Tools
Amyloid Beta Peptide
Introduction
Amyloid-β peptide appears to play a central role in the pathology of Alzheimer disease. Sporadic Alzheimer disease is the most common cause of dementia, accounting for an estimated 50% to 56% of cases in clinical and autopsy series. The condition typically begins insidiously, with advancing age as the principal risk factor. Symptoms usually start with memory impairment and gradually involve other cognitive domains. Death often occurs within 10 years of diagnosis. A hereditary form, known as familial Alzheimer disease, represents approximately 2% to 3% of cases. This subtype tends to manifest earlier in life, typically before age 60, in contrast to the age-related onset seen in sporadic Alzheimer disease.[1][2][3]
Clinical Pathology
Register For Free And Read The Full Article
Search engine and full access to all medical articles- 10 free questions in your specialty
- Free CME/CE Activities
- Free daily question in your email
- Save favorite articles to your dashboard
- Emails offering discounts
Learn more about a Subscription to StatPearls Point-of-Care
Clinical Pathology
The 2 pathological hallmarks of Alzheimer disease are extracellular plaque deposits of amyloid-β peptide and flame-shaped neurofibrillary tangles composed of the microtubule-associated protein τ. The production and accumulation of amyloid-β peptide appear to play a central role in disease pathogenesis and form the foundation of the amyloid cascade hypothesis.[4][5] Amyloid plaques are readily identified on routine hematoxylin and eosin (H&E) staining. These extracellular deposits may be highlighted using amyloid-specific stains such as thioflavin-S or Congo red. Under polarized light, these structures exhibit the characteristic apple-green birefringence typical of amyloid proteins.[6]
Biochemical and Genetic Pathology
Amyloid-β peptide is a 42–amino acid fragment derived from amyloid-β precursor protein (APP), a transmembrane glycoprotein that spans the cell membrane once. The APP gene is located on chromosome 21. Sequential cleavage of APP by β- and γ-secretases generates amyloid-β peptides containing 40 or 42 amino acids, referred to as "amyloid-β 1–40" and "amyloid-β 1–42," respectively. β-secretase produces the N-terminal, while γ-secretase generates the peptide’s C-terminal.[7]
Amyloid-β 1–42, the primary pathogenic species, is highly hydrophobic and prone to aggregation into oligomers and fibrils. This hydrophobicity is largely attributed to amino acids located at the peptide’s C-terminal. The resulting fibrils adopt β-pleated sheet configurations and contribute to the formation of amyloid plaques detectable on H&E staining or with amyloid-specific dyes. Emerging evidence indicates that oligomers, rather than plaques, may represent the principal neurotoxic agents in Alzheimer disease pathogenesis.[8]
Several clinical and genetic findings support the amyloid cascade hypothesis. One of the earliest observations in early-onset Alzheimer disease identified a genetic link to the condition. Individuals with Down syndrome, who carry an extra copy of chromosome 21, produce excess APP. By age 30, most have developed amyloid plaques, and many exhibit clinical features of Alzheimer disease dementia in their 40s. These findings suggest a role for APP overexpression or aberrant processing in disease development.
Mutations in the APP gene, one of the first implicated in familial Alzheimer disease, account for approximately 10% to 15% of familial cases. Additional mutations affecting the catalytic subunits of the γ-secretase complex—an enzyme responsible for APP processing—have also been linked to familial Alzheimer disease.
Presenilin 1 and 2 are the subunits of this γ-secretase complex. A mutation in the presenilin 1 gene (PSEN1), located on chromosome 14, is the most common cause of familial Alzheimer disease and accounts for up to 80% of cases. This mutation is believed to promote the overproduction of amyloid-β 1–42 rather than amyloid-β 1–40. The presenilin 2 gene (PSEN2) is located on chromosome 1.[9][10]
Another well-established genetic risk factor supporting the amyloid cascade hypothesis is the apolipoprotein E (ApoE) polymorphism. The ApoE gene (APOE) encodes 3 major isoforms: ApoE2, ApoE3, and ApoE4. Among these isoforms, the ApoE4 allele (APOE4) is associated with an increased risk of sporadic Alzheimer disease compared to the general population. This risk is higher in individuals who are homozygous for APOE4 than in those who are heterozygous, indicating a dose-dependent effect. Studies have demonstrated a strong correlation between APOE4 carrier status and amyloid plaque burden in both patients with Alzheimer disease and cognitively normal individuals.
Among its functions, ApoE serves as a chaperone that facilitates amyloid plaque clearance. The ApoE4 isoform appears to be less effective in this role, thereby promoting amyloid-β deposition.[11][12]
Mechanisms
The normal function of amyloid-β peptide remains unclear. Although the human brain contains mechanisms to degrade this peptide, a portion may persist and cross the blood-brain barrier. Disruption or imbalance in these clearance pathways appears to contribute to peptide accumulation. Emerging evidence suggests that amyloid-β oligomers play a more critical role in Alzheimer disease pathogenesis than the plaques themselves. These oligomers are believed to impair synaptic function, disrupt neural networks, and promote neuronal death.[12][13]
Clinicopathologic Correlations
Although amyloid-β plaques are pathognomonic of Alzheimer disease, plaque burden and spatiotemporal distribution do not strongly correlate with disease severity. Total plaque burden may increase over time. However, this association remains inconsistent. In contrast, the distribution of τ neurofibrillary tangles follows a more predictable progression. Tangles first appear in the entorhinal cortex and hippocampus, then gradually extend to other brain regions. The primary motor, sensory, and visual cortices are typically affected in the final stages of Alzheimer disease.[14]
Clinical Significance
Amyloid plaque burden and spatial distribution can now be visualized through imaging. The Food and Drug Administration (FDA) has approved Pittsburgh Compound B, a radiotracer used in positron emission tomography (PET) scans, for Alzheimer disease diagnosis. This compound selectively binds to amyloid-β plaques with high affinity and specificity, allowing estimation of plaque burden and distribution. PET is now widely used in Alzheimer disease clinical trials and is becoming increasingly common in clinical diagnosis.[15]
Free amyloid-β peptide levels can also be measured in cerebrospinal fluid (CSF) and plasma. In clinical trials, low CSF amyloid-β levels, potentially reflecting impaired clearance, and elevated τ protein serve as key biomarkers of Alzheimer disease.[16]
Amyloid-β as a Therapeutic Target
Several clinical trials have investigated immunotherapy aimed at reducing amyloid plaque burden to slow disease progression. Most early trials failed to meet primary endpoints or were discontinued due to safety concerns. However, as of July 2024, the FDA has approved at least 2 anti-amyloid monoclonal antibodies—lecanemab and donanemab—for early-stage Alzheimer disease. These agents reduce plaque burden on amyloid PET imaging and may offer modest benefits in delaying cognitive decline.[17]
Treatment with these antibodies carries a risk of amyloid-related imaging abnormalities (ARIA), a common adverse effect that can lead to cerebral edema or microhemorrhages. Symptoms of ARIA include headache, dizziness, nausea, confusion, and visual disturbances. While ARIA often resolves spontaneously, clinically significant cases may require intervention. Routine magnetic resonance imaging is necessary to monitor for this condition during treatment.[18]
Teaching Points
The following key points highlight the molecular and clinical relevance of amyloid-β peptide in Alzheimer disease:
- APP undergoes proteolytic cleavage to generate amyloid-β peptide. An imbalance in the production and clearance of this peptide appears to lead to oligomer accumulation and plaque formation. Amyloid plaques are the histopathological hallmark of Alzheimer disease.[19][20]
- The APP gene, located on chromosome 21, encodes a transmembrane protein cleaved by β- and γ-secretases to release amyloid-β peptide. Mutations in the APP gene or those encoding the catalytic subunits of the γ-secretase complex, PSN1 and PSN2, cause familial Alzheimer disease. APP gene mutation was the first identified genetic cause, but mutation in PSN1 is the most common, accounting for up to 80% of familial cases.[21][22]
- Familial Alzheimer disease presents with early-onset dementia, typically before age 60, and follows an autosomal dominant inheritance pattern.[23]
- APOE4 carrier status significantly increases the risk of sporadic Alzheimer disease, with homozygous carriers at higher risk than heterozygotes.[24]
- In clinical trials, low CSF amyloid-β peptide and elevated CSF τ protein serve as core biomarkers of Alzheimer disease.[25]
- Imaging biomarkers such as Pittsburgh Compound B can bind amyloid plaques and are used in PET imaging to visualize plaque burden and distribution.[26]
- Amyloid-β peptide is a key therapeutic target, with at least 2 FDA-approved drugs, lecanemab and donanemab, now available for early Alzheimer disease.[27][28]
These points underscore the central role of amyloid-β peptide in the diagnosis, pathogenesis, and treatment of Alzheimer disease.
References
Honcharenko D, Juneja A, Roshan F, Maity J, Galán-Acosta L, Biverstål H, Hjorth E, Johansson J, Fisahn A, Nilsson L, Strömberg R. Amyloid-β Peptide Targeting Peptidomimetics for Prevention of Neurotoxicity. ACS chemical neuroscience. 2019 Mar 20:10(3):1462-1477. doi: 10.1021/acschemneuro.8b00485. Epub 2019 Feb 6 [PubMed PMID: 30673220]
Sadiki FZ, Idrissi ME, Cioanca O, Trifan A, Hancianu M, Hritcu L, Postu PA. Tetraclinis articulata essential oil mitigates cognitive deficits and brain oxidative stress in an Alzheimer's disease amyloidosis model. Phytomedicine : international journal of phytotherapy and phytopharmacology. 2019 Mar 15:56():57-63. doi: 10.1016/j.phymed.2018.10.032. Epub 2018 Oct 31 [PubMed PMID: 30668354]
Kowalski K, Mulak A. Brain-Gut-Microbiota Axis in Alzheimer's Disease. Journal of neurogastroenterology and motility. 2019 Jan 31:25(1):48-60. doi: 10.5056/jnm18087. Epub [PubMed PMID: 30646475]
Murphy MP, LeVine H 3rd. Alzheimer's disease and the amyloid-beta peptide. Journal of Alzheimer's disease : JAD. 2010:19(1):311-23. doi: 10.3233/JAD-2010-1221. Epub [PubMed PMID: 20061647]
Level 3 (low-level) evidenceMoloney CM, Lowe VJ, Murray ME. Visualization of neurofibrillary tangle maturity in Alzheimer's disease: A clinicopathologic perspective for biomarker research. Alzheimer's & dementia : the journal of the Alzheimer's Association. 2021 Sep:17(9):1554-1574. doi: 10.1002/alz.12321. Epub 2021 Apr 2 [PubMed PMID: 33797838]
Level 3 (low-level) evidenceShehabeldin A, Hussey C, Aggad R, Truong L. Increased Diagnostic Specificity of Congo Red Stain for Amyloid: The Potential Role of Texas Red-Filtered Fluorescence Microscopy. Archives of pathology & laboratory medicine. 2023 Aug 1:147(8):907-915. doi: 10.5858/arpa.2021-0512-OA. Epub [PubMed PMID: 36343375]
Tan JZA, Gleeson PA. The role of membrane trafficking in the processing of amyloid precursor protein and production of amyloid peptides in Alzheimer's disease. Biochimica et biophysica acta. Biomembranes. 2019 Apr 1:1861(4):697-712. doi: 10.1016/j.bbamem.2018.11.013. Epub 2019 Jan 11 [PubMed PMID: 30639513]
Saha P, Sen N. Tauopathy: A common mechanism for neurodegeneration and brain aging. Mechanisms of ageing and development. 2019 Mar:178():72-79. doi: 10.1016/j.mad.2019.01.007. Epub 2019 Jan 19 [PubMed PMID: 30668956]
Panza F, Lozupone M, Logroscino G, Imbimbo BP. A critical appraisal of amyloid-β-targeting therapies for Alzheimer disease. Nature reviews. Neurology. 2019 Feb:15(2):73-88. doi: 10.1038/s41582-018-0116-6. Epub [PubMed PMID: 30610216]
Carmona S, Hardy J, Guerreiro R. The genetic landscape of Alzheimer disease. Handbook of clinical neurology. 2018:148():395-408. doi: 10.1016/B978-0-444-64076-5.00026-0. Epub [PubMed PMID: 29478590]
Gratuze M, Leyns CEG, Holtzman DM. New insights into the role of TREM2 in Alzheimer's disease. Molecular neurodegeneration. 2018 Dec 20:13(1):66. doi: 10.1186/s13024-018-0298-9. Epub 2018 Dec 20 [PubMed PMID: 30572908]
Souza RMDCE, da Silva ICS, Delgado ABT, da Silva PHV, Costa VRX. Focused ultrasound and Alzheimer's disease A systematic review. Dementia & neuropsychologia. 2018 Oct-Dec:12(4):353-359. doi: 10.1590/1980-57642018dn12-040003. Epub [PubMed PMID: 30546844]
Level 1 (high-level) evidenceSolana C, Tarazona R, Solana R. Immunosenescence of Natural Killer Cells, Inflammation, and Alzheimer's Disease. International journal of Alzheimer's disease. 2018:2018():3128758. doi: 10.1155/2018/3128758. Epub 2018 Nov 1 [PubMed PMID: 30515321]
Morris GP, Clark IA, Vissel B. Questions concerning the role of amyloid-β in the definition, aetiology and diagnosis of Alzheimer's disease. Acta neuropathologica. 2018 Nov:136(5):663-689. doi: 10.1007/s00401-018-1918-8. Epub 2018 Oct 22 [PubMed PMID: 30349969]
Maschio C, Ni R. Amyloid and Tau Positron Emission Tomography Imaging in Alzheimer's Disease and Other Tauopathies. Frontiers in aging neuroscience. 2022:14():838034. doi: 10.3389/fnagi.2022.838034. Epub 2022 Apr 22 [PubMed PMID: 35527737]
Lehmann S, Dumurgier J, Ayrignac X, Marelli C, Alcolea D, Ormaechea JF, Thouvenot E, Delaby C, Hirtz C, Vialaret J, Ginestet N, Bouaziz-Amar E, Laplanche JL, Labauge P, Paquet C, Lleo A, Gabelle A, Alzheimer’s Disease Neuroimaging Initiative (ADNI). Cerebrospinal fluid A beta 1-40 peptides increase in Alzheimer's disease and are highly correlated with phospho-tau in control individuals. Alzheimer's research & therapy. 2020 Oct 2:12(1):123. doi: 10.1186/s13195-020-00696-1. Epub 2020 Oct 2 [PubMed PMID: 33008460]
Beshir SA, Hussain N, Menon VB, Al Haddad AHI, Al Zeer RAK, Elnour AA. Advancements and Challenges in Antiamyloid Therapy for Alzheimer's Disease: A Comprehensive Review. International journal of Alzheimer's disease. 2024:2024():2052142. doi: 10.1155/2024/2052142. Epub 2024 Jul 23 [PubMed PMID: 39081336]
Doran SJ, Sawyer RP. Risk factors in developing amyloid related imaging abnormalities (ARIA) and clinical implications. Frontiers in neuroscience. 2024:18():1326784. doi: 10.3389/fnins.2024.1326784. Epub 2024 Jan 19 [PubMed PMID: 38312931]
O'Brien RJ, Wong PC. Amyloid precursor protein processing and Alzheimer's disease. Annual review of neuroscience. 2011:34():185-204. doi: 10.1146/annurev-neuro-061010-113613. Epub [PubMed PMID: 21456963]
Zhang H, Ma Q, Zhang YW, Xu H. Proteolytic processing of Alzheimer's β-amyloid precursor protein. Journal of neurochemistry. 2012 Jan:120 Suppl 1(Suppl 1):9-21. doi: 10.1111/j.1471-4159.2011.07519.x. Epub 2011 Nov 28 [PubMed PMID: 22122372]
Liu Y, Xiao X, Liu H, Liao X, Zhou Y, Weng L, Zhou L, Liu X, Bi XY, Xu T, Zhu Y, Yang Q, Zhang S, Hao X, Zhang W, Wang J, Jiao B, Shen L. Clinical characteristics and genotype-phenotype correlation analysis of familial Alzheimer's disease patients with pathogenic/likely pathogenic amyloid protein precursor mutations. Frontiers in aging neuroscience. 2022:14():1013295. doi: 10.3389/fnagi.2022.1013295. Epub 2022 Oct 14 [PubMed PMID: 36313020]
Homanics GE, Park JE, Bailey L, Schaeffer DJ, Schaeffer L, He J, Li S, Zhang T, Haber A, Spruce C, Greenwood A, Murai T, Schultz L, Mongeau L, Ha SK, Oluoch J, Stein B, Choi SH, Huhe H, Thathiah A, Strick PL, Carter GW, Silva AC, Sukoff Rizzo SJ. Early molecular events of autosomal-dominant Alzheimer's disease in marmosets with PSEN1 mutations. Alzheimer's & dementia : the journal of the Alzheimer's Association. 2024 May:20(5):3455-3471. doi: 10.1002/alz.13806. Epub 2024 Apr 4 [PubMed PMID: 38574388]
Bateman RJ, Aisen PS, De Strooper B, Fox NC, Lemere CA, Ringman JM, Salloway S, Sperling RA, Windisch M, Xiong C. Autosomal-dominant Alzheimer's disease: a review and proposal for the prevention of Alzheimer's disease. Alzheimer's research & therapy. 2011 Jan 6:3(1):1. doi: 10.1186/alzrt59. Epub 2011 Jan 6 [PubMed PMID: 21211070]
Liu CC, Liu CC, Kanekiyo T, Xu H, Bu G. Apolipoprotein E and Alzheimer disease: risk, mechanisms and therapy. Nature reviews. Neurology. 2013 Feb:9(2):106-18. doi: 10.1038/nrneurol.2012.263. Epub 2013 Jan 8 [PubMed PMID: 23296339]
Galasko D, Chang L, Motter R, Clark CM, Kaye J, Knopman D, Thomas R, Kholodenko D, Schenk D, Lieberburg I, Miller B, Green R, Basherad R, Kertiles L, Boss MA, Seubert P. High cerebrospinal fluid tau and low amyloid beta42 levels in the clinical diagnosis of Alzheimer disease and relation to apolipoprotein E genotype. Archives of neurology. 1998 Jul:55(7):937-45 [PubMed PMID: 9678311]
Yamin G, Teplow DB. Pittsburgh Compound-B (PiB) binds amyloid β-protein protofibrils. Journal of neurochemistry. 2017 Jan:140(2):210-215. doi: 10.1111/jnc.13887. Epub 2016 Dec 12 [PubMed PMID: 27943341]
Lukiw WJ. Amyloid beta (Aβ) peptide modulators and other current treatment strategies for Alzheimer's disease (AD). Expert opinion on emerging drugs. 2012 Mar 23:():. doi: 10.1517/14728214.2012.672559. Epub 2012 Mar 23 [PubMed PMID: 22439907]
Level 3 (low-level) evidenceZhang Y, Chen H, Li R, Sterling K, Song W. Amyloid β-based therapy for Alzheimer's disease: challenges, successes and future. Signal transduction and targeted therapy. 2023 Jun 30:8(1):248. doi: 10.1038/s41392-023-01484-7. Epub 2023 Jun 30 [PubMed PMID: 37386015]