Does ApoE4 affect aspects of Alzheimer’s disease other than amyloidosis? Animal studies have hinted as much, and now several brain imaging studies seem to agree. In a preprint posted to medRχiv on October 8, researchers led by Mark Bondi at the University of California, San Diego, report that at a given level of tau pathology, Alzheimer's Disease Neuroimaging Initiative participants with an ApoE4 allele perform worse on memory tests than noncarriers. The findings imply that ApoE4 amplifies the toxicity of tangles. Meanwhile, researchers led by Vijay Ramanan at the Mayo Clinic in Rochester, Minnesota, examined whether ApoE genotype exerts direct effects on tangles, independent of amyloidosis. In the October 23 JAMA Network Open, they reported finding few, although among cognitively healthy people with amyloid plaques, ApoE4 carriers did accumulate more tangles in the entorhinal cortex than did noncarriers. In that study, women of any genotype appeared to be more susceptible to the consequences of tangles than men, with worse brain metabolism at a given tangle burden. Other recent work suggests that ApoE4 may pack the biggest punch in women, with female carriers accumulating more tangles and having worse memories than male carriers.
- ApoE4 carriers have worse memories than noncarriers with the same tau burden.
- ApoE4 carriers with amyloid plaques have more tangles than do noncarriers.
- The effects of ApoE4 are worse in women than men.
David Holtzman at Washington University in St. Louis said more such imaging studies are needed to sort out how ApoE affects events downstream of amyloidosis. “The major prediction from the animal studies is that relative to other ApoE isoforms, ApoE4 will be linked with greater inflammation and greater progressive neurodegeneration once tau pathology develops,” he wrote to Alzforum (full comment below).
Holtzman’s work first implicated ApoE4 in exacerbating tau. In mouse tauopathy models, his group found that mice expressing a human E4 allele developed more phosphorylated tau, inflammation, and neurodegeneration than did those with other isoforms. Some data hinted the findings could apply to people. In a large observational cohort followed for 10 years, ApoE4 carriers declined faster cognitively than did noncarriers (Sep 2017 news).
Bondi and colleagues followed up on this by examining how the ApoE4 allele affects cognition. First author Alexandra Weigand analyzed data from 297 ADNI participants with an average age of 76. Just over a quarter had mild cognitive impairment, the rest were cognitively healthy, and one-third of the cohort carried ApoE4. As expected, carriers accumulated more amyloid and had more tau tangles in the medial temporal lobe (MTL) than noncarriers. Also as expected, after controlling for tau levels, the amount of amyloid a person had did not independently affect his or her cognitive performance. Tau pathology did. After controlling for amyloid, MTL tau associated with worse performance on tests of attention, executive function, language, and memory.
Unexpectedly, ApoE4 modified this association. At a given tau burden, ApoE4 carriers scored worse than noncarriers on memory tests, though not in the other cognitive domains. ApoE4 had this effect even in people at Braak stage I/II, when tangles are limited. Even among people without any amyloid plaques, ApoE4 carriers had worse memories than noncarriers with the same tau burden. “Our findings suggest that ApoE may exert deleterious effects on cognition through specific interactions with tau pathology, and these effects may occur independently of and prior to amyloidosis,” the authors noted.
Ramanan and colleagues took a different approach. They examined tau pathology and brain metabolism, not cognition, in ApoE4 carriers, analyzing data from 325 participants in the Mayo Clinic Study of Aging whose average age was also 76. Most were cognitively healthy, and 29 percent carried an ApoE4 allele. Across the whole cohort, tau pathology was no different between carriers and noncarriers, after adjusting for amyloid burden. However, when the researchers analyzed only people with a positive amyloid scan, ApoE4 carriers did have more tangles in the entorhinal cortex than noncarriers. “This suggests that ApoE4 may accelerate tau pathology in key AD regions, but only in the presence of amyloid, a conclusion consistent with prior postmortem neuropathology data in the ROS/MAP cohorts,” Ramanan wrote to Alzforum.
Notably, regardless of genotype, women with more entorhinal cortical tau had more sluggish brain metabolism, as seen by FDG PET, than men. To the authors, this suggests that women may succumb faster to the toxic effects of tangles. “This adds to a growing literature on the role of sex differences in AD, an exciting area that is getting a lot of attention,” Ramanan wrote.
Regarding women, a previous analysis of ADNI data found that p-tau levels in cerebrospinal fluid rise faster in female ApoE4 carriers than in noncarriers and men, suggesting a sex-specific effect of the E4 allele. Other research indicates that women with ApoE4 lose more white matter at menopause than do noncarriers, perhaps rendering their brains more prone to decline (Aug 2018 conference news; Buckley et al., 2019; Feb 2019 news). Other studies have reported a similar sex effect for ApoE4 (Altmann et al., 2014; May 2018 news).
Since then, researchers led by Yun Zhou at WashU and Rongfu Wang at Peking University First Hospital, Beijing, analyzed 108 ADNI participants with mild cognitive impairment. In the July Theranostics, they reported that the 15 female ApoE4 carriers had higher tau signals throughout the brain than did noncarriers and men, contradicting the Mayo Clinic study. The difference was most pronounced in entorhinal cortex, amygdala, parahippocampal gyrus, and fusiform gyrus. Female carriers also had more p-tau and total tau in CSF.
In a new paper in the October Neurology, Bondi and colleagues add to the evidence of a sex difference among ApoE4 carriers. Erin Sundermann at the University of California, San Diego, led this study, which focused on whether setting sex-specific cutoffs for verbal memory would improve the clinical detection of mild cognitive impairment. This is necessary because women routinely score better on tests of verbal memory than do men, and indeed, raising the cutoff for women and lowering it for men in a cohort of 985 ADNI participants sharpened diagnostic accuracy for MCI by 20 percent. Importantly, the authors found that women with memory loss were five times as likely to have an ApoE4 allele as were women whose memory was stable. Among men, there was no difference in ApoE4 prevalence among those with poor or preserved memory.
“This raises the possibility that the vulnerability to developing amnestic MCI in female ApoE4 carriers may have been underestimated in studies reporting no sex difference in the effect of the ApoE4 allele on AD risk,” the authors note. This study had no tau PET data, but CSF p-tau tracked with memory, being elevated in people with MCI, and somewhat higher in MCI women than men.—Madolyn Bowman Rogers
- ApoE4 Makes All Things Tau Worse, From Beginning to End
- Do Brain Changes at Menopause Make Women More Prone to Alzheimer’s?
- Is a Woman’s Brain More Susceptible to Tau Pathology?
- Study Finds Sex Influences CSF Tau Levels in ApoE4 Carriers
- Buckley RF, Mormino EC, Chhatwal J, Schultz AP, Rabin JS, Rentz DM, Acar D, Properzi MJ, Dumurgier J, Jacobs H, Gomez-Isla T, Johnson KA, Sperling RA, Hanseeuw BJ, Alzheimer's Disease Neuroimaging Initiative. Associations between baseline amyloid, sex, and APOE on subsequent tau accumulation in cerebrospinal fluid. Neurobiol Aging. 2019 Jun;78:178-185. Epub 2019 Mar 7 PubMed.
- Altmann A, Tian L, Henderson VW, Greicius MD, Alzheimer's Disease Neuroimaging Initiative Investigators. Sex modifies the APOE-related risk of developing Alzheimer disease. Ann Neurol. 2014 Apr;75(4):563-73. Epub 2014 Apr 14 PubMed.
- Ramanan VK, Castillo AM, Knopman DS, Graff-Radford J, Lowe VJ, Petersen RC, Jack CR Jr, Mielke MM, Vemuri P. Association of Apolipoprotein E ɛ4, Educational Level, and Sex With Tau Deposition and Tau-Mediated Metabolic Dysfunction in Older Adults. JAMA Netw Open. 2019 Oct 2;2(10):e1913909. PubMed.
- Sundermann EE, Maki P, Biegon A, Lipton RB, Mielke MM, Machulda M, Bondi MW, Alzheimer's Disease Neuroimaging Initiative. Sex-specific norms for verbal memory tests may improve diagnostic accuracy of amnestic MCI. Neurology. 2019 Nov 12;93(20):e1881-e1889. Epub 2019 Oct 9 PubMed.
- Liu M, Paranjpe MD, Zhou X, Duy PQ, Goyal MS, Benzinger TL, Lu J, Wang R, Zhou Y. Sex modulates the ApoE ε4 effect on brain tau deposition measured by 18F-AV-1451 PET in individuals with mild cognitive impairment. Theranostics. 2019;9(17):4959-4970. Epub 2019 Jul 9 PubMed.