CSF levels of Aβ1-42, tau and p-tau can discriminate Alzheimer disease patients from controls or from patients with other types of dementia, and can identify incipient AD among patients with mild cognitive impairment (Hansson et al., 2006; Blennow et al., 2003). However, large differences are reported in absolute biomarker levels between centers (Sunderland et al., 2003), making it difficult to set up multi-center studies including multicenter treatment trials. To overcome this problem, external quality control assessment schemes (EQAS) are needed (Libeer et al., 2001). Our study describes the first worldwide EQAS for CSF biomarkers (20 different centres measured the same CSF samples), reporting relatively high inter-center variations, especially for Aβ1-42 (>22 percent). Lower inter-center variability (  Read more

CSF levels of Aβ1-42, tau and p-tau can discriminate Alzheimer disease patients from controls or from patients with other types of dementia, and can identify incipient AD among patients with mild cognitive impairment (Hansson et al., 2006; Blennow et al., 2003). However, large differences are reported in absolute biomarker levels between centers (Sunderland et al., 2003), making it difficult to set up multi-center studies including multicenter treatment trials. To overcome this problem, external quality control assessment schemes (EQAS) are needed (Libeer et al., 2001). Our study describes the first worldwide EQAS for CSF biomarkers (20 different centres measured the same CSF samples), reporting relatively high inter-center variations, especially for Aβ1-42 (>22 percent). Lower inter-center variability (<10 percent) is required to reliably distinguish a difference in group, to make multicenter biomarker comparisons possible, and eventually to obtain an inter-center reference range for AD.

View all comments by Niek Verwey

This paper nicely describes the use of an elegant method for assessing brain-relevant biomarkers of protein metabolism in humans.

View all comments by Lary Walker

This paper presents interesting new data on a possible mechanism responsible for amyloidβ abnormality in patients with Alzheimer disease.

View all comments by Richard C. Mohs

This study adds further to our ability to exploit chemical and imaging biomarkers for the diagnosis of early AD, while emphasizing the need to identify other biomarkers that may predict who will progress to develop Abeta and tau pathologies prio to the onset of these AD pathologies.

View all comments by John Trojanowski

This new study showing association of SORL1 with late-onset Alzheimer disease (LOAD) provides further support for a role of this gene in AD, confirming earlier studies by Lah, Small, Gandy, Masters, and others implicating SORL1 in AD pathogenesis.

The novelty of this study is the inclusion of genetic association of several SNPs in SORL1 with various samples of different ethnicities. The results for specific SNPs across samples are interesting but inconsistent, with various SNPs showing positive results in some samples and negative data in others. This is often the case for many novel AD candidate genes when tested in multiple samples, either in a single study or across multiple studies.

The Alzgene.org database on Alzforum reveals no less than two dozen genes that exhibit statistically significant association with LOAD after meta-analyses of multiple samples. These can be found in the "Top Alzgene Results" box in the right margin of Alzgene. A full description of Alzgene and its findings can be found...  Read more

This new study showing association of SORL1 with late-onset Alzheimer disease (LOAD) provides further support for a role of this gene in AD, confirming earlier studies by Lah, Small, Gandy, Masters, and others implicating SORL1 in AD pathogenesis.

The novelty of this study is the inclusion of genetic association of several SNPs in SORL1 with various samples of different ethnicities. The results for specific SNPs across samples are interesting but inconsistent, with various SNPs showing positive results in some samples and negative data in others. This is often the case for many novel AD candidate genes when tested in multiple samples, either in a single study or across multiple studies.

The Alzgene.org database on Alzforum reveals no less than two dozen genes that exhibit statistically significant association with LOAD after meta-analyses of multiple samples. These can be found in the "Top Alzgene Results" box in the right margin of Alzgene. A full description of Alzgene and its findings can be found in Bertram et al., 2007 in this month's issue.

By statistical analyses on Alzgene prior to this paper, SORL1 would be roughly the twenty-fifth gene to show statistically significant association with LOAD after testing in multiple independent samples. To the authors' credit, a sufficient number of independent samples were tested in this new SORL1 paper to already lend itself to meta-analysis on Alzgene. According to Lars Bertram, these findings are now being added to the site and are summarized here. The bottom line is that several of the meta-analyses for the SORL1 SNPs tested are significant. However, the effect on risk is very modest—the strongest allelic odds ratio for SORL1 is only 1.21. This means that the strongest effect of any SNP in SORL1 in the new study would increase risk for AD by 21 percent. In contrast, one copy of ApoE4 increases risk by about 300 percent.

The top hits on the Alzgene site are ranked by strength of their effect on risk for AD. As expected, ApoE4 is number one. Based on the data in the new study by St George-Hyslop and colleagues, SORL1 would not make the top 10 list, but rank in at number 12 out of 25. So while SORL1 can be added to the list, its small effects on risk based on the multiple case-control samples tested, as well as the less impressive results across the family-based samples tested, would suggest that SORL1 will turn out to be a minor genetic risk factor for AD.

Additional replication testing will be needed to see if the effects on risk hold up over time. As with all AD gene candidates proposed beyond the established four AD genes (APP, PSEN1, PSEN2, ApoE), the true validity of SORL1 as a novel AD gene will need to await the identification of validated pathogenic mutations or variants.

View all comments by Rudy Tanzi

This work is welcome news from an excellent group of investigators. They will surely allow me to play devil’s advocate and caution two things. First, however enticing the cell biology might be, at this point it is a distraction. The question at hand is a genetic question, and to answer the genetics per se, the cell biology data is irrelevant. Unfortunately, journal editors often demand cell biology in genetics papers, even if it’s just an initial set of experiments.

Second, while many sample series were used, there is not an exact replication of the haplotypic association between the sample series, making these "replications," in my view, suspect. In this, the work resembles our own work (Li et al., 2006 and Grupe et al., 2006 on other risk genes). In these cases, too, we obtained multiple, but not entirely convincing replications.

Late-onset Alzheimer genetics is proving to be a very difficult problem. I personally doubt whether this is the new ApoE, but genuine attempts at...  Read more

This work is welcome news from an excellent group of investigators. They will surely allow me to play devil’s advocate and caution two things. First, however enticing the cell biology might be, at this point it is a distraction. The question at hand is a genetic question, and to answer the genetics per se, the cell biology data is irrelevant. Unfortunately, journal editors often demand cell biology in genetics papers, even if it’s just an initial set of experiments.

Second, while many sample series were used, there is not an exact replication of the haplotypic association between the sample series, making these "replications," in my view, suspect. In this, the work resembles our own work (Li et al., 2006 and Grupe et al., 2006 on other risk genes). In these cases, too, we obtained multiple, but not entirely convincing replications.

Late-onset Alzheimer genetics is proving to be a very difficult problem. I personally doubt whether this is the new ApoE, but genuine attempts at replication will sort that out reasonably quickly.

View all comments by John Hardy

Update: With regard to my earlier comment on the SORL1-AD genetic association study by Rogaeva et al, I initially commented that on the Alzgene list of "Top Alzgene Results", SORL1 ranked 12th out of 25 genes. (Ranking is based on effects of SNPs in the gene on risk for AD, with APOE at number 1).

Lars Bertram has now revised that ranking on the most updated "Top Alzgene Results" list:

SORL1 ranks 18th out of 27 genes listed on "Top Alzgene Results" that have statistically significant effects on AD risk following meta-analyses.

View all comments by Rudy Tanzi

The paper is well written and the study seems to be carried out very well, at least in regard to the data analysis. (Though an experimental scientist that I am, I was a bit surprised to see only half of the name of one of the used kits—the INNO-BIA kit—without further information on the experimental procedures.) In addition, the study is one of the biggest of its kind, and similar to the Rotterdam Study, although with different methodology.

Previously, different studies have reported increased Aβ1-40 and decreased Aβ1-42, and also decreased Aβ1-42/Aβ1-40 ratios in CSF, but there are conflicting data on the level of these Aβ species and the ratio of these species in blood.

Another striking thing is the decreased level of Aβ1-42 with progression of dementia (that has not been commented on in the paper), which is usually speculated to be due to absorption to the senile plaques in the brain. But some recent studies have demonstrated that this might depend on the methodology used. In an ELISA-based assay, the Aβ1-42 level is...  Read more

The paper is well written and the study seems to be carried out very well, at least in regard to the data analysis. (Though an experimental scientist that I am, I was a bit surprised to see only half of the name of one of the used kits—the INNO-BIA kit—without further information on the experimental procedures.) In addition, the study is one of the biggest of its kind, and similar to the Rotterdam Study, although with different methodology.

Previously, different studies have reported increased Aβ1-40 and decreased Aβ1-42, and also decreased Aβ1-42/Aβ1-40 ratios in CSF, but there are conflicting data on the level of these Aβ species and the ratio of these species in blood.

Another striking thing is the decreased level of Aβ1-42 with progression of dementia (that has not been commented on in the paper), which is usually speculated to be due to absorption to the senile plaques in the brain. But some recent studies have demonstrated that this might depend on the methodology used. In an ELISA-based assay, the Aβ1-42 level is decreased, while in a denaturing Western blot experiment, the level of Aβ1-42 is increased in the same model material.

The main part of the results in this paper conforms with the data from the Rotterdam Study, with some differences in the details, for instance, finding that the Aβ1-42/Aβ1-40 ratio in this study "may be associated with the risk of dementia only in individuals diagnosed at two years of follow-up," while in the case of the Rotterdam Study this time period is eight years. The current study has also included the measurement of other Aβ pieces (Aβn-40 and Aβn-42), which might shed light on some details.

Overall, my belief is that this paper, by confirming other well-done studies such as the Rotterdam Study, takes us one step closer to be convinced that blood Aβ might reflect brain and CSF Aβ. This, in turn, might take us to another level to try harder to detect and identify other toxic isomers of Aβ, such as Aβ oligomers in blood, which is a more non-invasive approach compared to the CSF. Of course, this might require that more powerful tools be developed and applied in the field. Having said that, I do not believe that the outcome of this paper will change the current situation and won't clarify much whether blood Aβ is a promising AD biomarker.

View all comments by Masood Kamali-Moghaddam

First, we would like to thank Dr Kamali-Moghaddam for his comments. Regarding the methodology, we apologize about the name of the kit used which is not fully written (INNO-BIA plasma Aβ forms). The strength of such a study is the use of a commercially available kit. Thus, experimental procedures are the manufacturer’s instructions. We did not think that it was necessary to add them in the materials and methods. However, for Alzforum readers, here is the experimental procedure. All plasma samples were diluted 1/3 with a buffer containing detergent before analysis.

Quantification of Aβ isoforms in plasma was performed using INNO-BIA plasma Aβ forms assays (Innogenetics, Ghent, Belgium), a multiplex microsphere-based Luminex xMAP technique that allows simultaneous analysis of Aβ1-40 and Aβ1-42 (module A) an Aβn-40 and Aβn-42 (module B).

The monoclonal antibodies (MAbs) 21F12 and 2G3, which specifically bind Aβ peptides ending at 42 and 40, respectively, were used as capture antibodies. The capture MAbs were covalently coupled to...  Read more

First, we would like to thank Dr Kamali-Moghaddam for his comments. Regarding the methodology, we apologize about the name of the kit used which is not fully written (INNO-BIA plasma Aβ forms). The strength of such a study is the use of a commercially available kit. Thus, experimental procedures are the manufacturer’s instructions. We did not think that it was necessary to add them in the materials and methods. However, for Alzforum readers, here is the experimental procedure. All plasma samples were diluted 1/3 with a buffer containing detergent before analysis.

Quantification of Aβ isoforms in plasma was performed using INNO-BIA plasma Aβ forms assays (Innogenetics, Ghent, Belgium), a multiplex microsphere-based Luminex xMAP technique that allows simultaneous analysis of Aβ1-40 and Aβ1-42 (module A) an Aβn-40 and Aβn-42 (module B).

The monoclonal antibodies (MAbs) 21F12 and 2G3, which specifically bind Aβ peptides ending at 42 and 40, respectively, were used as capture antibodies. The capture MAbs were covalently coupled to carboxylated beads of different regions (region 104 for Aβ42;, region 105 for Aβ40;, and region 102 for a non-Aβ binding MAb). MAb 3D6, which specifically binds Aβ peptides starting at Asp1, and MAb 4G8 which react with all N-terminally truncated Aβ peptides up to Val18, were used as detector antibodies.

In short, Aβ isoforms ending either at Aβ40 or Aβ42 were selectively captured by beads that have been coated with either MAb 21F12 for Aβ42 or MAb 2G3 for Aβ40. A third class of beads was coated with MAb AT120, used to measure matrix effects due to heterophilic antibodies in the plasma sample. In module A, biotinylated MAb 3D6, which selectively binds Aβ peptides starting at Aβ1, is used as detector antibody, providing specific quantification of Aβ1-42 and Aβ1-40 isoforms. In module B, biotinylated MAb 4G8, which binds all N-terminally truncated Aβ peptides up to those starting at Aβ18, is used as detector antibody, providing specific quantification of Aβn-42 and Aβn-40 isoforms.

The procedure could be described as follows: after sonication and vortexing, a mixture (100 μL/well) of the beads (either Module A or B) were added to 96 well filter plates (Millipore Corporation, Bedford, Massachusetts). After draining the wells using a vacuum manifold (Millipore Corporation, Bedford, Massachusetts), standards, blanks, or diluted (1:3) plasma samples were added (75 μL/well) in duplicate together with the biotinylated detector MAb (25 μL/well) (MAb 3D6 for Module A and MAb 2G3 for Module B) and incubated overnight at 2-8ºC in the dark (plates covered with aluminum foil) on a plate shaker (600 rpm). After washing, phycoerythrine-labeled streptavidine was added (100 μL/well) and incubated for one hour on a plate shaker. After a second wash step, 100 μL of phosphate-buffered saline was added. The assays were analyzed on a Luminex 200 IS instrument (Luminex, Austin, Texas). For each set of microspheres, 100 beads were analyzed, and the median fluorescence intensity (MFI) was used for quantification.

A ready-to-use calibrator series is included in duplicate in each assay run and, using the calibration curve constructed with the median fluorescence values for each of the standards, concentrations were determined by sigmoidal curve fitting. Moreover, in each series two run-validation control samples are also included.

I hope that this is helpful.

View all comments by Luc Buee
View all comments by Susanna Schraen

First of all, kudos to Lilly and DSMB—they did the right thing to make this public as soon they knew. As a disclosure, I have been an advisor to and received grants from many companies, including Lilly.

The IDENTITY findings are not entirely unexpected, since I thought the Phase 1 studies didn't have a clear signal, and adverse effects on skin cells and the immune system were always a consideration with this class of drugs. The interim analyses suggest the trials likely would have been not only clearly negative, but also have potentially harmed patients, both in terms of progression and side effects. Since risks exceeded benefits, stopping the trial is the right thing to do. I hope Lilly plans to offer free follow-up to all subjects to fully understand the side effects and ensure proper aftercare and safety.

The billion-dollar questions on everyone's mind are whether this is a body blow to the amyloid theory and what this means for all the planned prevention trials using similar drugs. I think the amyloid theory is still valid, but this clearly tells us that our...  Read more

First of all, kudos to Lilly and DSMB—they did the right thing to make this public as soon they knew. As a disclosure, I have been an advisor to and received grants from many companies, including Lilly.

The IDENTITY findings are not entirely unexpected, since I thought the Phase 1 studies didn't have a clear signal, and adverse effects on skin cells and the immune system were always a consideration with this class of drugs. The interim analyses suggest the trials likely would have been not only clearly negative, but also have potentially harmed patients, both in terms of progression and side effects. Since risks exceeded benefits, stopping the trial is the right thing to do. I hope Lilly plans to offer free follow-up to all subjects to fully understand the side effects and ensure proper aftercare and safety.

The billion-dollar questions on everyone's mind are whether this is a body blow to the amyloid theory and what this means for all the planned prevention trials using similar drugs. I think the amyloid theory is still valid, but this clearly tells us that our current views may be too simple—clearing amyloid at a late stage without affecting tau might not suffice as a cognitive enhancing treatment. Other trials have told us this before, but this one really drives it home, since the results seem pretty unambiguous. One thing that worries me about these findings is that we don't know if this was a toxicity unique to Lilly's drug given to a late stage population or whether it also applies to similar anti-amyloid therapies give at earlier stages of the disease. There are several other anti-amyloid trials that are set to report in the next few months. These data are going to help us better understand how useful biomarkers are as surrogate endpoints in treatment trials. But in terms of biomarkers for accurate diagnosis, I don't think these data will have as much of an impact. Since we define AD (and preclinical AD) on the basis of pathology, we will continue to need amyloid and tau biomarkers for enhancing diagnostic accuracy, staging disease, and predicting future risk.

Negative studies can be very informative as long as people put aside their preconceived notions and actually listen to what the data are telling them. The IDENTITY dataset has the potential to really help the field as it moves to design studies targeting people with MCI or preclinical AD. So it will be a win-win if Lilly makes this entire trial dataset public (not just placebo data, but all data in the drug-treated arms) so others don't repeat the same mistakes over and over. I would also like to see the field pull together a conference (with experts from other areas such as decision science) to examine all the data from the dozen or so anti-amyloid trials done to date to ensure we are all seeing the correct big picture and to optimize the well-being of participants in future trials.

I look forward to seeing these data more fully, and my comments are to be interpreted in that context.

View all comments by P. Murali Doraiswamy

Obviously, this is a serious disappointment. The negative effects on cognition and on the ability to complete activities of daily living are very bad news, and should raise questions about the usefulness of targeting γ-secretase for AD. However, this compound is not Notch sparing. The question is, To what extent Notch inhibition can explain the phenotype (Notch has been implicated in memory formation in mice and Drosophila). This needs close investigation, especially since the increase in skin cancer in the treated patients also suggests Notch signaling inhibition. The main conclusion is that there is apparently no such thing as a therapeutic window for classical γ-secretase inhibitors. The implication is that we should explore now, even more, Notch- (and other substrate-) sparing modulation of γ-secretase activity (e.g., blocking selectively Aph1B-γ-secretase). The other message, given the possibility that once Aβ has triggered tau pathology the disease becomes Aβ independent, is that we probably need to treat patients early, before Aβ...  Read more

Obviously, this is a serious disappointment. The negative effects on cognition and on the ability to complete activities of daily living are very bad news, and should raise questions about the usefulness of targeting γ-secretase for AD. However, this compound is not Notch sparing. The question is, To what extent Notch inhibition can explain the phenotype (Notch has been implicated in memory formation in mice and Drosophila). This needs close investigation, especially since the increase in skin cancer in the treated patients also suggests Notch signaling inhibition. The main conclusion is that there is apparently no such thing as a therapeutic window for classical γ-secretase inhibitors. The implication is that we should explore now, even more, Notch- (and other substrate-) sparing modulation of γ-secretase activity (e.g., blocking selectively Aph1B-γ-secretase). The other message, given the possibility that once Aβ has triggered tau pathology the disease becomes Aβ independent, is that we probably need to treat patients early, before Aβ gets the chance to do its destructive work in the brain. Probably a more healthy brain will be more able to cope with the possible side effects of anti-amyloid drug as well.

View all comments by Bart De Strooper

There is now a fair bit of evidence that γ-secretase inhibitors do cleave a number of additional growth factors and cause related side effects, not just on Notch signaling. I agree with the colleagues who point out that the negative effects of this “non-Notch sparing” γ-secretase inhibitor is not unexpected at all.

One issue is that we most likely do not even know all the substrates for γ-secretase, so that the development of “safe” inhibitors is questionable. It also would assume the existence of a wide range of different γ-secretases that are specific for only some of the substrates (e.g., only for APP) and have separate pharmacological profiles and can be inhibited individually. This does not seem very likely.

View all comments by Christian Hoelscher

Semagacestat continues the streak of late-phase trial failures. All failed for lack of efficacy, but as enzyme inhibitors and antibodies are advanced, serious toxicity in the trials may become more frequent as well. Sequential failures discovered late in the drug development process are demoralizing, enervating, and may cause broad swaths of the community to lose interest. We should not have to enroll 2,000 to 4,000 patients in Phase 3 programs in order to discover that a drug is ineffective, the dose range is wrong, or that it is too toxic. In traditional drug development, large Phase 2b and 3 trials are considered confirmatory trials of efficacy and safety that were previously established in earlier proof-of-concept and dose-finding phases. Proof-of-concept studies sometimes are designed to demonstrate target engagement when there are validated drug targets for the illnesses. We don’t have validated targets in AD; rather we have lots of potential targets.

Current Phase 2a AD trials are either designed as mini-Phase 3 trials, with too few patients to meaningfully assess...  Read more

Semagacestat continues the streak of late-phase trial failures. All failed for lack of efficacy, but as enzyme inhibitors and antibodies are advanced, serious toxicity in the trials may become more frequent as well. Sequential failures discovered late in the drug development process are demoralizing, enervating, and may cause broad swaths of the community to lose interest. We should not have to enroll 2,000 to 4,000 patients in Phase 3 programs in order to discover that a drug is ineffective, the dose range is wrong, or that it is too toxic. In traditional drug development, large Phase 2b and 3 trials are considered confirmatory trials of efficacy and safety that were previously established in earlier proof-of-concept and dose-finding phases. Proof-of-concept studies sometimes are designed to demonstrate target engagement when there are validated drug targets for the illnesses. We don’t have validated targets in AD; rather we have lots of potential targets.

Current Phase 2a AD trials are either designed as mini-Phase 3 trials, with too few patients to meaningfully assess efficacy, or as even smaller “pharmacodynamic” studies intended to show a particular, expected CNS effect. Semagacestat development used the latter pharmacodynamic model to justify its push to Phase 3, demonstrating effects on plasma Aβ, but not quite clearly on CSF Aβ, in a placebo-controlled, 14-week trial with 51 patients. (Its effect on Aβ might be considered evidence of target engagement if γ-secretase is a valid target for AD.)

By comparison, and as examples, tarenflurbil (Myriad and Lundbeck), bapineuzumab (Elan, Johnson & Johnson, and Pfizer), and scyllo-inositol (Elan and Transition) development programs used more of a “mini-Phase 3” approach, recruiting about 210 to 350 patients and treating from 1.0 to 1.5 years. None of these studies showed overall efficacy, but they were interpreted as showing potential efficacy in “subgroups,” and showing sufficient safety and enough dosing information that large Phase 3 programs involving 2,600 to 4,000 patients were undertaken or planned. So far, tarenflurbil failed Phase 3; the bapineuzumab program is ongoing but was modified; and a scyllo-insotitol trial is being planned. There are other examples as well.

Current development programs for AD drugs are not very efficient or effective. AD drug development is too consumptive of human capital to continue this way. There are too many plausible, candidate drugs for us to carry out Phase 3 after Phase 3 trial based on wisps of clinical evidence. How we do early human phase development, decide whether or not to advance drugs to later phases in MCI, AD or prevention, and how we do the later phase trials need to be re-conceptualized, but this is a hugely formidable endeavor.

Lilly and the ADCS, who conducted the early semagacestat study, understood the dilemma and the risks, as they presciently wrote in 2008:

“Given the slow rate of clinical progression in AD, we did not expect to see drug effects on measures of cognition or ADLs in this 14-week trial. Without this, a full risk-benefit assessment cannot be made. This trial sufficiently demonstrates that LY450139 can be tolerated, although not without risk. Given the potential for disease-modifying effects of this Aβ-lowering agent, and the arguably acceptable tolerance and safety profile of LY450139 demonstrated in this study, further large-scale efficacy trials are justified. Based, in part, on the results of this Phase 2 study, Eli Lilly & Co. launched a multinational Phase 3 trial in the second quarter of 2008, with an enrollment goal of 1,500 patients with AD.”

References:
Fleisher, A. S., R. Raman, et al. (2008). Phase 2 Safety Trial Targeting Amyloid {beta} Production With a gamma-Secretase Inhibitor in Alzheimer Disease. Arch Neurol 65(8):1031-1038. Abstract

View all comments by Lon Schneider

The observed accelerated cognitive deterioration following γ-secretase inhibition could be due to toxic effects on synapses. By performing in vivo two-photon imaging, we have recently shown that dendritic spines (i.e., the post-synaptic side of excitatory synapses) get irreversibly lost in the cerebral cortex of wild-type mice after applying the Lilly drug (Bittner et al., 2009). By repeating the experiments in APP-deficient mice, we revealed evidence that APP-cleavage products (probably an accumulation of C-terminal fragments, as also suggested by Tom Fagan above) are critically involved.

References:
Bittner T., Fuhrmann M., Burgold S., Jung C.K.E., Volbracht C., Steiner H., Mitteregger G., Kretzschmar H., Haass C. and Herms J. (2009) gamma-Secretase inhibition reduces spine density in vivo via an APP-dependent pathway. J Neurosci. 29:10405-10409. Abstract

View all comments by Jochen Herms

Negative outcomes in trials are always bad news, since patients don’t get access to new therapeutic interventions and we, as researchers, are forced to rethink our basic assumptions. Nevertheless, trials are an immensely rich resource that can lead to new knowledge about this disease. Congratulations to Lilly for committing to make these data public.

It will be of great interest to observe whether the patients can partially reverse their cognitive deficit after halting the medication in this trial. This could be a first indication whether the unintended effects of γ-secretase inhibition are real, irreversible toxicity issues (such as affecting other substrates, as suggested by other researchers), or merely a lowering of amyloid-β levels, which drives normal cognitive processes out of their optimal dose window, or a combination of the two. In this regard, it is interesting to consider the inverse U-shape response of glutamatergic functioning to amyloid-β (Abramov, 2009), which might modulate the balance between excitatory and inhibitory activity of brain...  Read more

Negative outcomes in trials are always bad news, since patients don’t get access to new therapeutic interventions and we, as researchers, are forced to rethink our basic assumptions. Nevertheless, trials are an immensely rich resource that can lead to new knowledge about this disease. Congratulations to Lilly for committing to make these data public.

It will be of great interest to observe whether the patients can partially reverse their cognitive deficit after halting the medication in this trial. This could be a first indication whether the unintended effects of γ-secretase inhibition are real, irreversible toxicity issues (such as affecting other substrates, as suggested by other researchers), or merely a lowering of amyloid-β levels, which drives normal cognitive processes out of their optimal dose window, or a combination of the two. In this regard, it is interesting to consider the inverse U-shape response of glutamatergic functioning to amyloid-β (Abramov, 2009), which might modulate the balance between excitatory and inhibitory activity of brain networks involved in cognitive aspects, such as working memory and executive control. The glutamatergic physiology is extremely tightly regulated, and too much reduction of amyloid-β could drive the system beyond its optimal point and change the emergent properties of the network sufficiently to be detected clinically.

This theory would predict that, after halting the medication, the cognitive deficit could be partially reversed and the degree of cognitive change would be correlated in a complex way to the change in amyloid-β level for each individual patient. This can readily be investigated in the database, although confounding parameters such as the baseline cognitive performance, different co-medications, and unknown genotypes need to be taken into account. Using well-calibrated, computer-based models of biophysically realistic, complex brain networks could be a way to address these issues, so that the valuable information from this trial can increase our knowledge on this devastating disease.

References:
Abramov E, Dolev I, Fogel H, Ciccotosto GD, Ruff E, Slutsky I. Amyloid-beta as a positive endogenous regulator of release probability at hippocampal synapses. Nat Neurosci. 2009 Dec;12(12):1567-76. Abstract

View all comments by Hugo Geerts