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.

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  1. Two interesting papers being published look at the effects of APOE genotype on different aspects of AD, in particular tau pathology and cognitive progression of disease.

    Bondi and colleagues studied 297 older adults without dementia being followed in ADNI. They found that after adjusting for amyloid PET, medial temporal lobe tau PET was associated with cognitive abnormalities and the strongest effects were in APOE4 carriers and with high levels of tau. Interestingly, this association persisted even in amyloid-negative individuals. This suggests that APOE4 is affecting tau pathology and cognitive progression in the presence or absence of amyloid deposition.

    Ramanan and colleagues studied 325 individuals in the Mayo Clinic Study of Aging 65 years of age and older who were cognitively unimpaired. They found that while APOE4 was associated with high tau deposition as seen on Tau PET in the entorhinal cortex and a lower FDG-to-tau ratio, these associations appeared to be attenuated when controlling for amyloid deposition.

    It is clear that APOE genotype has a huge effect on amyloid deposition in the brain, with APOE4-positive individuals having significantly more amyloid deposition on average than is present with APOE3, and even less amyloid deposition is seen with APOE2. Since amyloid deposition has been shown in both human and animal studies to in some way drive tau pathology, it has been difficult to untangle whether APOE may also be influencing tau pathology and the progression of cognitive decline and dementia in AD independent of the effect of APOE on amyloid.

    We recently found in the PS19 mouse model of tau pathology (in the absence of amyloid), which develops both significant tau accumulation as well as marked neurodegeneration, that APOE is involved in driving tau-mediated neurodegeneration, with APOE4 having the strongest effect and the lack of APOE abrogating the effect of neurodegeneration almost entirely (Shi et al., 2017). 

    In addition, we also just found that the effect of APOE is completely dependent on microglia (Shi et al., 2019), as did another group (Mancuso et al., 2019). Of note is that while APOE and APOE4 in these animal studies had some effect on tau accumulation, the biggest effect was on the ability of APOE and APOE4 to influence the amount of microglial activation and neurodegeneration.

    If these new findings were to translate to the human brain, what one might expect is that the presence of APOE4 might be associated with somewhat greater tau pathology in either the absence or presence of amyloid deposition, but that a much bigger effect of APOE4 would be on the amount of microglial activation that occurred over time with tau pathology (expected to be larger with E4) and that the progression of cognitive decline would be faster.

    The study of Bondi et al. did find greater tau pathology in the presence of E4 even in the absence of amyloid, as well as greater cognitive progression. The study by Ramanan et al. did not find a greater effect of E4 on tau pathology once the amount of amyloid was corrected for. To fully understand in humans the effect of APOE on microglial activation and progression of neurodegeneration, longitudinal studies need to be done with the types of imaging biomarkers used in these studies but also markers of neuroinflammation (when available), amyloid, tau, and also structural MRI and cognitive assessments.

    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. These two studies are beginning to get at the amyloid and tau part of the story and to some extent cognitive change in the Bondi et al. paper. Further studies will be needed to sort out these other issues in humans during normal aging, preclinical AD, AD, and in primary tauopathies.

    References:

    Shi Y, Yamada K, Liddelow SA, Smith ST, Zhao L, Luo W, Tsai RM, Spina S, Grinberg LT, Rojas JC, Gallardo G, Wang K, Roh J, Robinson G, Finn MB, Jiang H, Sullivan PM, Baufeld C, Wood MW, Sutphen C, McCue L, Xiong C, Del-Aguila JL, Morris JC, Cruchaga C, Alzheimer’s Disease Neuroimaging Initiative, Fagan AM, Miller BL, Boxer AL, Seeley WW, Butovsky O, Barres BA, Paul SM, Holtzman DM. ApoE4 markedly exacerbates tau-mediated neurodegeneration in a mouse model of tauopathy. Nature. 2017 Sep 28;549(7673):523-527. Epub 2017 Sep 20 PubMed.

    Shi Y, Manis M, Long J, Wang K, Sullivan PM, Remolina Serrano J, Hoyle R, Holtzman DM. Microglia drive APOE-dependent neurodegeneration in a tauopathy mouse model. J Exp Med. 2019 Nov 4;216(11):2546-2561. Epub 2019 Oct 10 PubMed.

    Mancuso R, Fryatt G, Cleal M, Obst J, Pipi E, Monzón-Sandoval J, Ribe E, Winchester L, Webber C, Nevado A, Jacobs T, Austin N, Theunis C, Grauwen K, Daniela Ruiz E, Mudher A, Vicente-Rodriguez M, Parker CA, Simmons C, Cash D, Richardson J, NIMA Consortium, Jones DN, Lovestone S, Gómez-Nicola D, Perry VH. CSF1R inhibitor JNJ-40346527 attenuates microglial proliferation and neurodegeneration in P301S mice. Brain. 2019 Oct 1;142(10):3243-3264. PubMed.

    View all comments by David Holtzman

  2. We and Weigand et al. both take advantage of the availability of tau PET to ask important—but quite different—questions about AD pathophysiology. APOE ɛ4 is well-known to be associated with amyloidosis, but whether this allele may directly impact tau has been less clear.

    The ADNI study is primarily focused on cognition. Weigand et al. confirms prior work that medial temporal lobe tau burden is likely more proximally related to cognition than cortical amyloid load. The study also reports that APOE ɛ4 carriers display worse memory than noncarriers for the same level of medial temporal tau and after adjusting for amyloid. As a result, the authors conclude that APOE ɛ4 may interact with tau independently of amyloid. One challenge here is that cognition is a late endpoint in AD and is likely influenced by multiple factors including but not limited to amyloid and tau pathology. The finding that APOE ɛ4 strengthens the negative association between tau and cognition may be related to a mechanistic impact of APOE on tau as the authors hypothesize, but may alternatively reflect effects and factors downstream of tau. Nevertheless, it’s an interesting study which effectively calls more attention to the topic.

    Our Mayo Clinic Study of Aging work was focused on investigating factors that may be related to resistance, i.e., avoiding and conversely susceptibility to tau, and resilience, i.e., coping with tau. As part of this work, we directly tested whether APOE ɛ4 was associated with regional tau burden using a population-based sample. In fact we found that global amyloid load was the factor most strongly associated with regional tau deposition, and that after accounting for this effect, there were no main associations of APOE ɛ4 with regional tau burden.

    Interestingly, we did find that in the presence of substantial amyloidosis, for the same level of amyloid, APOE ɛ4 carriers displayed higher levels of tau in the entorhinal cortex compared to noncarriers. Taken together, this suggests that APOE ɛ4 may accelerate tau pathology in key AD regions, but that this would appear to be only in the presence of amyloid (a conclusion consistent with prior postmortem neuropathology data in the ROS/MAP cohorts).

    Our work also suggested that women may be vulnerable to greater neuronal damage (measured by FDG-PET) than men at the same level of entorhinal cortex tau burden. This adds to a growing literature on the role of sex differences in AD, which is an exciting area that is getting a lot of attention.

    View all comments by Vijay Ramanan

  3. We thank Alzforum for covering this important area of research on the relationship between APOE genotype and tau PET. We’d like to provide a note on the seemingly contradictory findings between Ramanan et al. and our group (Weigand et al.). The primary outcome of the Ramanan et al. study, to examine differential effects of ε4 genotype on tau PET level, was not a direct goal of our study. Notably, we did find higher tau PET levels among ε4 carriers when examining group differences, but we did not assess whether this effect occurred independently of amyloid. Rather, the focus of our study was on associations between tau and cognition, as well as the moderating effect of ε4 carrier status on those associations, with all effects examined independently of amyloid.

    We found that tau PET level was associated with all cognitive domains, whereas amyloid PET exhibited no such associations. Further, we found that ε4 carriers had a stronger association between tau PET and memory independently of amyloid PET level, and this moderating effect persisted when we included only those individuals with negative amyloid PET scans. Thus, methodological differences in model specification may explain discrepancies between our findings and those of Ramanan et al. It’s possible that ε4 genotype may not directly increase tau accumulation, but rather may interact with tau pathology to exert compounding consequences on neuronal and cognitive integrity.

    This interactive effect may be largely influenced by inflammatory mechanisms, as has been demonstrated in Shi et al., 2017, 2019, in which ε4 genotype exacerbated tau-mediated neurodegeneration primarily via microglial activation (see Oct 2019 news). This effect occurred independently of amyloid, as did our findings of ε4 carrier status strengthening the association between tau and memory.

    Thus, while tau pathology and ε4 genotype may not directly influence one another (although this remains to be determined), they may have additive negative effects on neuronal and cognitive outcomes. However, further converging evidence using multiple methods (e.g., animal models, neuropathological studies, PET) are needed to better disentangle the complex interactions between APOE, amyloid, and tau.

    References:

    Shi Y, Yamada K, Liddelow SA, Smith ST, Zhao L, Luo W, Tsai RM, Spina S, Grinberg LT, Rojas JC, Gallardo G, Wang K, Roh J, Robinson G, Finn MB, Jiang H, Sullivan PM, Baufeld C, Wood MW, Sutphen C, McCue L, Xiong C, Del-Aguila JL, Morris JC, Cruchaga C, Alzheimer’s Disease Neuroimaging Initiative, Fagan AM, Miller BL, Boxer AL, Seeley WW, Butovsky O, Barres BA, Paul SM, Holtzman DM. ApoE4 markedly exacerbates tau-mediated neurodegeneration in a mouse model of tauopathy. Nature. 2017 Sep 28;549(7673):523-527. Epub 2017 Sep 20 PubMed.

    Shi Y, Manis M, Long J, Wang K, Sullivan PM, Remolina Serrano J, Hoyle R, Holtzman DM. Microglia drive APOE-dependent neurodegeneration in a tauopathy mouse model. J Exp Med. 2019 Nov 4;216(11):2546-2561. Epub 2019 Oct 10 PubMed.

    View all comments by Alexandra Weigand

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