Petit D, Fernández SG, Zoltowska KM, Enzlein T, Ryan NS, O'Connor A, Szaruga M, Hill E, Vandenberghe R, Fox NC, Chávez-Gutiérrez L. Aβ profiles generated by Alzheimer's disease causing PSEN1 variants determine the pathogenicity of the mutation and predict age at disease onset. Mol Psychiatry. 2022 Jun;27(6):2821-2832. Epub 2022 Apr 1 PubMed.

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  1. I found the associations between the Aβ(37+38+40)/Aβ(42+43) ratio and the age at onset of symptoms in PSEN mutations carriers reported by the Chavez-Guttierez group, and between the Aβ37/42 ratio and pathogenicity and clinical diagnosis as reported by the Selkoe lab, very convincing.

    To me, these results provide further evidence that modulation of the γ-secretase protease, shifting Aβ generation toward shorter peptides, is a very interesting therapeutic approach for both familial and non-familial forms of AD. However, clinical trials evaluating such γ-secretase modulators should likely be performed during the early, asymptomatic stages of the disease to have a reasonable chance to substantially diminish the accumulation of toxic Aβ aggregates.

    View all comments by Oskar Hansson

  2. The paper by Petit and colleagues emphasizes an aspect of AD pathology that is increasingly gaining attention: the importance of Aβ species other than Aβ40 and Aβ42 in AD onset and progression.

    FAD-associated mutations in PSEN1 destabilize the interaction between the γ-secretase complex and APP/Aβn substrate, promoting the formation of longer aggregation-prone Aβ peptides (Arber et al., 2019; Szaruga et al., 2021). Yet the age of onset (AAO) in PSEN1 mutant carriers varies incredibly. Why? This article reveals that the (37 + 38 + 40) / (42 + 43) ratio not only predicts AAO but does so more accurately than the canonical Aβ42/40 ratio, underlying the importance of additional Aβ species.

    In line with this, the paper by Liu and colleagues suggests that the Aβ37/42 ratio in the CSF, rather than the Aβ42/40 ratio, is a better biomarker for AD pathology for familial and sporadic cases. Moreover, a mixture of all Aβ37, Aβ38, and Aβ40 has a greater inhibitory effect on Aβ42 aggregation compared to each single peptide in vitro (Braun et al., 2022). Importantly, these findings further distinguish longer, more aggregation-prone Aβ42 and Aβ43 peptides from shorter species in pathogenesis and clinical onset in AD.

    The fact that the profiles of Aβ species predict AAO suggests that we could use such a profile to understand if novel PSEN1 mutations are pathogenic or not. This would have a fundamental impact in the clinical setting. Of note, AD is a complex disease where environmental and other genetic factors can also influence AAO. As discussed by Petit et al., APOE2 can delay AAO by eight years.

    We eagerly anticipate follow-up studies that will determine the similarities/differences when it comes to employing these ratios to estimate AAO of APP mutations—e.g., mutations around γ-secretase versus β-secretase cleavage sites. We also look forward to seeing these ratios in action in clinical settings, where the healthy allele may lead to more complex profiles that the mutation in isolation.

    Overall, Petit et al. further confirm the crucial role diverse Aβ species play in AD pathology, and that Aβ profiles of several Aβ species (not only Aβ40 and Aβ42) best predict AAO. Moreover, AAO is strongly linked to longer, more aggregation-prone Aβ species, suggesting that shifting Aβ profiles toward shorter and less-amyloidogenic peptides could be a valid therapeutic approach.

    References:

    Arber C, Villegas-Llerena C, Toombs J, Pocock JM, Ryan NS, Fox NC, Zetterberg H, Hardy J, Wray S. Amyloid precursor protein processing in human neurons with an allelic series of the PSEN1 intron 4 deletion mutation and total presenilin-1 knockout. Brain Commun. 2019;1(1):fcz024. Epub 2019 Oct 14 PubMed.

    Braun GA, Dear AJ, Sanagavarapu K, Zetterberg H, Linse S. Amyloid-β peptide 37, 38 and 40 individually and cooperatively inhibit amyloid-β 42 aggregation. Chem Sci. 2022 Feb 23;13(8):2423-2439. Epub 2022 Feb 7 PubMed.

    Szaruga M, Munteanu B, Lismont S, Veugelen S, Horré K, Mercken M, Saido TC, Ryan NS, De Vos T, Savvides SN, Gallardo R, Schymkowitz J, Rousseau F, Fox NC, Hopf C, De Strooper B, Chávez-Gutiérrez L. Alzheimer's-causing mutations shift Aβ length by destabilizing γ-secretase-Aβn interactions. Cell. 2021 Apr 15;184(8):2257-2258. PubMed.

    View all comments by Selina Wray

  3. I read this extensive and comprehensive report by Lei Liu et al. with great interest. Indeed, this and our study present complementary data and insights, as well as tools for the quantitative assessment of familial and sporadic AD.

    In the context of familial AD: Liu et al. focused on the analysis of single Aβ ratios versus AAO, while we looked at other Aβ peptide combinations based on γ-secretase mechanisms. We asked what peptide combination is the best predictor of AAO. We also performed a data-driven approach testing Aβ-AAO relationships; this analysis provided complementary insights into differential roles and contributions of Aβ peptides to pathology.

    Liu et al. identified the Aβ37/42 ratio as the best benchmark for differentiating FAD variants from the WT PSEN1. In line with their findings, our studies support the notion that the relationship between short and longer Aβ peptides plays a critical role in AD pathogenesis. In addition, our analyses show that the Aβ(37+38+40)/(42+43) ratio has predictive value in the assessment of AAO.

    Liu et al. also investigated the Aβ37/42 ratio in the context of the most common, sporadic AD. Interestingly, their analyses of brain samples revealed that the Aβ37/42 relationship better differentiates AD from non-demented, low-amyloid-pathology cases, relative to the canonical Aβ42/40 ratio. Furthermore, the assessment of Aβ peptide levels in CSF samples from AD, mild cognitive impairment (MCI) and control cases revealed that the Aβ37/42 ratio outperforms the Aβ42/40 ratio in distinguishing control versus disease (AD or MCI) cases.

    That both familial and sporadic samples showed similar alterations in the Aβ37/42 ratio is an intriguing observation. In this regard, it is worth noting previous studies associating changes in Aβ37 production levels, relative to Aβ42, with amyloid plaque deposition and cognitive trajectory (Lagomarsino et al., 2021). Why do changes in short versus longer Aβ peptides occur in SAD? This definitely warrants further investigation.

    Taken together, these studies support the critical importance of comprehensive evaluation of Aβ peptide profiles in deciphering AD pathogenesis. 

    References:

    Lagomarsino VN, Pearse RV 2nd, Liu L, Hsieh YC, Fernandez MA, Vinton EA, Paull D, Felsky D, Tasaki S, Gaiteri C, Vardarajan B, Lee H, Muratore CR, Benoit CR, Chou V, Fancher SB, He A, Merchant JP, Duong DM, Martinez H, Zhou M, Bah F, Vicent MA, Stricker JM, Xu J, Dammer EB, Levey AI, Chibnik LB, Menon V, Seyfried NT, De Jager PL, Noggle S, Selkoe DJ, Bennett DA, Young-Pearse TL. Stem cell-derived neurons reflect features of protein networks, neuropathology, and cognitive outcome of their aged human donors. Neuron. 2021 Nov 3;109(21):3402-3420.e9. Epub 2021 Sep 1 PubMed.

    View all comments by Lucia Chavez-Gutierrez

  4. Outside of Aβ42 and Aβ40, few species of Aβ are typically studied. Liu and colleagues performed a variety of experiments to characterize less-commonly-described forms of Aβ: They examined Aβ profiles produced by cell lines expressing familial AD mutations, Aβ profiles in human brain tissue, and Aβ profiles in human CSF.

    In the last set of experiments, they reported that CSF Aβ37/Aβ42 outperformed CSF Aβ42/Aβ40 in distinguishing MCI and/or AD cases from cognitively normal controls (ROC AUC of 0.96 versus 0.87). However, the cohort they used was very small (38 cognitively normal, 25 MCI, and 16 AD dementia), and it was not clear that the AD diagnosis was confirmed with AD biomarkers (e.g. amyloid PET). In fact, a couple of MCI cases had relatively high CSF Aβ42/Aβ40, and since CSF Aβ42/Aβ40 is a highly sensitive biomarker of amyloidosis, it seems possible that the cohort included some non-AD causes of MCI, complicating the interpretation. 

    As the authors noted, low CSF Aβ42/Aβ40 identifies individuals with brain amyloidosis, including cognitively normal individuals with brain amyloidosis, and prediction of clinical diagnosis based on CSF Aβ42/Aβ40 is often not very robust. Also, CSF Aβ42/Aβ40 plateaus after individuals develop brain amyloidosis (the so-called L-shape), and may not distinguish well between clinical diagnoses/stages. If the results of this study are replicated and Aβ37/Aβ42 is better correlated with clinical diagnosis/stage, it may suggest that Aβ37/Aβ42 is changing later in the AD course, allowing for better prediction of clinical diagnosis/stage.

    Both Liu et al. and Petit et al. examined Aβ profiles associated with many different familial AD mutations. Interestingly, the Aβ profiles produced by cells expressing these familial AD mutations were associated with the typical age at symptom onset for the mutation. Liu et al. found strong associations of both Aβ42/Aβ40 and Aβ37/Aβ42 with the age at symptom onset; Petit et al. found a strong association of (Aβ37 + Aβ38 + Aβ40)/(Aβ42 + Aβ43) and a moderate association of Aβ42/Aβ40 with the age at symptom onset. 

    Overall, this suggests that ratios combining multiple short-to-long species of Aβ could potentially be better biomarkers of AD than Aβ42/Aβ40. However, it will be important to evaluate this hypothesis in sporadic AD.

    View all comments by Suzanne Schindler

  5. The results presented in the two papers by Liu et al. and Petit et al., respectively, are highly interesting. They suggest that shorter Aβ species could play an important role in predicting age at onset (AAO), but potentially could also be important from a therapeutic perspective as the results suggest that shifting Aβ profiles toward shorter and less-amyloidogenic peptides could be a valid approach. These data, as well as results from Cullen et al. earlier this year, show that higher CSF Aβ38 levels are associated with less cognitive decline and lower risk of developing AD, give further credit to the hypothesis that a lower ratio of shorter to longer Aβ peptides could play a role in amyloid toxicity and pathogenicity. In light of these findings, it was also interesting to read the recent paper by Braun et al., where they investigated the aggregation of various Aβ species and were able to demonstrate that Aβ37, 38, and 40 individually and cooperatively inhibit Aβ42 aggregation.

    γ-Secretase modulators, such as AlzeCure's compounds ACD679 and ACD680, represent a promising class of Aβ42-lowering anti-amyloidogenic compounds for the treatment of AD. GSMs exhibit several key features that make them suitable for the treatment in early AD, especially in view of the results discussed above: 1) They reduce amyloidogenic Aβ42 production while stimulating the formation of Aβ37 and 38, and 2) they modulate but do not affect total γ-secretase activity, a property that is of central importance from a safety perspective. As such, GSMs modulate the formation of secreted Aβ, while sparing the γ-secretase-mediated processing event resulting in the release of the cytoplasmic APP intracellular domain making GSMs an interesting Aβ-targeting therapy in early AD. A new wave of AD therapeutics will likely include GSMs and it will be highly interesting to see the outcome of these clinical studies.

    References:

    Cullen N, Janelidze S, Palmqvist S, Stomrud E, Mattsson-Carlgren N, Hansson O, Alzheimer’s Disease Neuroimaging Initiative. Association of CSF Aβ38 Levels With Risk of Alzheimer Disease-Related Decline. Neurology. 2022 Mar 1;98(9):e958-e967. Epub 2021 Dec 22 PubMed.

    Braun GA, Dear AJ, Sanagavarapu K, Zetterberg H, Linse S. Amyloid-β peptide 37, 38 and 40 individually and cooperatively inhibit amyloid-β 42 aggregation. Chem Sci. 2022 Feb 23;13(8):2423-2439. Epub 2022 Feb 7 PubMed.

    View all comments by Johan Sandin

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