Dincer A, Chen CD, McKay NS, Koenig LN, McCullough A, Flores S, Keefe SJ, Schultz SA, Feldman RL, Joseph-Mathurin N, Hornbeck RC, Cruchaga C, Schindler SE, Holtzman DM, Morris JC, Fagan AM, Benzinger TL, Gordon BA. APOE ε4 genotype, amyloid-β, and sex interact to predict tau in regions of high APOE mRNA expression. Sci Transl Med. 2022 Nov 16;14(671):eabl7646. PubMed.
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McGill University
Lund University
Dincer et al. address an important question in the understanding of the links between APOE4 genotype and Aβ on tau deposition, both on soluble p-tau and insoluble tau aggregates. Global Aβ was the main predictor of both tau measures, but there were interesting interactions with sex and genotype; in women who are APOE4 carriers there was a stronger association between Aβ and tau. This was not the case in men. These results add to the mounting evidence of sex differences in tau pathology (Smith et al., 2020; Buckley et al., 2020). It will be interesting to study these associations on tau accumulation over time, to further understand the links with progression of pathology.
Results related to the mRNA expression of APOE also converge with a recent study that identified APOE playing a key role in tau network-related genes (Montal et al., 2022). Combining in vivo biomarker data with genetic expression is an exciting avenue to leverage our understanding of regional vulnerability. Still, the underlying links between Aβ and tau are likely multifactorial complex and considering genes related to APOE might also help gain new insight in disease mechanisms.
References:
Smith R, Strandberg O, Mattsson-Carlgren N, Leuzy A, Palmqvist S, Pontecorvo MJ, Devous MD, Ossenkoppele R, Hansson O. The accumulation rate of tau aggregates is higher in females and younger amyloid-positive subjects. Brain. 2020 Dec 1;143(12):3805-3815. PubMed.
Buckley RF, Scott MR, Jacobs HI, Schultz AP, Properzi MJ, Amariglio RE, Hohman TJ, Mayblyum DV, Rubinstein ZB, Manning L, Hanseeuw BJ, Mormino EC, Rentz DM, Johnson KA, Sperling RA. Sex Mediates Relationships Between Regional Tau Pathology and Cognitive Decline. Ann Neurol. 2020 Nov;88(5):921-932. Epub 2020 Aug 31 PubMed.
Montal V, Diez I, Kim CM, Orwig W, Bueichekú E, Gutiérrez-Zúñiga R, Bejanin A, Pegueroles J, Dols-Icardo O, Vannini P, El-Fakhri G, Johnson KA, Sperling RA, Fortea J, Sepulcre J. Network Tau spreading is vulnerable to the expression gradients of APOE and glutamatergic-related genes. Sci Transl Med. 2022 Jul 27;14(655):eabn7273. PubMed.
Washington University in St. Louis
In this new publication, Dincer et al. evaluate whether APOE ε4 carrier status exerts an additive or interaction effect with increasing amounts of Aβ in predicting tau PET. Interestingly, thanks to imaging of more than 300 participants, the authors demonstrate that while APOE ε4 mostly influences tau pathology through its regulation of Aβ, the APOE ε4 allele seems to potentiate the tau pathology above the effects that can be ascribed to Aβ alone. My main takeaway from this study is that the APOE ε4 allele can potentiate tau aggregation in both an Aβ-dependent and Aβ-independent manner. These findings are consistent with previous PET studies showing that APOE ε4 is associated with greater tau aggregation, whether this associates with Aβ pathology or not (Weigand et al., 2021; Therriault et al., 2020; Therriault et al., 2020; Baek et al., 2020; La Joie et al., 2021; Salvadó et al., 2021; Yan et al., 2021).
This study raises the question of the possible contribution of APOE ε4 in primary tauopathies. Only a few studies have tried to answer this question. Recently, a study by Sabir et al. found no evidence to implicate APOE in the neuropathogenesis of corticobasal degeneration and progressive supranuclear palsy, two other tauopathies (Sabir et al., 2019). This absence of an APOE effect can be attributed to the neuropathological heterogeneity across tauopathies, but also to a small effect of APOE ε4 on tau pathology in the absence of Aβ pathology that might not be detectable in small cohorts of primary tauopathies patients.
While further studies in larger cohorts will be required to evaluate the role of APOE ε4 in primary tauopathies, Dincer et al.’s work supports the strong literature on in vivo animal data that links APOE ε4 to tau pathology and tau-mediated neurodegeneration (Gratuze et al., 2022; Wang et al., 2021; Gratuze et al., 2022; Shi et al., 2017; Shi et al., 2019; Litvinchuk et al., 2021). Those animal studies might help us to better understand mechanisms through which APOE influences tau pathology. Previous studies clearly demonstrated a strong contribution by microglia, since their depletion strongly attenuates the worsening effect from APOE ε4 on tau-mediated neurodegeneration (Shi et al., 2019), and since the removal of astrocyte-derived APOE ε4 reduced tau-associated neurodegeneration and microglial reactivity (Wang et al., 2021) in P301S tau transgenic mice expressing human APOE ε4. Recently, we were able to demonstrate, in the same mouse model, that APOE ε4 facilitates tau pathology and tau-mediated neurodegeneration through TREM2-independent microgliosis (Gratuze et al., 2022). Altogether, APOE ε4-mediated sustained neuroinflammation, which can be exacerbated by blood-brain barrier disruption (Montagne et al., 2020), worsens tau pathology and tau-mediated neurodegeneration.
In addition to microglia, another novel mechanism has been recently suggested to drive APOE ε4-dependent tau pathology. Saroja et al. showed that by interacting with APOE ε4 and its receptor LRP1, the astrocyte-secreted protein glypican-4 is a key driver of APOE ε4-mediated abnormal hyperphosphorylation of tau (Saroja et al., 2022). It will be interesting to evaluate in future studies whether glypican-4 can contribute to neuroinflammation/gliosis in the presence of tau pathology.
Another interesting finding by Dincer et al. came from the analysis of the regional APOE mRNA gene expression in the brain from the Allen Human Brain Atlas. They detected a clear association between APOE mRNA expression and the pattern of APOE ε4-predicted tau pathology. These important data reinforce a study published earlier this year, showing that the greater ApoE expression was in a given region, the more susceptible that region was to neurofibrillary tangles (Montal et al., 2022).
In conclusion, Dincer et al. wrote that “our data suggest that APOE ε4 carrier status should be considered for clinical trials targeting tau hyperphosphorylation or aggregation.” I totally support this statement, but I think it can work in both ways: Those studies clearly show that targeting ApoE4 becomes an attractive therapeutic strategy to counteract tau pathology in AD, given that tau pathology, and not Aβ, strongly correlates with local brain atrophy, neuronal death, and cognitive decline.
In animal models, the Holtzman laboratory developed a human specific anti-ApoE4 and ApoE3 antibody, HAE-4, shown to reduce parenchymal amyloidosis after passive immunotherapy (Liao et al., 2018; Xiong et al., 2021). We recently demonstrated that HAE-4 also decreases Aβ-mediated tau seeding and spreading in the brain of a transgenic mouse model of amyloid pathology expressing human APOE ε4 (Gratuze et al., 2022). Interestingly, in males only, we observed a significant decrease of seeded tau pathology per plaque in HAE-4-treated mice, suggesting that HAE-4 can affect tau pathology that is independent of Aβ plaque reduction, suggesting that, similarly to Dincer et al.’s findings, targeting APOE ε4 allele can decrease tau propagation in both an Aβ-dependent and -independent manner. The use of antisense nucleotides against human APOE seems also promising: ASO treatment significantly protected against tau pathology and associated neurodegeneration, while decreasing neuroinflammation and preserving synaptic density in P301S tau transgenic mice expressing human APOE ε4 (Litvinchuk et al., 2021).
Altogether, this study provides data essential to elucidate the complex interaction between Aβ, tau, and APOE ε4, and hopefully, to develop new strategies to reduce cognitive decline in AD.
References:
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La Joie R, Visani AV, Lesman-Segev OH, Baker SL, Edwards L, Iaccarino L, Soleimani-Meigooni DN, Mellinger T, Janabi M, Miller ZA, Perry DC, Pham J, Strom A, Gorno-Tempini ML, Rosen HJ, Miller BL, Jagust WJ, Rabinovici GD. Association of APOE4 and Clinical Variability in Alzheimer Disease With the Pattern of Tau- and Amyloid-PET. Neurology. 2021 Feb 2;96(5):e650-e661. Epub 2020 Dec 1 PubMed.
Salvadó G, Grothe MJ, Groot C, Moscoso A, Schöll M, Gispert JD, Ossenkoppele R, Alzheimer’s Disease Neuroimaging Initiative. Differential associations of APOE-ε2 and APOE-ε4 alleles with PET-measured amyloid-β and tau deposition in older individuals without dementia. Eur J Nucl Med Mol Imaging. 2021 Jul;48(7):2212-2224. Epub 2021 Feb 1 PubMed.
Yan S, Zheng C, Paranjpe MD, Li Y, Li W, Wang X, Benzinger TL, Lu J, Zhou Y, Alzheimer's Disease Neuroimaging Initiative. Sex modifies APOE ε4 dose effect on brain tau deposition in cognitively impaired individuals. Brain. 2021 Apr 20; PubMed.
Sabir MS, Blauwendraat C, Ahmed S, Serrano GE, Beach TG, Perkins M, Rice AC, Masliah E, Morris CM, Pihlstrom L, Pantelyat A, Resnick SM, Cookson MR, Hernandez DG, Albert M, Dawson TM, Rosenthal LS, Houlden H, Pletnikova O, Troncoso J, Scholz SW. Assessment of APOE in atypical parkinsonism syndromes. Neurobiol Dis. 2019 Jul;127:142-146. Epub 2019 Feb 21 PubMed.
Gratuze M, Schlachetzki JC, D'Oliveira Albanus R, Jain N, Novotny B, Brase L, Rodriguez L, Mansel C, Kipnis M, O'Brien S, Pasillas MP, Lee C, Manis M, Colonna M, Harari O, Glass CK, Ulrich JD, Holtzman DM. TREM2-independent microgliosis promotes tau-mediated neurodegeneration in the presence of ApoE4. Neuron. 2023 Jan 18;111(2):202-219.e7. Epub 2022 Nov 10 PubMed.
Wang C, Xiong M, Gratuze M, Bao X, Shi Y, Andhey PS, Manis M, Schroeder C, Yin Z, Madore C, Butovsky O, Artyomov M, Ulrich JD, Holtzman DM. Selective removal of astrocytic APOE4 strongly protects against tau-mediated neurodegeneration and decreases synaptic phagocytosis by microglia. Neuron. 2021 May 19;109(10):1657-1674.e7. Epub 2021 Apr 7 PubMed.
Gratuze M, Jiang H, Wang C, Xiong M, Bao X, Holtzman DM. APOE Antibody Inhibits Aβ-Associated Tau Seeding and Spreading in a Mouse Model. Ann Neurol. 2022 Jun;91(6):847-852. Epub 2022 Mar 31 PubMed.
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Saroja SR, Gorbachev K, Julia T, Goate AM, Pereira AC. Astrocyte-secreted glypican-4 drives APOE4-dependent tau hyperphosphorylation. Proc Natl Acad Sci U S A. 2022 Aug 23;119(34):e2108870119. Epub 2022 Aug 15 PubMed.
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Cliniques Universitaires Saint-Luc and Massachusetts General Hospital
Dincer and colleagues report here a synergistic effect of amyloid and ApoE genotype on the extent of tau-PET signals. This interaction is particularly relevant in the context of clinical trial results showing that anti-amyloid antibodies more effectively slow down tau progression and cognitive decline in APOE4 carriers than in noncarriers, as these results converge on a closer association between amyloid and tau in APOE ε4 carriers.
The impact of amyloid on tau was greater in female e4 carriers than in male e4 carriers, as previously shown using CSF data, encouraging the field to look at the results of trials by both sex and APOE4 carriage (Altmann et al., 2014; Buckley et al., 2019).
This article further suggests that the expression of ApoE mRNA is driving the increased association between amyloid and tau pathology, as the regional expression of ApoE mRNA correlated with the effect of the ApoE-amyloid interaction on tau-PET. ApoE status may thus be important for anti-tau therapies as well, and drugs specifically targeting ApoE expression may reduce the risk of developing tau pathology.
Of note, the authors did not observe any additive effect between ApoE and amyloid on tau, suggesting that ApoE mainly potentiates the effect of amyloid on tau, but that it does not affect tau directly. Interestingly, a rhinal region of interest was not included in this paper, whereas we reported that the ApoE effect on rhinal tau was not fully mediated by amyloid, unlike the ApoE effect on neocortical tau (Sanchez et al., 2021). Altogether these data suggest that ApoE has a direct effect on the region where tau initially occurs in the medial temporal lobe; and an indirect, amyloid-dependent effect on regions where tau spreads within and outside the MTL.
References:
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.
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.
Sanchez JS, Becker JA, Jacobs HI, Hanseeuw BJ, Jiang S, Schultz AP, Properzi MJ, Katz SR, Beiser A, Satizabal CL, O'Donnell A, DeCarli C, Killiany R, El Fakhri G, Normandin MD, Gómez-Isla T, Quiroz YT, Rentz DM, Sperling RA, Seshadri S, Augustinack J, Price JC, Johnson KA. The cortical origin and initial spread of medial temporal tauopathy in Alzheimer's disease assessed with positron emission tomography. Sci Transl Med. 2021 Jan 20;13(577) PubMed.
University of Pennsylvania
This is an exciting paper by Aylin Dincer and colleagues from Brian Gordon’s group at WashU. The study makes several important contributions. First, the authors find more tau pathology in APOE e4 carriers compared to noncarriers, though this effect more or less disappears after accounting for Aβ status. The authors conclude that APOE increases Aβ pathology, thereby exacerbating the expression of tau pathology. While this is not supported by mediation analysis, it is a reasonable conclusion, especially given the composition of the sample is mostly cognitively normal—only 13 percent has a CDR greater than zero.
The study also makes a strong case for the continued utility of tau-PET even given advances in fluid biomarkers. The three-way interaction nominates women APOE e4 carriers to be at greatest risk for accumulating tau pathology using tau-PET, replicating previous work (e.g., Yan et al., 2021). However, no e4 or sex interaction emerged in the same analysis using CSF phosphorylated tau (p-tau), which instead closely tracked with the degree of Aβ pathology. CSF p-tau181 continues to be an excellent and accessible biomarker for AD pathology in general, but this study is another reminder that tau-PET and fluid biomarkers are not necessarily conveying the same information.
The centerpiece of this study replicates several previous PET and neuropathology papers in finding the medial temporal lobe (MTL) to be specifically vulnerable to tau pathology in APOE e4 carriers (e.g., La Joie et al., 2021). Going further, the study joins two other recent papers in finding a correlation between regional vulnerability to AD pathology in APOE e4 carriers and regional expression of APOE transcripts (Montal et al., 2022; Wagstyl et al., 2022). This is an excellent use of an existing whole-brain normative RNA transcription dataset, and I hope it will encourage other AD researchers to blend imaging and transcriptomics to move beyond biomarkers and into molecular mechanisms in humans. In this spirit, Dincer and coauthors show that regions with a greater abundance of brain-expressed APOE accumulate more tau pathology in APOE e4 carriers, strongly implicating a specific relationship between APOE and tau.
Future work will need to resolve the nature of this relationship. Recent high-impact work has nominated APOE e4 effects on blood-brain barrier breakdown as a possible mechanism, and both animal work and human epidemiological studies suggest APOE e4 may impact AD pathology indirectly through neurovascular influences and/or changes to circulating lipid profiles (Belloy et al., 2019). However, APOE is expressed in the brain, chiefly by astrocytes and microglia, and this study should be drawing our attention to APOE expression in the brain directly influencing pathways leading to AD pathology. There is interesting literature showing that increased ApoE concentrations in plasma are related to AD and AD pathology (e.g., Giannisis et al., 2022), though the relationship between CSF ApoE and AD pathology is admittedly less clear. However, there are a growing number of open datasets of human metabolomics, genomics, and single-cell transcriptomics that are very likely to provide insight into the question of whether and how APOE directly influences the expression of tau pathology. By taking advantage of such a dataset, this paper by Dincer and coauthors is certainly moving us in the right direction.
References:
Yan S, Zheng C, Paranjpe MD, Li Y, Li W, Wang X, Benzinger TL, Lu J, Zhou Y, Alzheimer's Disease Neuroimaging Initiative. Sex modifies APOE ε4 dose effect on brain tau deposition in cognitively impaired individuals. Brain. 2021 Apr 20; PubMed.
La Joie R, Visani AV, Lesman-Segev OH, Baker SL, Edwards L, Iaccarino L, Soleimani-Meigooni DN, Mellinger T, Janabi M, Miller ZA, Perry DC, Pham J, Strom A, Gorno-Tempini ML, Rosen HJ, Miller BL, Jagust WJ, Rabinovici GD. Association of APOE4 and Clinical Variability in Alzheimer Disease With the Pattern of Tau- and Amyloid-PET. Neurology. 2021 Feb 2;96(5):e650-e661. Epub 2020 Dec 1 PubMed.
Montal V, Diez I, Kim CM, Orwig W, Bueichekú E, Gutiérrez-Zúñiga R, Bejanin A, Pegueroles J, Dols-Icardo O, Vannini P, El-Fakhri G, Johnson KA, Sperling RA, Fortea J, Sepulcre J. Network Tau spreading is vulnerable to the expression gradients of APOE and glutamatergic-related genes. Sci Transl Med. 2022 Jul 27;14(655):eabn7273. PubMed.
Wagstyl K, Adler S, Seidlitz J, Vandekar S, Mallard TT, Dear R, DeCasien AR, Satterthwaite TD, Liu S, Vértes PE, Shinohara RT, Alexander-Bloch A, Geschwind DH, Raznahan A. Transcriptional Cartography Integrates Multiscale Biology of the Human Cortex. bioRxiv 2022.06.13.495984 bioRxiv
Belloy ME, Napolioni V, Greicius MD. A Quarter Century of APOE and Alzheimer's Disease: Progress to Date and the Path Forward. Neuron. 2019 Mar 6;101(5):820-838. PubMed.
Giannisis A, Al-Grety A, Carlsson H, Patra K, Twohig D, Sando SB, Lauridsen C, Berge G, Grøntvedt GR, Bråthen G, White LR, Kultima K, Nielsen HM. Plasma apolipoprotein E levels in longitudinally followed patients with mild cognitive impairment and Alzheimer's disease. Alzheimers Res Ther. 2022 Aug 24;14(1):115. PubMed.
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