Table 1.
Overview of extracellular vesicle (EV)-associated biomarkers in Alzheimer’s disease (AD).
| EV QC | AD vs. ctrl | ||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|
| Source | Cohort | EV Isolation Method | NTA | TEM | EV Markers | Category | Biomarker | Result | Statistics | Additional Potential | Ref |
| CSF | AD: 10 Ctrl: 10 |
Differential centrifugation | x | x | + | Neurotoxic protein | p-Tau | = | ns | [64] | |
| AD: 21 Ctrl: 9 |
Ultracentrifugation + sucrose gradient fractionation |
+ | Ratio EV pT181 Tau/EV t-Tau | ↑ | p = 0.04 | Prognostic | [78] | ||||
| Ratio EV pT181 Tau/CSF pT181 Tau | p = 0.002 | ||||||||||
| AD: 7 ctrl: 7 |
Total Exosome isolation kit |
miRNA | miR-193b | ↓ | p < 0.05 | [129] | |||||
| Serum | AD: 22 Ctrl: 16 |
ExoQuick | x | + | miR-223 | ↓ | AUC = 0.875 | [130] | |||
| AD: 39 MCI: 11 Ctrl: 59 |
Plasma/Serum exosome isolation kit |
miRNA signature (16 miRNAs) | ≠ | Sens: 87% Spec: 77% |
[131] | ||||||
| AD: 51 MCI: 43 ctrl: ? |
Total Exosome isolation kit |
miR-193b | ↓ | p < 0.05 | Prognostic | [129] | |||||
| AD: 107 MCI: 101 Ctrl: ? |
Total Exosome isolation kit |
x | + | miR-135a | ↑ | Sens: 95% Spec: 96% |
[132] | ||||
| miR-384 | Sens: 97% Spec: 99% |
Prognostic | |||||||||
| miR-193b | ↓ | Sens: 94% Spec: 86% |
|||||||||
| AD: 25 Ctrl: 17 |
ExoQuick + immunoprecipitation with L1CAM |
+ | Synaptic protein | SNAP25 | ↓ | AUC = 0.826 | [133] | ||||
| Plasma/serum | AD: 57 Ctrl: 57 FU AD: 24 |
ExoQuick + immunoprecipitation with L1CAM |
x | + | Neurotoxic proteins | t-Tau | = | [134] | |||
| pS396 Tau pT181 Tau |
↑ | AUC = 0.999 | Preclinical | ||||||||
| Aβ1-42 | Preclinical, prognostic | ||||||||||
| Plasma | AD 1: 120 Ctrl 1: 222 AD 2: 35 Ctrl 2: 29 |
x | x | +; - | Neurotoxic proteins | Aβ1-42 | = | Optimal model cohort 1: AUCtrain = 0.896; AUCtest = 0.8 Optimal model cohort 2: AUCtrain = 0.989; AUCtest = 0.767 |
[135] | ||
| t-Tau | |||||||||||
| pT181 Tau | ↑ | Preclinical | |||||||||
| pT231 | |||||||||||
| Insulin signaling | IRS-1-pS312 | ||||||||||
| IRS-1-pTyr | |||||||||||
| AD: 10 ADC: 20 MCI: 20 Ctrl: 10 |
x | x | + | Neurotoxic proteins | pT181 Tau | ↑ | AUC = 1 | Prognostic | [75] | ||
| pS396 Tau | AUC = 0.98 | ||||||||||
| Aβ1–42 | AUC = 0.98 | ||||||||||
| Synaptic protein | Neurogranin | ↓ | AUC = 1 | ||||||||
| Survival factor | REST | AUC = 1 | |||||||||
| AD: 20 MCI: 10 Ctrl: 10 |
x | + | Neurotoxic proteins | t-Tau pT181 Tau |
= | ns | [136] | ||||
| AD: 26 Ctrl: 26 FU AD: 22 |
+ | Insulin signaling | IRS-1-pS312 | ↑ | AUC = 0.932 | Preclinical | [137] | ||||
| IRS-1-pTyr | ↓ | AUC = 1 | |||||||||
| Ratio IRS-1-pS312/IRS-1 pTyr | ↑ | AUC = 1 | |||||||||
| AD: 12 Ctrl: 12 FU AD: 9 |
+ | Synaptic protein | Synaptotagmin | ↓ | AUC = 0.99 | Preclinical Prognostic |
[138] | ||||
| Synaptophysin | AUC = 1 | ||||||||||
| Synaptopodin | AUC = 0.97 | ||||||||||
| Neurogranin | AUC = 0.99 | ||||||||||
| GAP43 | AUC = 0.79 | ||||||||||
| AD: 26 Ctrl: 16 FU AD: 20 |
+ | Lysosomal proteins | LAMP-1 | ↑ | p = 0.00051 | Preclinical | [139] | ||||
| Cathepsin D | AUC = 1 | ||||||||||
| Ubiquitinylated proteins | |||||||||||
| Heat-shock protein | HSP70 | ↓ | |||||||||
| AD: 24 Ctrl: 24 FU AD: 16 |
+ | Survival factors | LRP6 | ↓ | AUC = 0.924 | Preclinical | [140] | ||||
| HSF1 | AUC = 0.944 | ||||||||||
| REST | AUC = 0.944 | ||||||||||
| AD: 28 Ctrl: 28 FU AD: 18 |
+ | Synaptic proteins | AMPA4 | ↓ | p < 0.0001 | Preclinical Prognostic |
[141] | ||||
| NLGN1 | |||||||||||
| NRXN2 | |||||||||||
| NPTX2 | p < 0.01 | ||||||||||
| AD: 106 Ctrl: 106 |
Immunocapture with L1CAM | x | Neurotoxic protein | Tau | = | ns | [142] | ||||
| AD: 12 Ctrl: 10 |
ExoQuick + immunoprecipitation with L1CAM or GLAST |
x | + | Neurotoxic proteins | BACE1 | ADE ↑ NDE = |
p < 0.0001; ns | [143] | |||
| Gamma secretase | ADE = NDE = |
ns; ns | |||||||||
| sAPPα | ADE = NDE ↑ |
ns; p = 0.0008 | |||||||||
| sAPPβ | ADE ↑ NDE ↑ |
p = 0.0159; p = 0.0028 | |||||||||
| pT181 and pS396 Tau | ADE = NDE ↑ |
ns; - | |||||||||
| Aβ1-42 | ADE ↓ NDE ↑ |
p < 0.05; - | |||||||||
| Neural protein | Septin-8 | ADE ↓ NDE = |
p < 0.0001; ns | ||||||||
| AD: 28 Ctrl: 28 FU AD: 16 |
ExoQuick + immunoprecipitation with GLAST |
x | x | +; - | Inflammatory cytokines | IL-6, TNF-α, IL-1β | ↑ |
p < 0.001; p < 0.01; p < 0.001 |
[67,68] | ||
| Complement proteins | C1q, C3b, C3d, C4b, C5b-C9 TCC | p < 0.0001 | |||||||||
| Factor B, Factor D, Fragment Bb | |||||||||||
| CR1, CD46 | ↓ | p < 0.01 | |||||||||
| CD59, DAF | p < 0.0001 | Preclinical, prognostic |
|||||||||
| AD: 24 Ctrl: 24 FU AD: 15 |
ExoQuick + immunoprecipitation with CSPG4 and PDGFRa |
x | + | Neurotrophic factors | HGF | ↓ | p < 0.0001 | Preclinical | [144] | ||
| FGF2 | |||||||||||
| IGF1 | |||||||||||
| FGF13 | p < 0.01 | ||||||||||
| AD: 101 MCI: 96 Ctrl: 101 |
ExoQuick + immunoprecipitation with NCAM |
x | + | Neurotoxic proteins | t-Tau | ↑ | AUCtrain = 0.87; AUCtest = 0.89 | Preclinical Prognostic |
[125] | ||
| pT181 Tau | AUCtrain = 0.89; AUCtest = 0.88 |
||||||||||
| Aβ1-42 | AUCtrain and AUCtest = 0.93 |
||||||||||
| AD: 35 Ctrl: 35 |
Differential centrifugation | + | miRNA | miRNA signature | ≠ | AUC = 0.919 | [145] | ||||
| AD: 31 MCI: 16 Ctrl: 16 |
ExoQuick + immunoprecipitation with L1CAM |
+ | miR-212 miR-132 |
↓ | AUC: 0.77 AUC: 0.84 |
[146] | |||||
| AD: 40 Ctrl: 40 |
x | x | + | miR-100-3p miR-23a-3p miR-223-3p miR-190a-5p |
↓ | p = 0.008 | [147] | ||||
| ↑ |
p = 0.008 p = 0.016 p = 0.003 |
||||||||||
This table only discusses results obtained in Alzheimer’s disease (AD) patients, patients with mild cognitive impairment (MCI) and controls (ctrl). Follow-up (FU) AD patients provided samples at two time-points: first when cognitively intact and later when diagnosed with AD. ADC patients are MCI patients who are converting to AD. For reference [135], cohort 1 consists of longitudinal samples collected from AD patients prior to symptom onset and respective controls, whereas cohort 2 consists of longitudinal samples of clinical AD patients and respective controls. In the extracellular vesicle (EV) markers column, the + symbol indicates the assessment of typical EV markers whereas the—symbol indicates the assessment of non-EV markers. For statistics, preferably the area under the receiver operating curve (AUC) or alternatively the sensitivity (sens) and specificity (spec) or p-value are indicated. Preclinical biomarkers have the potential to identify patients at an early disease stage before the occurrence of clinical symptoms. Prognostic biomarkers have the potential to differentiate between different stages of AD and follow-up disease progression. Abbreviations: QC, quality control; NTA, nanoparticle tracking analysis; TEM: transmission electron microscopy; CSF, cerebrospinal fluid; p-Tau, phosphorylated Tau; t-Tau, total Tau; SNAP25, synaptosomal-associated-protein 25; Aβ, amyloid beta; REST, repressor element 1-silencing transcription factor; IRS-1, insulin receptor substrate-1; GAP43, growth-associated protein 43; LAMP-1, lysosome-associated membrane protein 1; HSP70, heat-shock protein 70; LRP6, lipoprotein receptor-related protein 6; HSF1, heat-shock factor-1; AMPA4, GluA4-containing glutamate; NLGN1, neuroligin 1; NRXN2, neurexin 2a; NPTX2, neuronal pentraxin 2; BACE1, β-site APP cleaving enzyme-1; sAPPα, soluble APPα; sAPPβ, soluble APPβ; IL-6, interleukin 6; TNF-α, tumor necrosis factor α; IL-1β, interleukin 1 β; TCC, terminal complement complex; CR1, complement receptor type 1; DAF, decay-accelerating factor; HGF, hepatocyte growth factor; FGF, fibroblast growth factor; IGF1, insulin-like growth factor 1; L1CAM, L1 cell adhesion molecule; NCAM, neural cell adhesion molecule; GLAST, glutamine aspartate transporter; CSPG4, chondroitin sulfate proteoglycan 4; PDGFRα, platelet growth factor receptor α; ADE, astrocyte-derived EV; NDE, neural-derived EV.