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Reiman EM, Arboleda-Velasquez JF, Quiroz YT, Huentelman MJ, Beach TG, Caselli RJ, Chen Y, Su Y, Myers AJ, Hardy J, Paul Vonsattel J, Younkin SG, Bennett DA, De Jager PL, Larson EB, Crane PK, Keene CD, Kamboh MI, Kofler JK, Duque L, Gilbert JR, Gwirtsman HE, Buxbaum JD, Dickson DW, Frosch MP, Ghetti BF, Lunetta KL, Wang LS, Hyman BT, Kukull WA, Foroud T, Haines JL, Mayeux RP, Pericak-Vance MA, Schneider JA, Trojanowski JQ, Farrer LA, Schellenberg GD, Beecham GW, Montine TJ, Jun GR, Alzheimer’s Disease Genetics Consortium. Exceptionally low likelihood of Alzheimer's dementia in APOE2 homozygotes from a 5,000-person neuropathological study. Nat Commun. 2020 Feb 3;11(1):667. PubMed.
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Maastricht University; VU University Medical Centre
In general the data confirm previous findings, and highlights that intervening in APOE-related mechanisms is still a useful therapeutic avenue for AD.
The neuropathological confirmation in a subset of 5,000 participants is a strong asset. It is of interest that the APOE e4 allele is not associated with hippocampal sclerosis and vascular brain injury. This may partly explain why the OR of e4 for AD is higher in the pathologically confirmed subgroup, since hippocampal sclerosis and vascular injury may lead to a clinical diagnosis of dementia mimicking clinical AD. The APOE-e4 allele is associated with Lewy body pathology, suggesting that aggregation of amyloid and α-synuclein share a common mechanism.
Reiman et al. is a very interesting study, showing that the risk of Alzheimer's disease for APOE-ε2 homozygotes is extremely low even when compared with APOE-ε2 heterozygotes. This result, even not surprising, has an impact on how we should think about the effect of APOE genotype on Alzheimer's disease.
Until now, due to the low frequency of the ε2 allele, few studies had focused their attention on its impact on Alzheimer's disease; and those that have done it have usually studied only the ε2 heterozygote group or ε2 carriers merging heterozygotes and homozygotes. Hence, studies like this, in emphasizing the ε2 homozygosity effect, are most interesting.
One of the strongest points of this paper is the large amount of neuropathological data gathered. This allowed study of the actual APOE effects on Alzheimer's risk without confounding effects of misclassified patients. As shown here, in the non-autopsy cohort, both ε2 and ε2 allele effects are smaller than in the neuropathological cohort. Even if it cannot be confirmed with this data set, this suggests that AD-misclassified cases and preclinical AD cases could account for this difference, reinforcing the significance of autopsy results.
Another interesting point was the differential effect found on tau tangle severity after adjusting by amyloid plaque severity. This result points toward additional mechanisms through which the ε2 allele confers its protective effect beyond decreasing amyloid deposition. We are starting to figure out the different mechanisms through which ε2 is protective. In that regard, we have recently conducted a multicohort study including MRI of an unprecedented number of cognitively unimpaired individuals including APOE-ε2 homozygotes. We analysed the ε2 allele dose-effect on gray-matter volumes, and found bigger volumes in key AD-related areas with increasing number of ε2 alleles. This suggests that ε2 homozygotes may confer additional resilience through distinct brain structural patterns, even before there is pathological protein accumulation.
In summary, this study is a starting point to a more detailed study of the ε2 allele, specifically ε2ε2, regarding the mechanisms behind its protective effects on Alzheimer's disease. As it has been shown on these analyses, even with a limited amount of ε2 homozygotes, the protective effect of this allele is higher than previously reported, and the implications and causes of this should be further studied.
Columbia University Medical Center
We’d like to pick up on several of the interesting themes raised in these studies as based on our own work in this area.
In a study of 1,557 brains in the NACC v 10 database (which we presented at AAIC, 2019, and which we’ve now submitted) we found that E2 was associated with significantly reduced risk of neuritic plaques, diffuse plaques, and Braak stage. Odds Ratios in E2 v E3/E3 contrasts were around .50 for these three neuropathologies and ORs in E2 v E4 contrasts were around .90, again for the three AD pathologies. In a mediation analysis we found that E2 had direct effects on tau Braak stage, as well as indirect effects via amyloid.
However, there were sharp limits to E2 neuroprotection. When the E2 isoform was in the presence of the e4 isoform, i.e., in the E2/E4 genotype, E2 was not protective (see also Oveisgharan et al., 2018). This genotype “behaved” like other E4 carrier cases in terms of promoting pathology. Second and unexpectedly, E2 demonstrated trends for increases in FTLD related pathologies (including TDP-43 and select tauopathies).
We’ve also conducted microarray transcriptional profiling studies in human postmortem neocortex to identify E2-associated pathways. We found that E2 was linked to increased expression of transcripts in an integrin/extracellular matrix KYOTO pathway (Conejero-Goldberg et al., 2014). The potential importance of this finding (and the HSPG binding related to the APOE mutation) is that matrix neurobiology might play a role in tau propagation as suggested by Lendvai et al., 2012.
Conejero-Goldberg C, Gomar JJ, Bobes-Bascaran T, Hyde TM, Kleinman JE, Herman MM, Chen S, Davies P, Goldberg TE. APOE2 enhances neuroprotection against Alzheimer's disease through multiple molecular mechanisms. Mol Psychiatry. 2014 Feb 4; PubMed.
Lendvai D, Morawski M, Négyessy L, Gáti G, Jäger C, Baksa G, Glasz T, Attems J, Tanila H, Arendt T, Harkany T, Alpár A. Neurochemical mapping of the human hippocampus reveals perisynaptic matrix around functional synapses in Alzheimer's disease. Acta Neuropathol. 2012 Sep 9; PubMed.
Oveisgharan S, Buchman AS, Yu L, Farfel J, Hachinski V, Gaiteri C, De Jager PL, Schneider JA, Bennett DA. APOE ε2ε4 genotype, incident AD and MCI, cognitive decline, and AD pathology in older adults. Neurology. 2018 Jun 12;90(24):e2127-e2134. Epub 2018 May 11 PubMed.View all comments by Terry Goldberg
University of Michigan
This is a very interesting finding, and parallels recent findings from the Kaczorowski lab (in mice). In our recent study, we took the approach to map modifiers that protect/delay onset of cognitive deficits in a genetically diverse population of transgenic mice carrying human familial AD mutations in APP and PSEN1 (Neuner et al., 2019). In this way, we identified genetic variants in the receptor binding domain of mouse Apoe associated with cognitive resilience (Figure 2). Specifically, strains of mice with ADAD mutations that were resilient to cognitive decline despite high amyloid burden had two copies of the C57BL/6J allele at the ApoE locus. Our results are consistent with the present report, that variants in ApoE modify the impact on ADAD mutations on cognition (even absent effects on amyloid).
Perhaps more importantly, since most AD mouse models are maintained on a pure C57BL/6J background, we speculate that preclinical studies that failed to translate to human clinical trials may be due to studies being run in mice that harbor protective variants at ApoE that modify the impact of ADAD mutations.
Neuner SM, Heuer SE, Huentelman MJ, O'Connell KM, Kaczorowski CC. Harnessing Genetic Complexity to Enhance Translatability of Alzheimer's Disease Mouse Models: A Path toward Precision Medicine. Neuron. 2019 Feb 6;101(3):399-411.e5. Epub 2018 Dec 27 PubMed.View all comments by Catherine Kaczorowski
USC Alzheimer’s Therapeutic Research Institute
This valuable paper from Eric Reiman and colleagues provides a strong rationale for targeting APOE in AD therapeutic research. APOE alleles are the most important risk factors and protective factors in sporadic AD; understanding the mechanisms of these effects should provide clues to therapeutic interventions. The impact of the rare APOE3 Christchurch mutation on the age of onset of cognitive impairment in an individual with autosomal dominant AD and a heavy plaque load points to the role of APOE in connecting amyloid to downstream neurodegeneration; if this mechanism can be translated into a therapeutic that delays symptom onset in AD for a decade or two, or three, we will have made enormous progress toward controlling the pandemic.View all comments by Paul Aisen
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