolo M, Christensen A, Moser A, Liu J, Pike CJ, Smith C, LaDu MJ, Sullivan PM, Morgan TE, Dolzhenko E, Charidimou A, Wahlund LO, Wiberg MK, Shams S, Chiang GC, Alzheimer's Disease Neuroimaging Initiative, Finch CE. The APOE4 allele shows opposite sex bias in microbleeds and Alzheimer's disease of humans and mice. Neurobiol Aging. 2016 Jan;37:47-57. Epub 2015 Oct 19 PubMed.
View all comments by Christian PikeInternational Biomedical Research Training Program (IBRTP) Roskamp Institute,
In this study, the authors found a stronger association between ApoE4 and CSF tau levels in women than men from four independent data sets. However, no sex differences were found between ApoE genotypes and brain pathologies (tangles and plaques) in the autopsy brains from six additional independent data sets. Although ApoE genotype has been well recognized as a sex-specific risk factor for AD, this study is novel as it shows the association between ApoE4 and CSF tau level, rather than amyloid pathogenesis as previously reported. It is also interesting that the sex difference in ApoE genotype is only associated with CSF TAU level, not with neurofibrillary tangles in the brain. It is important to point out that the age of subjects in CSF data sets were younger (60-70s) than those in autopsy data (70s-90). As previous data showed a sex-specific window for higher risk of AD in women only between ages 65–75 (Neu et al., 2017), it would be interesting to investigate whether the ApoE4 effect on CSF tau in women at young age could serve as a potential sex-specific risk marker for AD. Also, it would be interesting to know whether the narrow age window of ApoE4 on tau is related to the earlier onset of menopause in ApoE 4 carriers (Koochmeshgi et al., 2004), since early onset of menopause is known to have a higher risk of AD than late onset.
In addition, while the sex differences of ApoE4 was only found in CSF tau, not in Aβ in this study, an independent, autopsy study reported sex-specific elevation of Aβ peptides in the brain of female AD ApoE4 carriers and correlated them with the proportional expression of BACE1/β-secretase and ADAM10/α-secretase in the cortex and with nicastrin (γ-secretase) expression in the hippocampus (Nyarko et al., 2018). Since BACE1 activity in plasma might predict early stage of AD (Shen et al., 2018), could it be possible that only testing Aβ levels might miss the sex-specific effect of ApoE4 on amyloid pathogenesis? Perhaps using more sensitive biomarkers, such as BACE1 activity rather than Aβ levels, will reveal a sex specific effect (Ewers et al., 2008 and Hou et al., 2015).
All told, this study is interesting and opens broad possibilities for us to understand sex differences in ApoE genotypes in AD.
References:
Neu SC, Pa J, Kukull W, Beekly D, Kuzma A, Gangadharan P, Wang LS, Romero K, Arneric SP, Redolfi A, Orlandi D, Frisoni GB, Au R, Devine S, Auerbach S, Espinosa A, Boada M, Ruiz A, Johnson SC, Koscik R, Wang JJ, Hsu WC, Chen YL, Toga AW. Apolipoprotein E Genotype and Sex Risk Factors for Alzheimer Disease: A Meta-analysis. JAMA Neurol. 2017 Oct 1;74(10):1178-1189. PubMed.
Koochmeshgi J, Hosseini-Mazinani SM, Morteza Seifati S, Hosein-Pur-Nobari N, Teimoori-Toolabi L. Apolipoprotein E genotype and age at menopause. Ann N Y Acad Sci. 2004 Jun;1019:564-7. PubMed.
Nyarko JN, Quartey MO, Pennington PR, Heistad RM, Dea D, Poirier J, Baker GB, Mousseau DD. Profiles of β-Amyloid Peptides and Key Secretases in Brain Autopsy Samples Differ with Sex and APOE ε4 Status: Impact for Risk and Progression of Alzheimer Disease. Neuroscience. 2018 Mar 1;373:20-36. Epub 2018 Jan 11 PubMed.
Shen Y, Wang H, Sun Q, Yao H, Keegan AP, Mullan M, Wilson J, Lista S, Leyhe T, Laske C, Rujescu D, Levey A, Wallin A, Blennow K, Li R, Hampel H. Increased Plasma Beta-Secretase 1 May Predict Conversion to Alzheimer's Disease Dementia in Individuals With Mild Cognitive Impairment. Biol Psychiatry. 2017 Mar 27; PubMed.
Ewers M, Zhong Z, Bürger K, Wallin A, Blennow K, Teipel SJ, Shen Y, Hampel H. Increased CSF-BACE 1 activity is associated with ApoE-epsilon 4 genotype in subjects with mild cognitive impairment and Alzheimer's disease. Brain. 2008 May;131(Pt 5):1252-8. PubMed.
Hou X, Adeosun SO, Zhang Q, Barlow B, Brents M, Zheng B, Wang J. Differential contributions of ApoE4 and female sex to BACE1 activity and expression mediate Aβ deposition and learning and memory in mouse models of Alzheimer's disease. Front Aging Neurosci. 2015;7:207. Epub 2015 Oct 31 PubMed.
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