Alzheimer never suggested plaques and tangles were the cause of dementia. Indeed, this is what he wrote in 1911: “So scheint wirklich kein stichhaltiger Grund vorhanden, diese Falle als durch einen besonderen Krankheitzprozeβ verursacht zu betrachten” [1, p. 378]. “There is then no tenable reason to consider these cases as caused by a specific disease process” [2, p. 93].
Eleanor Drummond and colleagues [3] have catalogued the proteins in amyloid plaques and neurofibrillary tangles, which were localized in formalin-fixed paraffin-embedded (FFPE) brain samples by immunostaining, microdissected by laser capture, solublized with formic acid, deparaffinized, reduced, alkylated, proteinase digested, and analyzed by quantitative LC-MS. This unbiased and simultaneous quantification detected ~900 proteins in plaques and ~500 proteins in tangles.
Inherited dominant mutations in the APP, PS1, or PS2 gene cause Alzheimer dementia (AD) at the patient age of 19–55, at about the same age as their mother or father, and their mother or father developed dementia, the exact timing of onset being dictated by the gene and the particular mutation.These observations provide the best evidence for the amyloid hypothesis of AD, the ‘die-hard’ hypothesis that has almost singularly misguided AD research and drug development for 30 years.
According to the amyloid hypothesis, AD begins in the brain with Aβ peptides accumulation, aggregation, and amyloid formation. Yet, in clinical trial studies, reducing Aβ peptides production and brain amyloid did not slow cognitive decline or improve daily living of AD patients. Similarly, preventive trials in cognitively unimpaired people at high risk, or genetically destined, of developing AD have failed to slow cognitive decline. The results of these studies are against the amyloid hypothesis. The amyloid hypothesis is too good to be true [4], but is it “too big to fail” [5], as Rudy Castellani and Mark A. Smith said in 2011, or should we change our thinking about AD etiology, its origin and disease mechanisms [6].
Of course, a hypothesis can never been proven right, but it can be proven wrong. When Sun et al. [7] studied 138 pathogenic PS1 mutations on the in vitro production of the Aβ42 and Aβ40 peptides by γ-secretase, they could not find any correlation between the amount of Aβ peptides produced or the Aβ42/40 ratio and the age of onset of AD. Remarkably, one third of the PS1 mutations produced no Aβ peptides, and yet they can cause AD at different ages of onset. This observation agrees with a study in which inactivation of one PS1 gene in the adult mouse brain caused neurodegeneration and progressive memory loss [8].
Osaka mutation (E693Δ) deletes glutamate from position 693 in APP, position 22 in Aβ peptide, which enhances oligomerization while it reduces fibril formation. This unique property of the mutant (E22Δ) Aβ peptide is explained by its higher hydrophobicity resulting in faster oligomerization. This agrees with the observation that in familial AD caused by Osaka mutation, patients have very low levels of Aβ amyloid in the brain [9]. Not suprisingly, these cases of AD without amyloid are taken as an evidence for Aβ oligomers causing AD [10].
Naturally, of course, APP is more than the precursor protein for Aβ peptides, and Aβ peptides do much more than form amyloid [11], In addition, besides the γ-secretase, PS1 has other proteins to interact with, such as the glutamate transporter EAAT2 [12], and there are 149 substrates for PS1 [13].
1. Alzheimer A (1911) Über eigenartige Krankheitsfalle des spateren Alters. Z Gesamte Neurol Psychiat 4:356–385
2. Förstl H, Levy R (1991) On certain peculiar diseases of old age. Hist Psychiatry 2:74–99
3. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5811767/pdf/nihms940664.pdf
4. Kurkinen M (2017). The amyloid hypothesis is too good to be true. Alzheimer’s Dement Cogn Neurol 1, 1–9.
5. Castellani RJ, Smith MA (2011) Compounding artefacts with uncertainty, and an amyloid cascade hypothesis that is ‘too big to fail’. J Pathol 224, 147-152.
6. Kurkinen M et al. (2023) The amyloid cascade hypothesis in Alzheimer’s disease: Should we change our thinking? Biomolecule 13:453
7. Sun et al. (2017). Analysis of 138 pathogenic mutations in presenilin-1 on the in vitro production of Aβ42 and Aβ40 peptides by γ-secretase. Proc Natl Acad Sci USA 114, E476–E485.
8. Shen J, Kelleher RJ 3rd (2007) The presenilin hypothesis of Alzheimer’s disease: Evidence for a loss-of-function pathogenic mechanism. Proc Natl Acad Sci USA 104, 403–409.
9. Tomiyama T, Shimada H (2020) APP Osaka mutation in familial Alzheimer;s disease – its discovery, phenotypes, and mechanisms of recessive inheritance. Int J Mol Sci 21:1413
10. Ghosh S, Ali R, Verma S (2023) Aβ-oligomers: A potential therapeutic target for Alzheimer’s disease. Int J Biol Macromol 239:124231
11. Kurkinen M (2022). Astrocyte glutamate transporter EAAT2 in Alzheimer dementia. Glutamate and Neuropsychiatric Disorders—Current and Emerging Treatments; Pavlovic, Z.M., Ed.; Springer Nature: Berlin, Germany, pp. 229–260
12. Zoltowska et al. (2018) Novel interaction between Alzheimer’s disease-related protein presenilin 1 and glutamate transporter 1. Sci Rep 8, 8718.
13. Güner G, Lichtenthaler SF (2020) The substrate repertoire of γ-secretase/presenilin. Semi Cell Dev Biol 105, 27–42.
© Markku Kurkinen 6/17/2023