The apolipoprotein E4 (ApoE4) allele, the strongest known genetic risk factor for late-onset sporadic Alzheimer’s disease, puts women at higher risk for the disease than men, but how remains unclear. Now, a large meta-analysis of genetic, biomarker, and autopsy data from 10 longitudinal cohorts indicates that ApoE4 raises CSF tau in women more than in men, particularly in people with amyloid. Other markers of AD pathology—CSF Aβ, or plaques and tangles—showed no such effect of sex in E4 carriers. The study, led by Timothy Hohman, Vanderbilt University in Nashville, Tennessee, appeared in the May 7 JAMA Neurology.

While the results suggest that ApoE4 promotes plaques and tangles equally in women and men, it hints that women carriers are at higher risk for neurodegeneration downstream since elevated CSF tau signals ongoing neuronal loss.

“[This study] 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,” wrote Christian Pike, University of Southern California, Los Angeles, in an email to Alzforum.

For reasons that are not clear, more women than men with E4 get clinical Alzheimer’s disease (Farrer et al., 1997). This dichotomy varies with age, reaching its peak between the ages of 55 and 75, and then declining (Sep 2017 news). 

What could explain the sex difference? It’s known that ApoE4 drives earlier and higher amyloid deposition in carriers, possibly by blocking amyloid clearance from the brain (Apr 2013 news). ApoE4 also affects tau: Carriers have more tau in the CSF and more neurofibrillary tangles in the brain, and animal work suggests E4 accelerates tau deposition and toxicity (Sep 2017 news). However, not much work has addressed how sex factors in, and results have been mixed.

To remedy that, Hohman and colleagues analyzed data from the 10 studies. To determine sex effects on CSF biomarkers, the investigators pooled data from four longitudinal aging studies that measured CSF Aβ42, total tau, and phospho-tau in a total of 1,792 participants in the Alzheimer’s Disease Neuroimaging Initiative (ADNI), and three smaller studies—the Biomarkers of Cognitive Decline among Normal Individuals (BIOCARD), the Vanderbilt Memory and Aging Project (VMAP), and the Wisconsin Registry of Alzheimer’s Prevention (WRAP). The average age of participants was 70, half were women, and between 34 and 46 percent of each cohort carried at least one ApoE4 allele. Of the nearly 1,800 subjects, 226 had a clinical diagnosis of AD, and the rest had mild cognitive impairment or were cognitively normal. To evaluate sex effects on brain pathology, the researchers also aggregated postmortem neuropathologic data on 5,109 subjects from six studies into an autopsy cohort. The average age was 84, with an equal split between men and women, and approximately 40 percent carried at least one ApoE4 allele.

As expected, Apoe4 status correlated with plaque and tangle pathology in the group as a whole, whether measured by biomarkers or postmortem analysis. ApoE4 carriers had higher CSF total tau (t-tau) and phosphorylated tau (p-tau) and lower CSF Aβ42 than noncarriers. Carrier status was associated with plaque and tangle positivity, based on the Consortium to Establish a Registry for Alzheimer's Disease (CERAD) neuritic plaque score, and Braak staging, respectively.

However, when the investigators broke out the results by sex, they found stronger effects of ApoE4 on the elevation of CSF tau in women compared to men. The association depended on amyloidosis being established, because when the investigators separately analyzed amyloid-positive and -negative women, they only saw it in the former. No interaction of sex and ApoE was seen for CSF Aβ42.

The results support previous results from the ADNI cohort on CSF t-tau (Jun 2012 news, Altmann et al., 2014), and extend the sex difference to p-tau. That they saw similar results in three additional cohorts, with widely varying recruitment criteria, length of follow-up, age and number of people with AD, lend credence to the findings, Hohman told Alzforum. “The four data sets are different, yet the results consistently show the interaction of ApoE4 and sex on tau. That makes for a more convincing association,” he said.

The findings are consistent with previous work showing that female ApoE4 carriers have more hippocampal atrophy and cognitive decline at lower amyloid loads compared to men (Koran et al., 2017). Why so remains to be seen, but estrogen boosts ApoE gene expression and release from microglia, and its loss in post-menopausal E4 carriers could leave them with a greater deficit of “good” ApoE than women with ApoE2/3 alleles.

In contrast to the CSF results, the researchers found no sex difference in either neurofibrillary tangle or amyloid load in ApoE4 carriers in the autopsy samples. This might be because these subjects were much older. However, the investigators saw no sex effect even among those younger than 75. The results further support the idea that the sex-specific increase in CSF tau levels signals an excess of neurodegeneration due to ApoE4, rather than higher cortical tau or amyloid deposition. Alternatively, the Braak staging scheme might be too crude to pick up subtle, sex-specific ApoE effects, Hohman said. He suggested more comprehensive, continuous measures of tauopathy will be needed to explore that idea.

Comorbidities might explain the results as well. In epidemiological studies, researchers can't account for men who have already died from cardiovascular disease, but who would also have been a high risk for dementia had they lived long enough. Because ApoE4 affects cardiovascular risk, this survival effect could weigh on men and women differently, creating an apparent sex difference in dementia risk. Hohman is now using mortality data to better estimate and account for survivor effects in his statistical models.

Finally, in a subtle twist, Hohman assumed going into the study he would see sex differences in the ApoE4 effect on CSF Aβ42, but he did not. Nonetheless, the study does not rule out sex-specific effects on amyloid, noted Michael Greicius, Stanford University, Palo Alto, California. “This is a nice study and very well done, but a limitation of healthy aging studies of people in their 60s and 70s is that some of the ApoE-related amyloid effects might already be in play ahead of that,” he told Alzforum. “It’s not to say there aren’t amyloid-independent effects of ApoE—that’s an exciting and testable hypothesis—but we can’t exclude the possibility that the effect they see is the result of amyloid overproduction and misprocessing that starts five years earlier in women E4 carriers compared to men,” Greicius said. To sort that out will take longitudinal studies beginning earlier than even ADNI, which enrolls people 55 and over. And while a few groups are starting to study younger people, as yet nobody has enough subjects for a statistical analysis of people in the critical window between 45 and 65, Greicius said. —Pat McCaffrey

Comments

  1. 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:

    . Alzheimer's disease, apolipoprotein E4, and gender. JAMA. 1994 May 4;271(17):1316-7. PubMed.

    . 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.

  2. 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:

    . Apolipoprotein E Genotype and Sex Risk Factors for Alzheimer Disease: A Meta-analysis. JAMA Neurol. 2017 Oct 1;74(10):1178-1189. PubMed.

    . Apolipoprotein E genotype and age at menopause. Ann N Y Acad Sci. 2004 Jun;1019:564-7. PubMed.

    . 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.

    . 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.

    . 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.

    . 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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References

News Citations

  1. New Look at Sex and ApoE4 Puts Women at Risk Earlier than Men
  2. ApoE Does Not Bind Aβ, Competes for Clearance
  3. ApoE4 Makes All Things Tau Worse, From Beginning to End
  4. What’s Sex Got to Do With It? Differences in Connectivity, Synapses

Paper Citations

  1. . 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.
  2. . Sex modifies the APOE-related risk of developing Alzheimer disease. Ann Neurol. 2014 Apr;75(4):563-73. Epub 2014 Apr 14 PubMed.
  3. . Sex differences in the association between AD biomarkers and cognitive decline. Brain Imaging Behav. 2017 Feb;11(1):205-213. PubMed.

External Citations

  1. Alzheimer’s Disease Neuroimaging Initiative
  2. Biomarkers of Cognitive Decline among Normal Individuals
  3. Vanderbilt Memory and Aging Project
  4. Wisconsin Registry of Alzheimer’s Prevention

Further Reading

No Available Further Reading

Primary Papers

  1. . Sex-specific association of Apolipoprotein E with cerebrospinal fluid levels of tau. JAMA Neurol. 2018 May 7