Perneczky R, Tsolakidou A, Arnold A, Diehl-Schmid J, Grimmer T, Förstl H, Kurz A, Alexopoulos P. CSF soluble amyloid precursor proteins in the diagnosis of incipient Alzheimer disease. Neurology. 2011 Jul 5;77(1):35-8. Epub 2011 Jun 22 PubMed.
AlzBiomarker Database
Meta-Analysis
- MCI-AD vs MCI-Stable : Aβ42 (CSF)
- MCI-AD vs MCI-Stable : sAPPα (CSF)
- MCI-AD vs MCI-Stable : sAPPβ (CSF)
- MCI-AD vs MCI-Stable : tau-total (CSF)
Curated Study Data
| Biomarker (Source) |
Cohort (N) |
Measurement Mean ± SD |
Method; Assay Name; Manufacturer |
Diagnostic Criteria |
|---|---|---|---|---|
| Aβ42 (CSF) |
MCI-AD (21) |
622.95 ± 275.61 ng/L |
ELISA; Innotest; Innogenetics |
Winblad et al., 2004; McKhann et al., 1984 |
| Aβ42 (CSF) |
MCI-Stable (35) |
789.91 ± 383.12 ng/L |
ELISA; Innotest; Innogenetics |
Winblad et al., 2004 |
| sAPPα (CSF) |
MCI-AD (21) |
373.73 ± 141.27 ng/L |
ELISA; Other/Not Specified; Immuno-Biological Laboratories |
Winblad et al., 2004; McKhann et al., 1984 |
| sAPPα (CSF) |
MCI-Stable (35) |
298.26 ± 155.73 ng/L |
ELISA; Other/Not Specified; Immuno-Biological Laboratories |
Winblad et al., 2004 |
| sAPPβ (CSF) |
MCI-AD (21) |
1200.29 ± 452.4 ng/L |
ELISA; Other/Not Specified; Immuno-Biological Laboratories |
Winblad et al., 2004; McKhann et al., 1984 |
| sAPPβ (CSF) |
MCI-Stable (35) |
931.88 ± 399.46 ng/L |
ELISA; Other/Not Specified; Immuno-Biological Laboratories |
Winblad et al., 2004 |
| tau-total (CSF) |
MCI-AD (21) |
542.1 ± 276.66 ng/L |
ELISA; Innotest; Innogenetics |
Winblad et al., 2004; McKhann et al., 1984 |
| tau-total (CSF) |
MCI-Stable (35) |
340.2 ± 203.77 ng/L |
ELISA; Innotest; Innogenetics |
Winblad et al., 2004 |
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Comments
Universität Duisburg-Essen
Perneczky and colleagues report that CSF measurement of sAPPβ may be useful and superior to Aβ1-42 in the early and differential diagnosis of incipient (preclinical) Alzheimer's dementia. These data validate our earlier observations (Lewczuk et al., 2010), which also revealed a significant elevation of sAPPβ in incipient AD that was as pronounced as in early Alzheimer's dementia (AD). In both studies, other dementias did not show elevated CSF sAPPβ. Whereas in our study, the clinical diagnosis and stratification of mild cognitive impairment (MCI) patients was cross-validated by other CSF dementia biomarkers (total tau; phospho-tau181; Aβ1-42), Perneczky and colleagues used the clinical course of the patients (conversion to AD/MCI-AD; stable MCI; or conversion to cognitive normal/non-AD, i.e., MCI-NAD) to stratify the different MCI subgroups at baseline. Moreover, both groups applied different quantitative immunoassays to measure sAPPα and sAPPβ, whereas the same assays were used to measure CSF total tau and Aβ1-42.
The observations of Perneczky and colleagues are of high clinical relevance; however, some critical issues have to be addressed.
Though the MCI-AD and MCI-NAD groups show a significant age difference, age was included in the statistical discriminator model (sAPPβ, total tau, age). The authors do not report if overall sAPPβ and age are significantly correlated. Surprisingly, Aβ1-42 was not significantly lowered in MCI-AD as compared to MCI-NAD or patients with frontotemporal dementia. The available literature clearly indicates that CSF Aβ1-42 is already decreased in incipient AD (high-risk MCI). Since no further control group is provided, these data are hard to interpret but may question the conclusion that sAPPβ is superior to Aβ1-42 in the early and differential diagnosis of incipient AD. In this respect, and in general, an independent statistical analysis of the MCI-AD subgroup of patients who converted back to cognitive normal (n = 8) may have helped to clarify this issue. Since the mean clinical follow-up time was comparatively short (33.1 months), slow converters (MCI to AD) may be hidden within the MCI-NAD cohort. Perneczky et al. did not report data on CSF values of phosphorylated tau (e.g., phospho-tau181). Together with total tau, these data could have been helpful to define a subgroup of slow MCI to AD converters.
A puzzling difference between the data reported by the two groups is that we also found significantly elevated CSF sAPPα in MCI-AD as compared to MCI-NAD. This may be explained by the two different phenotyping strategies applied to stratify the patient subgroups at baseline. However, this may also be due to the different assays which were applied in the two independent studies. Both groups reported a strong correlation of sAPPβ and sAPPα; however, we measured much higher values of sAPPα relative to sAPPβ (Meso Scale Discovery, Gaithersburg, USA; multiplex assay) as compared to Perneczky and colleagues (IBL Gunma, Japan; monoplex ELISA). This assay-dependent difference is unlikely to be due to cross-reactivity within the multiplex assay, since we controlled for cross-reactivity by independent Western blot analysis.
In summary, the data of Perneczky and coworkers are very promising, but they need further validation regarding the claim of a diagnostic superiority of sAPPβ relative to Aβ1-42 and the performance of sAPPβ relative to sAPPα. Moreover, to approximate the true predictive value of sAPPβ for incipient AD, longer clinical follow-up times should be applied for age-matched MCI subgroups. Together with CSF data on elevated BACE protein content and enzyme activity in preclinical AD (Zhong et al., 2007; Zetterberg et al., 2008), it is tempting to speculate that β-secretase activity is also increased in early (preclinical) multigenetic AD, as known for genetic AD (Bateman et al., 2011). This finding would reinforce β-secretase as a potential therapeutic target for the preventive drug treatment of AD in high-risk MCI patients. However, total CSF Aβ—unlike sAPPβ—is not consistently reported to be elevated in preclinical AD as a consequence of elevated β-secretase activity. In the event that increased Aβ peptide generation is initially paralleled by increased oligomerization, resulting in epitope masking (soluble oligomers) and subsequent precipitation into insoluble Aβ, this may not be a contradiction.
References:
Lewczuk P, Kamrowski-Kruck H, Peters O, Heuser I, Jessen F, Popp J, Bürger K, Hampel H, Frölich L, Wolf S, Prinz B, Jahn H, Luckhaus Ch, Perneczky R, Hüll M, Schröder J, Kessler H, Pantel J, Gertz HJ, Klafki HW, Kölsch H, Reulbach U, Esselmann H, Maler JM, Bibl M, Kornhuber J, Wiltfang J. Soluble amyloid precursor proteins in the cerebrospinal fluid as novel potential biomarkers of Alzheimer's disease: a multicenter study. Mol Psychiatry. 2010 Feb;15(2):138-45. PubMed.
Zhong Z, Ewers M, Teipel S, Bürger K, Wallin A, Blennow K, He P, McAllister C, Hampel H, Shen Y. Levels of beta-secretase (BACE1) in cerebrospinal fluid as a predictor of risk in mild cognitive impairment. Arch Gen Psychiatry. 2007 Jun;64(6):718-26. PubMed.
Zetterberg H, Andreasson U, Hansson O, Wu G, Sankaranarayanan S, Andersson ME, Buchhave P, Londos E, Umek RM, Minthon L, Simon AJ, Blennow K. Elevated cerebrospinal fluid BACE1 activity in incipient Alzheimer disease. Arch Neurol. 2008 Aug;65(8):1102-7. PubMed.
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