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

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.

The nonlinear relationship between cerebrospinal fluid Aβ42 and tau in preclinical Alzheimer’s disease

“…On the other hand, Aβ 40, Aβ 38, and X-tau were significantly and positively age associated. This result is consistent with one prior cross-sectional aging study that also examined a broad age range (47-84y) and similarly observed that the younger subjects (47-62y) showed a positive correlation between age and Aβ 42 levels, whereas the older subjects showed a negative correlation [ 8 ]. Other studies that examined subjects of advanced age reported either no changes in Aβ 42 [ 28 , 29 ] or reductions with age [ 30 ].…”

“…However, this clinical view of early AD lesions conflicts with the neuropathology which identifies tauopathy more commonly than Aβ lesions in younger brains [ 6 ]. Moreover, adding to the uncertainty, normal aging studies have been inconsistent, showing that CSF Aβ 42 levels increase [ 7 , 8 ] or decrease [ 9 ], or do not change with age [ 10 ]. Offering a clue to this discrepancy, transgenic animal models show CSF Aβ 42 elevations occur prior to Aβ 42 reductions and brain deposition [ 11 ], a trend also seen in early onset AD [ 12 , 13 ].…”

Current state of Alzheimer’s fluid biomarkers

“…Several subsequent studies have consistently shown that CSF levels of Aβ42 correlate inversely with plaque load as observed in autopsies and in vivo with positron emission tomography (PET) [ 82 , 114 , 158 , 343 , 353 ]. CSF Aβ43 is also reported to decrease in AD, but it has similar diagnostic accuracy to CSF Aβ42 [ 39 , 193 ] so research has focused on the latter.…”

Role of Body-Fluid Biomarkers in Alzheimer’s Disease Diagnosis

“…Many studies have reported that phosphorylated tau turns up in peoples' plasma decades before they show signs of dementia. The data bore the promise of a blood test for early Alzheimer's disease-one that is simpler than measuring the notoriously finicky plasma Aβ, and more specific than neurofilament light [27,28,34,59,60,[85][86][87][88]. In AD patients, plasma tau concentrations are increased compared with in normal controls, which can be measured using ultrasensitive assays but not as clearly as in the CSF [89].…”