Table 1.
Summary of selected candidate AD fluid biomarkers
| Biomarker | Stage of clinical validation | Levels in AD vs healthy controls | Stage of assay development | |
|---|---|---|---|---|
| CSF | Plasma/serum | |||
| Aβ42 | CSF Aβ42 is accepted as part of research criteria [75, 247] IWG-2 criteria recommend using CSF Aβ42 in combination with CSF t-tau or p-tau [75] Many studies on plasma but inconsistent results [160, 227, 271, 273, 274, 377] |
Consistently decreased in CSF Inconsistent results in plasma, although recent studies have shown a decrease |
Commercially available assays, including fully automated (IVDs in Europe) | Commercially available assays |
| Aβ40 | Many studies on CSF and plasma Inconsistent results for Aβ40 alone [73, 83, 160, 243, 248, 271, 338] Consistent results for ratio of CSF Aβ42/Aβ40 [161, 202, 205, 275, 276, 294] Consistent results for ratio of plasma Aβ42/Aβ40 [31, 87, 179, 261, 273, 371, 373, 377, 383] |
Aβ40 alone: inconsistent results in CSF and plasma Ratio of Aβ42/Aβ40: consistently decreased in CSF and plasma |
Commercially available assays (IVDs in Europe) | Commercially available assays |
| Aβ38 | Several studies on CSF Aβ38 alone Inconsistent results for Aβ38 alone [161, 243, 271] Very few studies on CSF Aβ42/Aβ38 [161, 259] One study on plasma Aβ38 [273] |
Aβ38 alone: inconsistent results in CSF and plasma Ratio of Aβ42/Aβ38: decreased in CSF but data are limited |
Commercially available assays | Commercially available assays |
| BACE1 | Several studies on CSF Inconsistent results [79, 81, 258, 283, 311, 392, 401, 407] Very few studies on plasma [330, 393] |
Inconsistent results in CSF but most studies showed increased levels/activity Increased activity in plasma but data are limited |
Commercially available assays | Commercially available assays |
| T-tau | CSF t-tau is accepted as part of research criteria [75, 247] IWG-2 criteria recommend using CSF t-tau in combination with CSF Aβ42 [75] Several studies on plasma Consistent results [61, 68, 245, 251, 271, 404] |
Consistently increased in CSF Consistently increased in plasma |
Commercially available assays, including fully automated (IVDs in Europe) | Commercially available assays |
| P-tau | CSF p-tau is accepted as part of research criteria [75, 247] IWG-2 criteria recommend using CSF p-tau in combination with CSF Aβ42 [75] Few studies on plasma or serum Consistent results [329, 358, 395] |
Consistently increased in CSF Increased in plasma and serum but data are limited |
Commercially available assays, including fully automated (IVDs in Europe) | In-house assays |
| hFABP | Several studies on CSF Consistent results [53, 67, 119, 146, 154, 201, 271] Very few studies on plasma or serum [254, 271] |
Consistently increased in CSF No change in plasma or serum but data are limited |
Commercially available assays | Commercially available assays |
| TREM2 | Few studies on CSF Inconsistent results [38, 107, 139, 141, 287, 344, 346] Few studies on blood [145, 255, 352] |
Inconsistent results in CSF but most studies showed an increase No change in plasma levels but data are limited; increased mRNA and protein levels in blood cells but data are limited |
Commercially available assays | Commercially available assays |
| YKL-40 | Several studies on CSF Inconsistent results [2–4, 11, 23, 57, 106, 138, 176, 244, 271, 303, 347, 384] Very few studies on plasma [54, 57] |
Inconsistent results in CSF but most studies showed an increase Increased in plasma but data are limited |
Commercially available assays | Commercially available assays |
| IP-10 | Few studies on CSF Inconsistent results [29, 101, 384] Very few studies on plasma or serum [102, 154] |
Inconsistent results in CSF Inconsistent results in plasma or serum |
Commercially available assays | Commercially available assays |
| Neurogranin | Many studies on CSF Inconsistent results [63, 64, 138, 175, 189, 190, 221, 242, 282, 291, 310, 347, 354, 361] Few studies on plasma [63, 110, 190, 389] |
Inconsistent results in CSF but most studies showed an increase No change in plasma but studies are limited; decreased in plasma neuronally derived exosomes but data are limited |
Commercially available assays | Commercially available assays |
| SNAP-25 | Two studies on CSF [36, 347] No studies on plasma |
Increased in CSF but data are limited Unknown for plasma |
Commercially available assays | Commercially available assays |
| Synaptotagmin | One study on CSF [270] One study on plasma [110] |
Increased in CSF but data are limited Decreased in plasma neuronally derived exosomes but data are limited |
Commercially available assays | Commercially available assays |
| α-Synuclein | Few studies on CSF Inconsistent results [27, 170, 172, 183, 232, 339, 366] Very few studies on plasma [49, 331] |
Inconsistent results in CSF but most studies showed an increase No change in plasma but data are limited |
Commercially available assays | Commercially available assays |
| TDP-43 | No studies on CSF Very few studies on plasma [97, 387] |
Unknown for CSF Increased in plasma but data are limited |
Commercially available assays | Commercially available assays |
| Ferritin | Very few studies on CSF [13–15] Very few studies on plasma [15, 112] |
No change in CSF but data are limited; increased CSF levels are associated with cognitive decline but data are limited No change in plasma but data are limited; plasma levels are associated with PET Aβ but data are limited |
Commercially available assays | Commercially available assays |
| VILIP-1 | Several studies on CSF Inconsistent results [17, 176, 194, 230, 257, 271, 347, 355–357] One study on plasma [355] |
Inconsistent results in CSF but most studies showed an increase Increased in plasma but data are limited |
Commercially available assays | Commercially available assays |
| NF-L | Several studies on CSF Consistent results [4, 220, 271, 282, 288, 334, 335, 403] Few studies on plasma or serum [240, 385, 408] |
Consistently increased in CSF Increased in plasma but data are limited |
Commercially available assays (IVDs in Europe) | Commercially available assays |
Aβ38 amyloid beta 38, Aβ40 amyloid beta 40, Aβ42 amyloid beta 42, AD Alzheimer’s disease, BACE1 β-site amyloid precursor protein cleaving enzyme 1, CSF cerebrospinal fluid, hFABP heart-type fatty acid-binding protein, IP-10 interferon-γ-induced protein 10, IVD in vitro diagnostic, IWG-2 International Working Group 2, NF-L neurofilament light, P-tau phosphorylated tau, SNAP-25 synaptosome-associated protein 25, TDP-43 transactive response DNA-binding protein 43, TREM2 triggering receptor expressed on myeloid cells 2, T-tau total tau, VILIP-1 visinin-like protein 1