Cerebrospinal Fluid Aβ43 Is Reduced in Early-Onset Compared to Late-Onset Alzheimer's Disease, But Has Similar Diagnostic Accuracy to Aβ42.

Camilla Lauridsen,Precious K Pomary,Øyvind Salvesen,Gøril R Grøntvedt,Guro Berge,Linda R White,Sigrid B Sando,Geir Bråthen,Ina Møller

doi:10.3389/fnagi.2017.00210

Camilla Lauridsen, Precious K Pomary + Show 7 more

Open Access

https://doi.org/10.3389/fnagi.2017.00210

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Abstract

Background: Amyloid beta 1–43 (Aβ43) may be a useful additional biomarker for diagnosing Alzheimer’s disease (AD). We have investigated cerebrospinal fluid (CSF) levels of Aβ43 in patients with early-onset AD in contrast to levels in late-onset AD. For comparison, in addition to the ‘core’ biomarkers, several other analytes were also determined [YKL-40, neurofilament light (NF-L), glial fibrillary acidic protein (GFAP), and progranulin].Material and Methods: Cerebrospinal fluid samples were obtained from patients with early-onset AD (age ≤ 62, n = 66), late-onset AD (age ≥ 68, n = 25), and groups of cognitively intact individuals (age ≤ 62, n = 41, age ≥ 68, n = 39). Core CSF AD biomarkers [amyloid beta 1–42 (Aβ42), total tau, phosphorylated tau] were analyzed, as well as levels of Aβ43 and other analytes, using commercially available enzyme-linked immunosorbent assays.Results: Cerebrospinal fluid Aβ43 was significantly reduced in early-onset AD compared to late-onset AD (14.8 ± 7.3 vs. 21.8 ± 9.4 pg/ml, respectively), whereas the levels of Aβ42 in the two AD groups were not significantly different (474.9 ± 142.0 vs. 539.6 ± 159.9 pg/ml, respectively). Aβ43 and all core biomarkers were significantly altered in patients with AD compared to corresponding controls. NF-L was significantly increased in early-onset AD compared to younger controls, an effect not found between the older groups. Relationships between the Aβ peptides and tau proteins, YKL-40, NF-L, GFAP and progranulin were also investigated without finding marked associations. However, age-associated increases in levels of tau proteins, YKL-40, NF-L and GFAP were found with respect to age in healthy controls. Results for these other analytes were similar to previously published data. Aβ43 did not improve diagnostic accuracy in either AD group compared to Aβ42. Discussion: Cerebrospinal fluid Aβ43, but not Aβ42 levels, varied significantly with age in patients with AD. If CSF levels of Aβ peptides reflect amyloid deposition in brain, the possibility arises that there is a difference between Aβ43 and Aβ42 deposition in younger compared to older brain. However, the level of Aβ43 in CSF shows no improvement over Aβ42 regarding diagnostic accuracy.

Highlights

Alzheimer’s disease (AD) is often separated according to age, whereby onset prior to age 65 years is considered to be early-onset AD, while onset from an age of 65 years is termed late-onset AD
The most interesting result in this study is that the reduction in cerebrospinal fluid (CSF) levels of Aβ43 was more marked in early-onset compared to late-onset AD, and seems to be age-related
The data do not suggest that Aβ43 has better diagnostic accuracy for AD than Aβ42

Summary

Introduction

Alzheimer’s disease (AD) is often separated according to age, whereby onset prior to age 65 years is considered to be early-onset AD, while onset from an age of 65 years (which is much more common) is termed late-onset AD. The pathological burden of amyloid plaques and neurofibrillary tangles has been shown to be greater in early-onset AD than in patients with late-onset AD (Ho et al, 2002; Marshall et al, 2007), imaging studies have indicated the global burden to be similar between the two groups (Rabinovici et al, 2010), though sometimes with variation in regional anatomical distribution of amyloid (Ossenkoppele et al, 2012; Cho et al, 2013) Such putative differences in the distribution of amyloid pathology have not been found to alter levels of the core cerebrospinal fluid (CSF) biomarkers for AD; amyloid beta 1–42 (Aβ42), total tau (t-tau) and phosphorylated tau (p-tau) protein, in early- compared to late-onset AD (Bouwman et al, 2009; Chiaravalloti et al, 2016). In addition to the ‘core’ biomarkers, several other analytes were determined [YKL-40, neurofilament light (NF-L), glial fibrillary acidic protein (GFAP), and progranulin]

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