Up to 1.4 million people in Germany suffer from primary dementia, which is directly attributable to changes in the brain. Alzheimer's dementia is a special form of dementia—and one that is on the rise.  It is estimated that there will up to 3.3 million cases in Germany alone by 2050. Alzheimer's disease usually occurs in very old age. Women are affected more often than men because they live longer. One change that is observed in the brains of all those affected is the formation of extracellular beta-amyloid deposits (senile plaques) and intracellular neurofibrils. While short-term memory problems occur in the early stages, advanced stages lead to complete disorientation, bedriddenness, urinary and fecal incontinence, and for example, chewing, swallowing, and breathing problems. ⁽²⁾ No one wants to suffer from such a progressive loss of nerve cells in old age.

Alzheimer's disease is incurable. Researchers have now developed two antibodies—lecanemab and donanemab. Donanemab binds specifically to an insoluble form of β-amyloid and is designed to support the removal of amyloid plaques by enabling the brain's immune cells (microglia) to remove the construct via phagocytosis without causing microbleeds in the brain. It is not yet approved in Europe. Lecanemab was also approved in Europe on April 25. 

Animal experiments do not investigate the complex cascade
The antibodies were studied in mice. However, it should be noted that Alzheimer's mouse models only represent (and treat) amyloid plaque pathology, not the complex cascade that leads to the dramatic loss of nerve cells responsible for memory loss. Accordingly, only the symptoms of Alzheimer's can be treated. However, the effect is not as clear as hoped, the drugs are expensive, have side effects, and must be administered at a very early stage of the disease. Alzheimer's, however, is usually only diagnosed at a later stage. New treatment methods are therefore urgently needed.

However, despite decades of animal testing, the dreaded Alzheimer's disease in humans is still incurable, and it is recommended that research into new treatment methods using so-called NAMs (New Approach Methodologies) such as organ-on-chip methods or deep learning models be accelerated. 

Uncovering complex relationships with new methods  
A research team from Florida has succeeded in replicating important biological aspects of aging and senescence in a multicellular microphysiological system (MPS) respectively human-on-a-chip system. The model is suitable for facilitating drug screening and the development of Alzheimer's therapies. Furthermore, complex disease mechanisms can be uncovered, such as the role of inflammation in the development of Alzheimer's disease. The model is suitable for facilitating drug screening and the development of Alzheimer's therapies. In addition, complex disease mechanisms can be uncovered, such as the role of inflammatory factors in neuronal senescence. ⁽³⁾

Using mass spectrometry to analyze the proteome in the spinal fluid of Alzheimer's patients, a Dutch research team has discovered that there are five different subtypes of Alzheimer's disease. Understanding this heterogeneity is crucial for the development of Alzheimer's drugs. According to the authors, if the Alzheimer's subtypes are not taken into account, treatment methods could be partially ineffective or only effective to a limited extent. ⁽⁴⁾

Differentiated investigations can be carried out in vitro. For example: using an Alzheimer's cell culture model, an American research team discovered that the integrin αV/β5 receptor is the binding site for the “athlete” protein irisin: when the protein binds, neprilysin is released and can thus exert its effect. At the same time, irisin blocks interleukin-6/ERK signal transduction, increases secNEP release, and thus reduces STAT3 levels. The scientists have thus discovered a cellular and molecular mechanism through which irisin weakens amyloid-β pathology, which could offer a new approach for therapies to prevent and treat Alzheimer's disease. ⁽⁵⁾

Based on a patient study, an American-Swedish research team is convinced that dementia is not caused by increasing deposits of amyloid plaques in the brain, but rather by a decrease in the amount of soluble amyloid beta in the brain. ^{(6, 7)}

Sources:
⁽¹⁾ https://www.journalonko.de/news/deutschland-meist-gefuerchtete-krankheiten
⁽²⁾ https://www.journalmed.de/neurologie-psychiatrie/neurodegenerative-erkrankungen/alzheimer/alzheimer
⁽³⁾ Gallo LH, Akanda N, Autar K, et al. A functional aged human iPSC-cortical neuron model recapitulates Alzheimer's disease, senescence, and the response to therapeutics. Alzheimer's Dement. 2024; 1-21. https://doi.org/10.1002/alz.14044 
⁽⁴⁾ Tijms, B.M., Vromen, E.M., Mjaavatten, O. et al. Cerebrospinal fluid proteomics in patients with Alzheimer's disease reveals five molecular subtypes with distinct genetic risk profiles. Nat Aging (2024). https://doi.org/10.1038/s43587-023-00550-7
⁽⁵⁾ Kim E, Kim H, Jedrychowski MP, Bakiasi G, Park J, Kruskop J, Choi Y, Kwak SS, Quinti L, Kim DY, Wrann CD, Spiegelman BM, Tanzi RE, Choi SH. (2023). Irisin reduces amyloid-β by inducing the release of neprilysin from astrocytes following downregulation of ERK-STAT3 signaling. Neuron. Aug 30:S0896-6273(23)00623-2. doi: 10.1016/j.neuron.2023.08.012. Epub ahead of print. PMID: 37689059.
⁽⁶⁾ Sturchio A, Dwivedi AK, Malm T, Wood MJA, Cilia R, Sharma JS, Hill EJ, Schneider LS, Graff-Radford NR, Mori H, Nübling G, El Andaloussi S, Svenningsson P, Ezzat K, Espay AJ; Dominantly Inherited Alzheimer Consortia (DIAN). High Soluble Amyloid-β42 Predicts Normal Cognition in Amyloid-Positive Individuals with Alzheimer's Disease-Causing Mutations. J Alzheimers Dis. 2022 Sep 16. doi: 10.3233/JAD-220808. Epub ahead of print. PMID: 36120786.
⁽⁷⁾ Espay AJ, Sturchio A, Schneider LS, Ezzat K. Soluble Amyloid-β Consumption in Alzheimer's Disease. J Alzheimers Dis. 2021;82(4):1403-1415. doi: 10.3233/JAD-210415. PMID: 34151810