What’s Sex Got to Do With It? Differences in Connectivity, Synapses

Women run a higher risk of getting Alzheimer’s disease than do men, yet surprisingly little is known about how gender interacts with the disease or affects the brain. Three new papers attempt to shed some light on this. In the June 13 Journal of Neuroscience, researchers led by Michael Greicius at Stanford University School of Medicine, Palo Alto, California, report that healthy elderly women who carry the apolipoprotein E4 allele, the primary genetic risk factor for late-onset AD, have weaker connections in a key brain region than do men with the same genotype, or women without the allele. Poor brain connectivity is considered an early biomarker of the disease. The authors observed a similar gender-ApoE interaction in a second biomarker, namely total tau levels in cerebrospinal fluid (CSF). The findings suggest that ApoE4 represents a greater risk factor for women than for men, although the reasons for this remain unclear.

The other two papers focus on the molecular end of the spectrum, highlighting sex differences in basic synaptic mechanisms. In the June 7 Neuron, researchers led by Catherine Woolley at Northwestern University, Evanston, Illinois, report that estrogen dampens inhibitory synaptic transmission in female, but not male, rats. Likewise, a group led by Gabriele Rune at University Medical Center Hamburg-Eppendorf, Hamburg, Germany, found that a drug that blocks estrogen synthesis in the brain harms synaptic plasticity in female mice more than in male mice. Their results are also described in the June 13 Journal of Neuroscience.

“Together, these papers show that sex differences span all the way from the mechanistic level through to the systems level,” Woolley told Alzforum. The data highlight the importance of taking gender differences into account in basic research, she added.

Most people carry two copies of the ApoE3 allele, which is thought not to affect AD risk. Only about 25 percent of the population possess one or more ApoE4 alleles, but E4 carriers make up around two-thirds of people with the disease (for a review, see Huang, 2011). Some previous studies have found that the ApoE4 genotype confers more risk to women than men (see Payami et al., 1996; Bretsky et al., 1999), with a meta-analysis reporting that women with one copy of E4 have a fourfold increased risk of AD, while men with the same genotype have about the same risk as their E3/E3 peers (see Farrer et al., 1997). Other studies have shown gender-related physical differences, reporting smaller hippocampal volumes in female E4 carriers who have mild cognitive impairment compared to their male counterparts (see Fleisher et al., 2005), and a higher load of amyloid plaque and neurofibrillary tangles in female than male carriers at autopsy Corder et al., 2004).

Greicius and colleagues wondered if they could find similar gender differences at the preclinical stage. They used functional magnetic resonance imaging to measure the strength of connections in the brain’s default-mode network (DMN), which is most active when the brain is at rest. Connectivity in this network falters as AD advances, and these regions are the first to become choked with plaque in both humans (see ARF related news story; and ARF news story) and mice (see ARF related news story). Previous studies have shown connectivity differences between E4 and E3 carriers in this region, but did not examine the effect of gender (see ARF related news story; ARF news story on Machulda et al., 2011; and Westlye et al., 2011). First author Jessica Damoiseaux analyzed fMRI data from about 130 cognitively normal volunteers with an average age of 70. Of these, 39 people carried one ApoE4 allele and four participants had two; the rest were E3 homozygotes. (Because the rare ApoE2 allele is believed to have a protective effect, the authors excluded E2 carriers.) The authors found weaker connectivity in the precuneus and posterior cingulate cortex, which function as the central hub of the DMN, in female E4 carriers than in either female E3 homozygotes or male carriers.

This study could not distinguish whether women with the E4 allele always had weaker connections than their peers, or whether this is an early sign of degeneration, Greicius noted. However, one earlier study indicated that young E4 carriers have stronger connections in the DMN than do non-carriers (see ARF related news story), suggesting the latter scenario. Intriguingly, another AD risk gene, clusterin, currently the third top result in AlzGene, has also been linked to weakened brain connectivity (see ARF related news story).

Damoiseaux and colleagues extended the findings to fluid markers, looking at levels of Aβ42, phospho-tau, and total tau in CSF samples from the Alzheimer’s Disease Neuroimaging Initiative dataset. Participants included 93 cognitively healthy controls who had an average age of 75. For all three biomarkers, the 26 E4 carriers had significantly worse average CSF values than their E3 peers. In the case of total tau, there was also an interaction between ApoE and gender, with female E4 carriers having the highest CSF total tau. The lack of a gender effect in Aβ levels may be because amyloid pathology peaks up to a decade before tau pathology, and so levels had already reached a plateau in both sexes in this elderly cohort, the authors suggest.

Together with the previous meta-analysis, the data support the idea that a man with one E4 allele may not have much more risk of AD than an E3 homozygote, Greicius said, but added, “If you have two copies of the E4 allele, whether you are a man or a woman, there is no question that your risk leaps tremendously.” He is analyzing older datasets to see if the interaction between gender and ApoE genotype holds, and is also looking for genes that act synergistically with ApoE in women but not men.

“It certainly is possible that women are more susceptible to the toxic influences of ApoE4 than men,” agreed Adam Fleisher at the Banner Alzheimer’s Institute in Phoenix, Arizona. Treatment trials should take account of this, he suggested, perhaps separating by gender within the ApoE4 genotype. Fleisher, who was not involved in this work, emphasized that these results need to be repeated, especially using other biomarkers, for example, β amyloid imaging or fluorodeoxyglucose positron emission tomography, which measures brain metabolic activity. Future studies should also address whether the gender-ApoE interaction is the result of some environmental factor that differs between the sexes, such as a lifestyle difference or medical comorbidity, by carefully matching cohorts according to these variables, he suggested.

Other commentators agreed. Deborah Blacker at Massachusetts General Hospital, Boston, noted that having an ApoE4 allele and being a man both predispose to cardiovascular problems. It is possible that some men with the E4 allele die young, and those who survive possess protective factors that their female peers do not, thus skewing results in these elderly cohorts, she suggested. David Jones at the Mayo Clinic, Rochester, Minnesota, pointed out that, although the authors corrected for years of education, there might still be lifestyle factors, such as employment, that differentially affected cognitive reserve in men and women of this generation. A next step might be to see if this gender-ApoE interaction occurs in different age groups, Jones added.

Conversely, the interaction between sex and ApoE4 may represent a biological mechanism in the brain, for example, something to do with estrogen, but more studies would be needed to show this, the commentators agreed. The estrogen literature suggests that hormonal regulation influences ApoE4 signaling and amyloid processing, Fleisher noted. One previous study found that hormone replacement therapy reduces the risk of cognitive decline in women without an E4 allele, but not in E4-positive women (see Yaffe et al., 2000).

In their Neuron paper, Woolley and first author Guang Zhe Huang demonstrate that estrogen can have sex-specific effects on brain memory mechanisms. Both male and female brains locally produce a key estrogen, 17β-estradiol, which signals rapidly at synapses and can stimulate excitatory transmission (see Woolley, 2007). Huang and Woolley focused instead on the steroid’s effect on inhibitory synapses. When they added estradiol to rat hippocampal slices, the steroid suppressed inhibitory transmission in about 50 percent of CA1 pyramidal neurons in female tissue, but not in male. The authors dissected the pathway using pharmacological blockers of various molecules, finding that estradiol binds to estrogen receptor α (ERα) in the post-synaptic cell. The neurosteroid and its receptor then appear to interact in some fashion with the glutamate receptor mGluR1, causing a signaling cascade that enhances production of the endocannabinoid anandamide. Anandamide released from the post-synapse feeds back to the pre-synapse, discouraging release of the inhibitory neurotransmitter GABA—but only if the pre-synapse contains the CB1 cannabinoid receptor.

Woolley is currently investigating why this interaction only occurs in females, given that male brains contain all the same molecular players. One possibility is that ERα and mGluR1 are less able to make contact in male brains, perhaps due to altered localization, she speculated. She is also intrigued by the presence of an endocannabinoid in this pathway, as these molecules are known to regulate learning and memory as well as emotional states. Women are twice as likely as men to be diagnosed with anxiety and depression, she pointed out. “We think this effect of endocannabinoids might be important in this sex difference.” Woolley noted that the vast majority of basic neuroscience research is done using male animals, because most scientists assume that brain mechanisms are the same in both sexes, except for regions involved in reproduction. These data show that, “There are at least some fundamental molecular mechanisms in the brain that differ between males and females,” Woolley said. “In order to make science and medicine relevant to everyone, we need to be studying both sexes.”

The paper from the German group adds more support for this idea. Rune and colleagues studied an inhibitor of estradiol synthesis, letrozole, which is frequently prescribed to older women with breast cancer and is suspected of causing memory problems in this population (see Shilling et al., 2001; Dowsett et al., 2005; Shilling et al., 2005). To get at the mechanisms that might underlie this, first author Ricardo Vierk treated male and female mice with the drug for up to seven days, then sacrificed the animals and examined their synapses using hippocampal slice cultures. In some experiments, the authors reversed the order, making slice cultures first and then applying letrozole. In females, letrozole treatment dampened and eventually eliminated long-term potentiation (LTP), a form of synaptic plasticity that is essential for learning and memory, and also led to the loss of synapses and spines in the hippocampus. The effects were much milder in males; they experienced only a 20 percent drop in LTP and lost only thin spines. Though the reason for this gender difference is not yet known, it adds to the evidence for sex-specific mechanisms of synaptic plasticity.—Madolyn Bowman Rogers

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References

News Citations

  1. Network Diagnostics: "Default-Mode" Brain Areas Identify Early AD
  2. Cortical Hubs Found Capped With Amyloid
  3. Functional Connectivity Predicts Aβ Deposition in Mice
  4. A Foreshadowing? ApoE4 Disrupts Brain Connectivity in Absence of Aβ
  5. ApoE Disrupts Brain Networks, Helps Microglia Clear Aβ
  6. ApoE4 Linked to Default Network Differences in Young Adults
  7. Neuroimaging Offers a CLU to AD Risk Factor’s Functional Effects

Paper Citations

  1. Huang Y. Roles of apolipoprotein E4 (ApoE4) in the pathogenesis of Alzheimer's disease: lessons from ApoE mouse models. Biochem Soc Trans. 2011 Aug;39(4):924-32. PubMed.
  2. Payami H, Zareparsi S, Montee KR, Sexton GJ, Kaye JA, Bird TD, Yu CE, Wijsman EM, Heston LL, Litt M, Schellenberg GD. Gender difference in apolipoprotein E-associated risk for familial Alzheimer disease: a possible clue to the higher incidence of Alzheimer disease in women. Am J Hum Genet. 1996 Apr;58(4):803-11. PubMed.
  3. Bretsky PM, Buckwalter JG, Seeman TE, Miller CA, Poirier J, Schellenberg GD, Finch CE, Henderson VW. Evidence for an interaction between apolipoprotein E genotype, gender, and Alzheimer disease. Alzheimer Dis Assoc Disord. 1999 Oct-Dec;13(4):216-21. PubMed.
  4. Farrer LA, Cupples LA, Haines JL, Hyman B, Kukull WA, Mayeux R, Myers RH, Pericak-Vance MA, Risch N, van Duijn CM. 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 Oct 22-29;278(16):1349-56. PubMed.
  5. Fleisher A, Grundman M, Jack CR, Petersen RC, Taylor C, Kim HT, Schiller DH, Bagwell V, Sencakova D, Weiner MF, Decarli C, Dekosky ST, van Dyck CH, Thal LJ, . Sex, apolipoprotein E epsilon 4 status, and hippocampal volume in mild cognitive impairment. Arch Neurol. 2005 Jun;62(6):953-7. PubMed.
  6. Corder EH, Ghebremedhin E, Taylor MG, Thal DR, Ohm TG, Braak H. The biphasic relationship between regional brain senile plaque and neurofibrillary tangle distributions: modification by age, sex, and APOE polymorphism. Ann N Y Acad Sci. 2004 Jun;1019:24-8. PubMed.
  7. Machulda MM, Jones DT, Vemuri P, McDade E, Avula R, Przybelski S, Boeve BF, Knopman DS, Petersen RC, Jack CR. Effect of APOE ε4 status on intrinsic network connectivity in cognitively normal elderly subjects. Arch Neurol. 2011 Sep;68(9):1131-6. PubMed.
  8. Westlye ET, Lundervold A, Rootwelt H, Lundervold AJ, Westlye LT. Increased hippocampal default mode synchronization during rest in middle-aged and elderly APOE ε4 carriers: relationships with memory performance. J Neurosci. 2011 May 25;31(21):7775-83. PubMed.
  9. Yaffe K, Haan M, Byers A, Tangen C, Kuller L. Estrogen use, APOE, and cognitive decline: evidence of gene-environment interaction. Neurology. 2000 May 23;54(10):1949-54. PubMed.
  10. Woolley CS. Acute effects of estrogen on neuronal physiology. Annu Rev Pharmacol Toxicol. 2007;47:657-80. PubMed.
  11. Shilling V, Jenkins V, Fallowfield L, Howell A. The effects of oestrogens and anti-oestrogens on cognition. Breast. 2001 Dec;10(6):484-91. PubMed.
  12. Dowsett M, Folkerd E, Doody D, Haynes B. The biology of steroid hormones and endocrine treatment of breast cancer. Breast. 2005 Dec;14(6):452-7. PubMed.
  13. Shilling V, Jenkins V, Morris R, Deutsch G, Bloomfield D. The effects of adjuvant chemotherapy on cognition in women with breast cancer--preliminary results of an observational longitudinal study. Breast. 2005 Apr;14(2):142-50. PubMed.

External Citations

  1. apolipoprotein E4
  2. clusterin
  3. AlzGene
  4. Alzheimer’s Disease Neuroimaging Initiative

Further Reading

Primary Papers

  1. Huang GZ, Woolley CS. Estradiol Acutely Suppresses Inhibition in the Hippocampus through a Sex-Specific Endocannabinoid and mGluR-Dependent Mechanism. Neuron. 2012 Jun 7;74(5):801-8. PubMed.
  2. Damoiseaux JS, Seeley WW, Zhou J, Shirer WR, Coppola G, Karydas A, Rosen HJ, Miller BL, Kramer JH, Greicius MD, . Gender modulates the APOE ε4 effect in healthy older adults: convergent evidence from functional brain connectivity and spinal fluid tau levels. J Neurosci. 2012 Jun 13;32(24):8254-62. PubMed.
  3. Vierk R, Glassmeier G, Zhou L, Brandt N, Fester L, Dudzinski D, Wilkars W, Bender RA, Lewerenz M, Gloger S, Graser L, Schwarz J, Rune GM. Aromatase inhibition abolishes LTP generation in female but not in male mice. J Neurosci. 2012 Jun 13;32(24):8116-26. PubMed.

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