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Saturday, May 15, 2021

On the toxicity of beta-amyloid

Published concentrations of beta-amyloid in patients are all over the map. What does it all mean?

I n this article I will discuss the concentrations of beta-amyloid, or Aβ, in the scientific literature. It's an important topic because Aβ is thought to be a contributing factor in Alzheimer's disease, or AD. But the numbers are all over the map.

As the old saying goes, the dose makes the poison. This means that almost anything can be called a poison if its concentration is high enough. In the case of Aβ it means that if the concentration is too low, it would call into question the claim that Aβ toxicity is involved in AD. This is a question that came up while writing a research proposal, so I put together a table to clarify the question.

Basic facts

These facts are accepted by most AD researchers:

  1. Monomeric Aβ has minimal toxicity.

  2. Amyloid plaques, which is to say insoluble Aβ, don't correlate with disease, and most researchers believe they have minimal toxicity.

  3. Oligomers, or soluble clumps, are the most toxic. This is what people use in the lab to study Aβ.

  4. The most abundant forms are Aβ40 and Aβ42, which have 40 and 42 amino acids respectively. Both forms aggregate spontaneously, which means they will form oligomers in a test tube. Aβ42 aggregates faster than Aβ40, and Aβ42 is higher in AD. This is taken to mean that aggregation causes Aβ to become toxic. Many labs use ASPDs, which are oligomers made in a certain way that makes them a uniform size.

  5. Aβ40 has a molecular weight of 4329.9. Aβ42 has a molecular weight of 4514.1.

  6. Biochemical effects of oligomers and ASPDs start to be detectable at 10 nM[a]. Toxicity starts to happen at 100 nM, and 1000 nM (1μM) is always toxic to cultured cells. Concentration is reported in terms of Aβ monomer, so if 100 nM oligomer is used it means 100 nM equivalent of monomers. In other words, the oligomer is not considered to be a molecule.

  7. Aβ is expected in the extracellular space, where amyloid plaques are found. Some Aβ is produced intracellularly and some is produced on the cell surface and released. Some of the Aβ applied to cultured cells is taken up by the cells.

Here are the published in vivo concentrations.

Beta-amyloid concentrations

Aβ40 nM
Aβ42 nM
Aβ40 nM
Aβ42 nM
Species Strain Age Site
Bero et al. 1996 [1]
0.56 0.0254 Mice Tg2576 17 mo Piriform cortex
0.37 0.01 Mice Tg2576 17 mo Hippocampus
van Helmond et al. 2010 [2]*
4.1 * 5 * HumanHealthy<40yr Brain
4.0 * 8 * HumanHealthy40–60 Brain
1.5 * 35 * HumanHealthy>60yr Brain
3.0 * 160 * HumanAD Brain
van Helmond et al. 2009 [3] ¶
1.67* 28* HumanHealthy80 yr Frontal cortex
3.0* 156* HumanAD 76.9 yr Frontal cortex
Wang et al. 1999 [4]
0.5 0.5 2** 2** HumanHealthy Brain
4.4 11 661** 2100**HumanAD Brain
Lue et al. 1999 [5]
0.0004 0 0.18 1.8 HumanHealthy Entorhinal cortex
0.0147 0.0034 11.9 26 HumanAD Entorhinal cortex
0.0006 0 0.24 2.6 HumanHealthy Sup.frontal gyrus
0.023 0.0015 23.3 31.5 HumanAD Sup.frontal gyrus
Kuo et al. 1996 [6]
2 0.38 4.7 HumanHealthy Brain
21 4.53 716 HumanAD Brain
McLean et al. [7]
21† 453† HumanHealthy Brain
69† 4914† HumanAD Brain
Haugabook et al. 2000 [8]
45 ** 22** Mice Tg25761–5mo Brain
82 ** 35** Mice Tg25764–8.5mo Brain
Kawarabayashi et al. 2001 [9]
20 ** 10** Mice Tg25760–4mo Brain
1000** 700** Mice Tg257616–24mo Brain
Hellström-Lindahl et al. 2009 [10]
2.2 0.6 55 44 HumanHealthy Brain
66 1.5 886 310 HumanAD Brain
Fišar et al. 2021 [11]
0.0605 0.0089 HumanHealthy Blood plasma
0.0677 0.0109 HumanAD Blood plasma

Soluble includes monomeric + oligomeric; * total Aβ40 + 42; ¶ = estimated from published graph. **=total, mostly insol. . †=Aβ40 and 42 combined. Spor.AD = sporadic AD. Fam.AD = familial AD, type not specified

A number of things are evident in this table. First, insoluble Aβ is consistently elevated in AD patients. Second, in no case do the levels of soluble Aβ40 or Aβ42 approach the toxic range of 100 nM. Third, there is enormous variability in the results. I didn't put the standard deviations in the table, but in many cases the SD is higher than the actual number. Fourth, according to Fišar et al., blood plasma concentrations of Aβ40 and Aβ42 in AD patients are scarcely different from controls. That's important because many people have proposed using the 42/40 ratio in plasma as a biomarker.

There could be many reasons for the high variability: every lab seems to be using a different antibody. Criteria for soluble and insoluble may differ from lab to lab. Measuring soluble Aβ may be difficult because of its tendency to aggregate and become insoluble. And of course, there is great variability among patient samples, which may have been in different stages of the disease at their time of death and might even have been misdiagnosed. Post-mortem intervals and patient ages, which would affect the results, are not always stated in these papers.

But just looking at the first two columns there is a consistent finding: except in cases of familial AD (which are almost never measured separately), soluble Aβ does not reach levels needed for toxicity that we see in the lab.


Amyloid is a generic term; it doesn't necessarily mean β-amyloid. When people talk about amyloidosis in kidney and liver they usually mean AA amyloidosis caused by a buildup of serum amyloid A (SAA) in chronic inflammation, or Aβ2M amyloidosis caused by a buildup of β-2-microglobulin in end-stage renal disease, or AL or AH amyloidosis from immunoglobulin light or heavy chain in myeloma. There are about 24 different types of amyloidosis, all caused by proteins that are totally different from the β-amyloid that is found in Alzheimer's, which comes from amyloid precursor protein.

The symptoms are all different as well. The external symptoms of AL amyloidosis include easy bruising, fingernail dystrophy, enlarged / dented tongue, and “raccoon eyes” or periorbital ecchymoses. Aβ2M amyloidosis is typically first noticed when it causes carpal tunnel syndrome.

The similarity sounds compelling. But why don't the concentrations match up? One possibility is that intracellular concentrations from Aβ applied to cultured cells are different compared to naturally expressed Aβ. This is unlikely, since Aβ is readily imported and exported from neurons. Another possibility is that the human brain is more sensitive to Aβ than cultured neurons, or that exposure for low concentrations over a long time causes a cumulative effect. This seems unlikely too, because of the brain's elaborate self-defense mechanisms. Another unlikely possibility is that some as-yet unknown target, not seen in cultured cells, is insanely sensitive to β-amyloid.

But that may be the clue: those elaborate self-defense mechanisms may be what's causing the disease. Maybe, for example, β-amyloid is merely a protective response or an effect of neuro­inflam­mation. If so, then lab measurements of toxicity are invalid unless experiments are done with the defense mechanisms in place, that is with neurons, astrocytes, microglia, and who knows what else.

The idea is naturally disquieting: people don't want to believe they spent thirty years barking up the wrong tree. But now that it's increasingly evident from clinical trials that eliminating β-amyloid from the brain has no effect on the disease, more and more researchers are considering the possibility that β-amyloid might not be the cause of AD after all.

[a] A nM means one nanomole per liter. For Aβ42, that is equivalent to 4.514 millionths of a gram (μg) per liter, or about six millionths of a gram in the entire brain. A toxic level is 100 times this, or about 600 μg or 0.6 milligrams of Aβ42 in the brain. That is about the same as 1/135 of a baby aspirin, which weighs 81 milligrams.

1 Bero AW, Yan P, Roh JH, Cirrito JR, Stewart FR, Raichle ME, Lee JM, Holtzman DM. Neuronal activity regulates the regional vulnerability to amyloid-beta deposition. Nat Neurosci. 2011 Jun;14(6):750–756. doi: 10.1038/nn.2801. PMID: 21532579; PMCID: PMC3102784.

2 van Helmond Z, Heesom K, Love S. Characterisation of two antibodies to oligomeric Abeta and their use in ELISAs on human brain tissue homogenates. J Neurosci Methods. 2009 Jan 30;176(2):206–212. doi: 10.1016/j.jneumeth.2008.09.002. PMID: 18824027.

3 van Helmond Z, Miners JS, Kehoe PG, Love S. Oligomeric Abeta in Alzheimer's disease: relationship to plaque and tangle pathology, APOE genotype and cerebral amyloid angiopathy. Brain Pathol. 2010 Mar;20(2):468–480. doi: 10.1111/j.1750-3639.2009.00321.x. PMID: 19725829.

4 Wang J, Dickson DW, Trojanowski JQ, Lee VM. The levels of soluble versus insoluble brain Abeta distinguish Alzheimer's disease from normal and pathologic aging. Exp Neurol. 1999 Aug;158(2):328–337. doi: 10.1006/exnr.1999.7085. PMID: 10415140.

5 Lue LF, Kuo YM, Roher AE, Brachova L, Shen Y, Sue L, Beach T, Kurth JH, Rydel RE, Rogers J. Soluble amyloid beta peptide concentration as a predictor of synaptic change in Alzheimer's disease. Am J Pathol. 1999 Sep;155(3):853–862. doi: 10.1016/s0002-9440(10)65184-x. PMID: 10487842; PMCID: PMC1866907.

6 Kuo YM, Emmerling MR, Vigo-Pelfrey C, Kasunic TC, Kirkpatrick JB, Murdoch GH, Ball MJ, Roher AE. Water-soluble Abeta (N-40, N-42) oligomers in normal and Alzheimer disease brains. J Biol Chem. 1996;271(8):4077–4081. Epub 1996/02/23. doi: 10.1074/jbc.271.8.4077. PMID: 8626743.

7 McLean CA, Cherny RA, Fraser FW, Fuller SJ, Smith MJ, Beyreuther K, Bush AI, Masters CL. Soluble pool of Abeta amyloid as a determinant of severity of neurodegeneration in Alzheimer's disease. Ann Neurol. 1999 Dec;46(6):860–866. doi: 10.1002/1531-8249(199912)46:6<860::aid-ana8>3.0.co;2-m. PMID: 10589538.

8 Haugabook SJ, Le T, Yager D, Zenk B, Healy BM, Eckman EA, Prada C, Younkin L, Murphy P, Pinnix I, Onstead L, Sambamurti K, Golde TE, Dickson D, Younkin SG, Eckman CB. Reduction of Abeta accumulation in the Tg2576 animal model of Alzheimer's disease after oral administration of the phosphatidyl-inositol kinase inhibitor wortmannin. FASEB J. 2001 Jan;15(1):16–18. doi: 10.1096/fj.00-0528fje. PMID: 11099491.

9 Kawarabayashi T, Younkin LH, Saido TC, Shoji M, Ashe KH, Younkin SG. Age-dependent changes in brain, CSF, and plasma amyloid (beta) protein in the Tg2576 transgenic mouse model of Alzheimer's disease. J Neurosci. 2001 Jan 15;21(2):372–381. doi: 10.1523/JNEUROSCI.21-02-00372.2001. PMID: 11160418; PMCID: PMC6763819.

10 Hellström-Lindahl E, Viitanen M, Marutle A. Comparison of Abeta levels in the brain of familial and sporadic Alzheimer's disease. Neurochem Int. 2009 Sep;55(4):243–252. doi: 10.1016/j.neuint.2009.03.007. PMID: 19524115; PMCID: PMC2919843.

11 Fišar Z, Jirák R, Zvěřová M, Setnička V, Habartová L, Hroudová J, Vaníčková Z, Raboch J. Plasma amyloid beta levels and platelet mitochondrial respiration in patients with Alzheimer's disease. Clin Biochem. 2019;72:71–80. doi: 10.1016/j.clinbiochem.2019.04.003. PubMed PMID: 30954436.

may 15 2021, 8:36 am

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