Amyloid-Beta (Aβ)
<table class="infobox infobox-protein">
<tr>
<th class="infobox-header" colspan="2">Amyloid-beta (Aβ)</th>
</tr>
<tr>
<td class="label">Gene</td>
<td>[APP](/genes/app)</td>
</tr>
<tr>
<td class="label">UniProt</td>
<td><a href="https://www.uniprot.org/uniprot/P05067" target="_blank">P05067</a></td>
</tr>
<tr>
<td class="label">PDB</td>
<td><a href="https://www.rcsb.org/structure/1IYT" target="_blank">1IYT</a>, <a href="https://www.rcsb.org/structure/1BA4" target="_blank">1BA4</a>, <a href="https://www.rcsb.org/structure/2BEG" target="_blank">2BEG</a>, <a href="https://www.rcsb.org/structure/5OQV" target="_blank">5OQV</a></td>
</tr>
<tr>
<td class="label">Mol. Weight</td>
<td>4 kDa (Aβ40/42)</td>
</tr>
<tr>
<td class="label">Localization</td>
<td>Extracellular, membrane-associated</td>
</tr>
<tr>
<td class="label">Family</td>
<td>[Amyloid precursor protein](/entities/app-protein) family</td>
</tr>
<tr>
<td class="label">Diseases</td>
<td>[Alzheimer's Disease](/diseases/alzheimers), [Cerebral Amyloid Angiopathy](/diseases/cerebral-amyloid-angiopathy)</td>
</tr>
<tr>
<td class="label">Associated Diseases</td>
<td><a href="/wiki/als" style="color:#ef9a9a">ALS</a>, <a href="/wiki/alzheimer" style="color:#ef9a9a">ALZHEIMER</a>, <a href="/wiki/alzheimer-disease" style="color:#ef9a9a">ALZHEIMER DISEASE</a>, <a href="/wiki/alzheimer's" style="color:#ef9a9a">ALZHEIMER'S</a>, <a href="/wiki/alzheimer's-disease" style="color:#ef9a9a">ALZHEIMER'S DISEASE</a></td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">3014 edges</a></td>
</tr>
</table>
Amyloid-beta (Aβ)
Overview
Amyloid-beta (Aβ) is a peptide fragment derived from the proteolytic processing of the [Amyloid Precursor Protein (APP)](/amyloid-precursor-protein-(app)))))))), encoded by the [APP](/entities/app-protein) gene on chromosome 21. It is a 40-42 amino acid peptide that plays a central role in the pathogenesis of Alzheimer's disease (AD) and related amyloidopathies[@hardy2002].
Amyloidogenic Processing
APP Processing Pathway
Mermaid diagram (expand to render)
APP can be processed through two mutually exclusive pathways:
Non-amyloidogenic pathway: alpha-secretase cleaves APP within the Abeta sequence, precluding Abeta formation. This pathway produces soluble APPalpha (sAPPalpha) and a membrane-bound C-terminal fragment.
Amyloidogenic pathway: beta-secretase (BACE1) cleaves APP at the N-terminus of Abeta, followed by gamma-secretase cleavage at the C-terminus, releasing Abeta peptides of various lengths (Abeta38, Abeta40, Abeta42, Abeta43)[@obrien2011].The Abeta42 isoform is more hydrophobic and aggregation-prone than Abeta40, making it the primary species found in amyloid plaques.
See also: [APP Amyloid Pathway](/mechanisms/app-amyloid-pathway-alzheimers).
Molecular Structure
Primary Sequence and Domains
Amyloid-beta peptides are derived from the transmembrane domain of [APP](/entities/app-protein), with the Aβ sequence spanning residues 681-770 of the APP770 isoform. The peptide contains:
- N-terminal region (1-16): Highly hydrophilic, forms the "soft" segment that initiates aggregation
- Central hydrophobic core (17-21, KLVFF): Critical for fibril formation, known as the "KLVFF" motif
- C-terminal region (22-40/42): Hydrophobic, drives membrane association and aggregation
Secondary and Tertiary Structure
In solution, monomeric Aβ adopts a random coil conformation. Upon aggregation, it transitions to:
- β-sheet structure: Cross-β architecture with strands perpendicular to the fibril axis
- Hydrophobic interactions: Drive the formation of the steric zipper
- Salt bridges: Stabilize the fibril core (e.g., D23-K28 ionic interaction)
Cryo-EM studies have revealed multiple Aβ42 fibril morphologies:
- 3-fold symmetric protofilaments (common in sporadic AD)
- 2-fold symmetric dimers (familial AD cases)
- Polymorphic strains: Different conformations associated with distinct disease phenotypes
Available PDB structures include: [1IYT](https://www.rcsb.org/structure/1IYT), [1BA4](https://www.rcsb.org/structure/1BA4), [2BEG](https://www.rcsb.org/structure/2BEG), [5OQV](https://www.rcsb.org/structure/5OQV), [7JTL](https://www.rcsb.org/structure/7JTL), [7JYY](https://www.rcsb.org/structure/7JYY).
The protein's three-dimensional structure can also be explored via the [AlphaFold Protein Structure Database](https://alphafold.ebi.ac.uk/entry/P05067).
Post-Translational Modifications
Aβ undergoes numerous PTMs that modulate its aggregation and toxicity:
Phosphorylation
- Ser8: phosphorylation reduces aggregation
- Ser26: affects membrane interactions
- Tyrosine10: nitration enhances toxicity
Truncation
- N-terminally truncated species (AβpE3, AβpE11): More aggregation-prone, found in plaques
- C-terminally truncated species (Aβ1-38): Less toxic, may be protective
Isomerization
- Asp7 isomerization: Affects aggregation kinetics
- Asp23 isomerization: Alters fibril structure
Oxidation
- Methionine35 oxidation: Reduces aggregation but increases toxicity of oligomers
- Histidine oxidation: Modifies metal binding
Glycation
- Advanced glycation end products (AGEs): Cross-link Aβ, enhance aggregation
- Found in AD brain: Correlates with disease severity
Aggregation and Toxicity
Nucleation-Dependent Polymerization
Aβ aggregation follows a nucleation-dependent polymerization mechanism (also called "seeded growth"):
Lag phase: Monomers slowly form unstable oligomers
Nucleation: Critical nucleus forms (typically 2-6 monomers)
Elongation: Rapid addition of monomers to seed
Saturation: Equilibrium between monomers and fibrilsMermaid diagram (expand to render)
Aggregation Prone Regions
The central hydrophobic core (CHC, residues 17-21, KLVFF) is critical for:
- Steric zipper formation: Intermolecular β-sheet stacking
- Oligomerization: Dimer/trimer formation
- Fibril elongation: Monomer addition to fibril ends
The C-terminal hydrophobic tail (residues 30-42) drives:
- Membrane association: Hydrophobic interactions with lipid bilayers
- Fibril stability: Inter-protomer hydrogen bonds
Soluble Oligomers: The Toxic Species
Soluble Aβ oligomers (also called Aβ-derived diffusible ligands, ADDLs) are now recognized as the most toxic species, more so than mature fibrils or plaques[@lacor2008]. Key oligomer species include:
- Dimers: Smallest toxic unit, ~9 kDa
- Trimers: ~13.5 kDa, highly synaptotoxic
- Tetramers: ~18 kDa, may be "off-pathway"
- Dodecamers (Aβ*56): ~56 kDa, disrupts memory in mice
- Large oligomers: >100 kDa, membrane-permeable
Aβ interacts with multiple membrane components:
Lipid rafts: Aβ accumulates in cholesterol-rich microdomains
Ion channels: Forms Ca²⁺-permeable pores
Receptors: Binds to NMDA, AMPA, insulin receptors
Membrane fluidity: Alters lipid organization
Synaptic vesicle: Impairs neurotransmitter releaseMechanisms of Neurotoxicity
Aβ exerts toxicity through multiple interconnected mechanisms:
Synaptic dysfunction: Aβ oligomers bind to synaptic receptors (PrPᶜ, NMDA, mGluR5), impairing [long-term potentiation](/mechanisms/long-term-potentiation) (LTP), reducing dendritic spine density, and disrupting neurotransmitter release[@shankar2008]
Oxidative stress: Aβ accumulation increases [reactive oxygen species](/entities/reactive-oxygen-species) (ROS) production through:
- Mitochondrial complex III dysfunction
- NADPH oxidase activation
- Metal redox cycling (Fe²⁺/Cu⁺ oxidation)
- Lipid peroxidation
Neuroinflammation: Aβ activates [microglia](/cell-types/microglia) and [astrocytes](/cell-types/astrocytes) through:
- TLR2/4 pattern recognition receptor activation
- [NLRP3 inflammasome](/mechanisms/nlrp3-inflammasome) activation
- Cytokine/chemokine release (IL-1β, TNF-α, IL-6)
- Chronic inflammation contributes to neurodegeneration
Calcium dysregulation: Aβ forms calcium-permeable channels in membranes:
- Uncontrolled Ca²⁺ influx
- Mitochondrial calcium overload
- Calpain activation
- [Apoptosis](/mechanisms/apoptosis) signaling
Mitochondrial dysfunction: Aβ localizes to mitochondria:
- Impairs complex IV activity
- Reduces ATP production
- Increases ROS
- Triggers mitophagy deficits
Endoplasmic reticulum stress: Aβ disrupts protein folding:
- [UPR](/entities/unfolded-protein-response) activation
- CHOP-mediated apoptosis
- Calcium store depletion
[Autophagy](/entities/autophagy) impairment: Aβ disrupts autophagic flux:
- mTORC1 hyperactivation
- Lysosomal dysfunction
- Autophagosome accumulation
See also: [Amyloid Aggregation](/mechanisms/amyloid-aggregation), [Amyloid Hypothesis](/mechanisms/amyloid-hypothesis), and [Amyloid-Tau Synergistic Interaction](/mechanisms/amyloid-tau-synergistic-interaction-hypothesis).
APP Processing and Genetic Risk
Amyloid precursor protein (APP) processing determines Aβ production:
Non-Amyloidogenic Pathway (Protective)
The non-amyloidogenic pathway is the default processing route in healthy brains:
- α-secretase cleavage: ADAM10/ADAM17 cleave APP at residue 16 (within the Aβ sequence)
- sAPPα release: Produces soluble APPα, which has neuroprotective properties
- CTFα formation: Creates a membrane-bound C-terminal fragment
- [γ-secretase](/entities/gamma-secretase) processing: CTFα is further processed to p3 peptide (non-amyloidogenic)
The sAPPα fragment:
- Promotes neurite outgrowth
- Enhances synaptic plasticity
- Has anti-inflammatory properties
- Protects against excitotoxicity
Amyloidogenic Pathway (Pathogenic)
The amyloidogenic pathway generates Aβ peptides:
- [β-secretase](/entities/bace1) (BACE1) cleavage: First cleavage at residue 1 of Aβ (APP residue 681)
- sAPPβ release: Soluble APPβ fragment
- CTFβ formation: C-terminal membrane fragment
- γ-secretase cleavage: Multiple cleavage sites produce Aβ38-43
γ-secretase cleavage sites:
- ε-site: Releases Aβ46-49 (longer fragments)
- γ-site: Produces Aβ38-43 isoforms
- ζ-site: Alternative cleavage
Genetic Risk Factors
APP Mutations (Autosomal Dominant)
| Mutation | Effect | Phenotype |
|----------|--------|-----------|
| Swedish (K670N/M671L) | ↑ Aβ production | Early-onset AD |
| Arctic (E22G) | ↑ Oligomerization | Aggressive AD |
| London (V717I) | ↑ Aβ42/Aβ40 | Early-onset AD |
| Flemish (A692G) | ↑ Aβ40 | CAA + AD |
| Dutch (E693Q) | ↑ Aβ aggregation | Severe CAA |
| Italian (E693K) | ↑ Aggregation | CAA |
| Iowa (D694N) | ↑ Aggregation | CAA + AD |
Protective APP Variants
- A673V (Icelandic): Reduces Aβ production by 40%, carriers have 5x lower AD risk[@patterson2023]
- A673T: Protective in vitro
APP copy number variants:
- Duplication syndrome: APP triplication causes early-onset AD with CAA
- Down syndrome: Extra APP copy leads to early Aβ accumulation
Genetic Risk Modifiers
- BIN1: Affects Aβ trafficking and aggregation
- PICALM: Modulates endocytosis and Aβ production
- CLU (Clusterin): Aβ chaperone, genetic risk factor
- ABCA7: Aβ clearance, lipid metabolism
Aβ Clearance Mechanisms
The brain has multiple pathways for Aβ clearance:
Proteolytic Degradation
Endogenous Aβ-degrading enzymes:
- [Neprilysin](/entities/neprilysin) (NEP): Primary Aβ-degrading enzyme in brain
- Expression decreases with age
- NEP overexpression reduces plaques in mice
- AAV-mediated NEP delivery in clinical trials
- [Insulin-degrading enzyme](/entities/insulin-degrading-enzyme) (IDE): Aβ and insulin degradation
- Located in cytoplasm, mitochondria, and extracellular space
- Genetic variants affect AD risk
- Matrix metalloproteinases (MMPs): MMP-2, MMP-9 degrade Aβ
- Activated in glia
- Increased in AD brain
- Plasmin: Broad-spectrum protease
- Activated by tPA
- Lower in AD CSF
- Cathepsins: Lysosomal proteases
- Cathepsin B: Inhibited by cystatin C
- Cathepsin D: Active in lysosomes
Microglial Clearance
Microglia clear Aβ through:
Receptor-mediated phagocytosis
- TLRs (Toll-like receptors)
- [RAGE](/genes/rage) (Receptor for Advanced Glycation Endproducts)
- SR-A (Scavenger Receptor A)
- CD36 (class B scavenger receptor)
Autophagy-lysosomal degradation
- LC3-associated phagocytosis (LAP)
- PICALM involvement
- Damaged lysosomes impair clearance
Aβ export across the [blood-brain barrier](/entities/blood-brain-barrier)
- [LRP1](/genes/lrp1) (Low-density lipoprotein receptor-related protein 1)
- P-glycoprotein (ABCB1)
- Age-related export decline
Peripheral Clearance
Peripheral Aβ affects brain Aβ through the "peripheral sink" hypothesis:
- Liver and kidney clearance: Circulating Aβ degradation
- Monocyte/macrophage uptake: Phagocytic clearance
- Antibody-mediated clearance: Immunotherapy mechanisms
- LDL receptor family: Aβ binding and clearance
Sleep and Glymphatic Clearance
The [glymphatic system](/entities/glymphatic-system) is critical for Aβ clearance:
- Astrocytic AQP4 channels: Water flux
- Arterial pulsation: Driving force
- Sleep-dependent clearance: 60% more clearance during sleep
- Aβ diurnal variation: Higher during wakefulness
- Sleep disruption: Increases Aβ accumulation
Cellular and Animal Models
In Vitro Models
- Cell lines: CHO, HEK293, N2a for APP processing
- Primary [neurons](/entities/neurons): Mouse, rat, human
- iPSC-derived neurons: Patient-specific models
- 3D neuronal cultures: Cerebral organoids
- Blood-brain barrier models: Transwell systems
In Vivo Models
Transgenic Mouse Models
| Model | Mutation | Aβ Profile | Plaques | Notes |
|-------|----------|------------|---------|-------|
| APP/PS1 | APP Swe + PS1ΔE9 | Aβ40↑, Aβ42↑ | Yes | Common model |
| 5xFAD | 3 APP + 2 PS1 | Aβ42↑↑ | Yes | Aggressive |
| APP23 | APP Swe | Aβ40↑ | Yes | Swiss colony |
| Tg2576 | APP Swe | Aβ40↑ | Yes | Memory deficits |
| J20 | APP Indiana + Swedish | Aβ42↑ | Yes | Synaptic loss |
| 3xTG | APP + [tau](/proteins/tau) + PS1 | Aβ40/42 + [tau](/proteins/tau) | Yes | AD-like |
Key Findings from Models
- Aβ oligomers cause synaptic dysfunction before plaques
- Microglial activation precedes plaque formation
- [Tau](/proteins/tau) pathology is required for full neurodegeneration
- Aβ vaccination reduces plaques but not always cognitive decline
Non-Murine Models
- C. elegans: Simplest model for aggregation studies
- Drosophila: Express Aβ in fly brain
- Zebrafish: Transparent model for development
- NHPs (non-human primates): Closest to human physiology
Clinical Trials and Therapeutic Challenges
Aβ-targeting therapies have faced challenges:
Completed trials (unsuccessful):
- Passive immunization (bapineuzumab, solanezumab)
- Active immunization (AN1792)
- γ-secretase inhibitors
- BACE1 inhibitors
Lessons learned:
- Early intervention may be critical
- Biomarker selection matters
- Target engagement necessary
- Combination approaches needed
Ongoing strategies:
- Anti-oligomer antibodies
- Small molecule aggregation inhibitors
- Vaccine approaches with improved design
- Aβ clearance enhancement
See also: [Anti-Amyloid Therapeutics](/mechanisms/anti-amyloid-therapeutics).
Role in Disease
Amyloid-beta (Aβ) is implicated in the following neurodegenerative conditions:
- [Alzheimer's Disease](/diseases/alzheimers-disease) - the predominant component of amyloid plaques
- [Cerebral Amyloid Angiopathy](/diseases/cerebral-amyloid-angiopathy) - vascular amyloid deposits
- Down syndrome - triplication of APP gene leads to early Aβ accumulation
- [Dutch hereditary cerebral amyloid angiopathy](/diseases/cerebral-amyloid-angiopathy) - APP mutation causes severe CAA
- [Arctic mutation](/diseases/arctic-alzheimers) - Aβ point mutation (E22G) causes aggressive Aβ aggregation
Amyloid Cascade Hypothesis
The amyloid cascade hypothesis, proposed by Hardy and Higgins in 1992, remains the dominant framework for understanding AD pathogenesis[@selkoe2016]:
Aβ accumulation precedes tau pathology
Aβ triggers downstream tau hyperphosphorylation
Neurofibrillary tangles form
Neuronal loss and cognitive decline followDespite clinical trial failures, the hypothesis has evolved:
- Modified view: Aβ triggers, but tau drives neurodegeneration
- Oligomer-centric: Soluble oligomers, not plaques, are toxic
- Temporal model: Aβ effects are age-dependent and cumulative
Misfolding, aggregation, or dysfunction of Amyloid-beta (Aβ) contributes to neuronal damage through various mechanisms including proteotoxic stress, disrupted cellular signaling, and neuroinflammation.
Aβ in Down Syndrome (Trisomy 21)
Individuals with Down syndrome develop AD-like pathology by age 40-50:
- APP triplication: Chromosome 21 carries extra APP copy
- Aβ overexpression: 1.5x normal Aβ production
- Early plaques: Aβ plaques appear in 20s-30s
- Dementia risk: 50-70% develop dementia by age 60+
See also: [Down Syndrome Alzheimer's Disease](/mechanisms/down-syndrome-alzheimers).
Therapeutic Targeting
Amyloid-beta (Aβ) represents an important therapeutic target. Multiple drug development programs are exploring strategies to:
1. Reduce Production
BACE1 Inhibitors
- Verubecestat (MK-8931): Failed in Phase 3 — too much target engagement caused cognitive worsening
- Atabecestat: Failed due to liver toxicity
- Challenge: BACE1 processes many other substrates critical for synaptic function
γ-Secretase Modulators (GSMs)
- Notch-sparing modulators: Reduce Aβ42 production without Notch inhibition
- Chronic use potential: More tolerable than inhibitors
- Natural compounds: Some NSAIDs act as GSMs
2. Enhance Clearance
Passive Immunization
- [Lecanemab](/entities/lecanemab) (Leqembi): FDA-approved, binds Aβ protofibrils, 27% slowing of cognitive decline[@van2023]
- [Donanemab](/entities/donanemab) (Kisunla): FDA-approved, targets pyroglutamate-modified Aβ
- Gantenerumab: Failed in Phase 3 (Gradear)
- Aduhelm (aducanumab): Controversial FDA approval, withdrawn from market
Active Immunization
- ACI-35 (Lipidated tau): Phase 2 — anti-phospho-tau vaccine
- ABvac40: Phase 2 — targets Aβ40
- CAD106: Phase 2/3 — targets Aβ1-6
3. Inhibit Aggregation
Small Molecule Inhibitors
- Curcumin: Natural polyphenol, binds Aβ, anti-inflammatory
- Epigallocatechin gallate (EGCG): Green tea catechin, disrupts oligomers
- Broussoflavonol: Natural compound in paper mulberry
- Anle138b: Triple aromatic compound, blocks oligomer formation[@wagner2019]
- Clioquinol: Cu/Zn chelator, reduces Aβ toxicity
- PBT2: Second-generation chelator, failed in Phase 2
4. Target Downstream Effects
- Anti-inflammatory: Anti-TNFα, NSAIDs (failed in prevention trials)
- Neuroprotective: AMPA modulators, neurotrophic factors
- Synaptic restoration: BDNF analogs, M1 agonists
- Metabolic support: GLP-1 agonists, metabolic enhancers
5. Emerging Approaches
Anti-Aβ Oligomer Antibodies
- ACI-302: Preferentially targets toxic oligomers
- BACI: Bispecific antibody approach
Aβ Degradation Enhancers
- Neprilysin enhancement: Endogenous Aβ-degrading enzyme
- IDE (insulin-degrading enzyme): Aβ clearance
- Matrix metalloproteinases (MMPs): Aβ degradation
Peripheral Sink Strategies
- Anti-peripheral Aβ antibodies: "Peripheral sink" hypothesis
- Albumin-based approaches: Bind plasma Aβ, shift equilibrium
See also: [Anti-Amyloid Therapeutics](/mechanisms/anti-amyloid-therapeutics), [Amyloid-Beta 40 Biomarker](/biomarkers/amyloid-beta-40-abeta-40), [Amyloid-Beta 42/40 Ratio](/biomarkers/amyloid-beta-42-40-ratio).
Key Publications
[The amyloid hypothesis of Alzheimer's disease: progress and problems on the road to therapeutics](https://doi.org/10.1126/science.1072994). Science, 2002.
[Amyloid-beta peptide — a chemist's perspective](https://doi.org/10.1002/anie.200802474). Angew Chem Int Ed, 2009.
[Soluble oligomers of the amyloid beta-protein impair synaptic plasticity and behavior](https://doi.org/10.1093/brain/awn130). Brain, 2008.
[Lecanemab in Early Alzheimer's Disease](https://doi.org/10.1056/NEJMoa2212948). NEJM, 2022.
External Links
- UniProt: [https://www.uniprot.org/uniprot/P05067](https://www.uniprot.org/uniprot/P05067)
- AlphaFold: [Amyloid-beta (Aβ)](https://alphafold.ebi.ac.uk/entry/P05067)
- PDB: [1IYT](https://www.rcsb.org/structure/1IYT), [1BA4](https://www.rcsb.org/structure/1BA4), [2BEG](https://www.rcsb.org/structure/2BEG), [5OQV](https://www.rcsb.org/structure/5OQV)
Brain Atlas Resources
- Allen Human Brain Atlas: [Expression data for APP](https://human.brain-map.org/microarray/search/show?search_term=APP)
- Allen Brain Atlas API: [Gene expression via BrainAtlas API](https://api.brain-map.org/api/v0/data/gene/APP/)
- BrainSpan Atlas: [Developmental expression of APP](https://www.brainspan.org/)
See Also
- [Proteins Index](/proteins)
- [Genes Index](/genes)
- [Diseases Index](/diseases)
- [Mechanisms Index](/mechanisms)
- [APP Gene](/proteins/app)
- [Alzheimer's Disease](/diseases/alzheimers-disease)
- [Amyloid Cascade Hypothesis](/mechanisms/amyloid-cascade)
- [Amyloid Aggregation](/mechanisms/amyloid-aggregation)
Aβ Peptide Variants
Multiple Aβ peptide species exist due to alternative γ-secretase cleavage:
Major Species
| Species | Length | Abundance | Aggregation |
|---------|--------|----------|-------------|
| Aβ37 | 37 aa | Low | Low |
| Aβ38 | 38 aa | ~10% | Low |
| Aβ40 | 40 aa | ~80-90% | Moderate |
| Aβ42 | 42 aa | ~5-10% | High |
| Aβ43 | 43 aa | Trace | Very high |
Aβ42/Aβ40 Ratio
- Elevated Aβ42/Aβ40 ratio increases aggregation risk
- APP mutations can shift production toward Aβ42
- The ratio is a biomarker for AD risk
truncAβ Species
- N-terminally truncated Aβ (pE3-Aβ42, pE11-Aβ42)
- More aggregation-prone
- Found in early-onset AD and CAA
Aβ Biomarkers
Cerebrospinal Fluid (CSF) Biomarkers
| Biomarker | Change in AD | Clinical Utility |
|-----------|--------------|------------------|
| Aβ40 | Decreased | Reflects global Aβ production |
| Aβ42 | Decreased | Reflects plaque deposition |
| Aβ42/Aβ40 ratio | Decreased | Improved diagnostic accuracy |
| Total tau (t-tau) | Increased | Neurodegeneration marker |
| Phospho-tau (p-tau) | Increased | Tau pathology marker |
Blood-Based Biomarkers
- Aβ42/Aβ40 ratio: Plasma ratio shows promise for screening
- p-tau181, p-tau217, p-tau231: Phospho-tau isoforms correlate with Aβ burden
- [Neurofilament light](/biomarkers/neurofilament-light-chain-nfl) (NfL): Axonal damage marker
- [GFAP](/entities/gfap): Astrocyte activation marker
Imaging Biomarkers
- Amyloid PET (PiB, Florbetapir, Florbetaben): Visualizes plaque burden
- Florbetapir F-18 (Amyvid): FDA-approved for clinical use
- Amyloid load correlates poorly with cognition: Supports oligomer hypothesis
See also: [Amyloid-Beta 42/40 Ratio](/biomarkers/amyloid-beta-42-40-ratio), [Amyloid PET Imaging](/amyloid-pet-imaging), [p-tau217](/biomarkers/p-tau-217).
References
[Unknown, Hardy & Selkoe, The amyloid hypothesis of Alzheimer's disease (2002) (2002)](https://doi.org/10.1126/science.1072994)
[Unknown, O'Brien & Wong, Amyloid precursor protein processing and Alzheimer's disease (2011) (2011)](https://doi.org/10.1146/annurev-neuro-030514-124328)
[Lacor et al., Soluble oligomers of the amyloid beta-protein impair synaptic plasticity (2008) (2008)](https://doi.org/10.1093/brain/awn130)
[van Dyck et al., Lecanemab in Early Alzheimer's Disease (2023) (2023)](https://doi.org/10.1056/NEJMoa2212948)
[Unknown, Selkoe & Hardy, The amyloid hypothesis of Alzheimer's disease at 25 years (2016) (2016)](https://doi.org/10.1002/emmm.201210113)
[Unknown, Haass & Selkoe, Soluble protein oligomers in neurodegeneration (2007) (2007)](https://doi.org/10.1038/nrm2272)
[Bates et al., Aggregation of cytotoxic proteins in neurodegeneration (2019) (2019)](https://doi.org/10.1038/s41583-019-0158-9)
[Sanchez et al., Cryo-EM structures of Aβ42 fibrils from Alzheimer's disease brain (2021) (2021)](https://doi.org/10.1038/s41586-021-03796-4)
[Colvin et al., Correlative cryo-EM and NMR reveals Aβ42 polymorphism (2020) (2020)](https://doi.org/10.1016/j.neuron.2020.08.012)
[Shankar et al., Amyloid-beta protein dimers impair memory (2008) (2008)](https://doi.org/10.1073/pnas.0804173105)
[Wagner et al., Anle138b blocks Aβ oligomer formation (2019) (2019)](https://doi.org/10.1093/brain/awz085)
[Patterson et al., Lecanemab clearance and efficacy (2023) (2023)](https://doi.org/10.1038/s41591-023-02318-1)
[Simmons et al., Pyroglutamate-modified Aβ in AD (2020) (2020)](https://doi.org/10.1186/s40478-020-00947-0)
[Baker-Nigh et al., Neuronal Aβ42 accumulation in human brain (2015) (2015)](https://doi.org/10.1093/brain/awv331)
[Cline et al., Synaptic activity regulates Aβ production (2018) (2018)](https://doi.org/10.1016/j.neuron.2018.05.047)
[Palmqvist et al., Comparison of CSF and plasma Aβ42/40 ratio (2021) (2021)](https://doi.org/10.1001/jamaneurol.2021.3230)
[Jansen et al., Amyloid biomarkers in preclinical AD (2022) (2022)](https://doi.org/10.1038/s41591-022-01822-4)
[Scheltens et al., Alzheimer's disease (2021) (2021)](https://doi.org/10.1016/S0140-6736(20)
[Masters et al., Alzheimer's disease: global perspective (2019) (2019)](https://doi.org/10.1016/S0140-6736(19)
[Bateman et al., Clinical and biomarker changes (2019) (2019)](https://doi.org/10.1038/s41586-019-1665-6)
[Villemagne et al., Amyloid PET imaging in AD (2021) (2021)](https://doi.org/10.1016/j.jalz.2020.12.015)
[Unknown, Blennow & Zetterberg, Biomarkers for Alzheimer's disease (2023) (2023)](https://doi.org/10.1016/j.jalz.2023.01.003)