A decisive factor in the progression of AD and the development of manifest cognitive disorders is the functional failure of the Tau protein due to its hyperphosphorylation at different sites of the molecule (e.g. p-tau 181 or p-tau 217). As mentioned at various points in the updates here, this change in the phosphorylation pattern of the Tau molecule is a process that is apparently modified or even initiated by lifestyle over time.
Tau regulation takes place during sleep, see above under The role of sleep & EEG and there (Holth & Fritschi, 2019). Irregularities in sleep caused by tau regulation in AD can be measured by EEG. An early AI-based prediction of AD is highly probable by EEG together with the new blood tests currently being developed in the Swedish BIOFINDER study, the reliability of which has been validated, which allow a differentiated detection of phosphorylations of the tau protein in Alzheimer's patients, see (Janelidze, 2020) and (Palmqvist, 2020), and by detecting this harbinger of later possible Alzheimer's dementia, a very early diagnosis and prognosis with an appropriate therapy, e.g. Gamma Entrainment, is possible.
References:
- Janelidze, S., Mattson, N., Palmqvist, S., Smith, R., Beach, Th.G., Serrano, G.E., Chai, X., Proctor, N.K., Eichenlaub, U., Zetterberg, H., Blennow, K., Reiman, E.M., Stomrud, E., Dage, J.L., Hansson, O., (2020), Plasma P-tau181 in Alzheimer’s disease: relationship to other biomarkers, differential diagnosis, neuropathology and longitudinal progression to Alzheimer’s dementia. Nature Medicine, https://www.nature.com/articles/s41591-020-0755-1
The sense of smell is the first sense that is lost in the course of the disease with Alzheimer's. Directly linked to this is the activity of so-called “grid cells”. The grid cells (https://en.wikipedia.org/wiki/Grid_cell) are located in the ERC, the entorhinal cortex (https://en.wikipedia.org/wiki/Entorhinal_cortex) and enable orientation in space. It is therefore not surprising that after the loss of the sense of smell in AD patients, the sense of orientation is the next to be lost.
As an early indicator of AD, even before the onset of initial cognitive deficits, a well-founded olfactory test is excellently suited, as used by Devanand et al.(2019) in a long cohort study (over 1000 participants) with 2 follow-ups (almost 800 participants) and examined for its predictive power with regard to the future occurrence of AD.
The B-SIT test used (12 odours, 5 min duration in total), a subset of UPSIT (https://en.wikipedia.org/wiki/University_of_Pennsylvania_Smell_Identification_Test), is inexpensive and would, according to Devanand (2019), if a memory test were also carried out with an intact sense of smell and acceptable memory, indicate the probability of a transition to AD in the next 4 years with only 3.4%. The current study showed that B-SIT in combination with a (simple, short) memory test was able to rule out the transition to AD for 96.6% of the subjects in the next 4 years due to its multimodality. It is assumed in Devanand (2019) that improved neuropsychological tests will be able to further improve this result. Of course, the personal context must be taken into account: history, nasal diseases, exposure to toxic substances, including smoking. Vasavada et al (2017) showed that the loss of the sense of smell is not caused by a deficit of the olfactory sensors but by the central olfactory system.
In the course of an extended literature search in QI 2020, the aim is to find out what other possibilities there are for using olfactory sense testing to predict AD as early as the preclinical stage.
References:
- Devanand D.P., Lee S., Luchsinger J.A., Andrews H., Goldberg T., Huey E.D., Schupf N., Manley J., Stern Y., Kreisl W.C., Mayeux R. (2019). Intact global cognitive and olfactory ability predicts lack of transition to dementia. Alzheimer’s & Dementia - (2019) 1-9. Elsevier Inc. https://doi.org/10.1016/j.jalz.2019.08.200
- Vasavada M.M., Martinez B., Wang J., Eslinger P.J., Gill D.J., Sun X., Karunanayaka P., Yang Q.X. (2017). Central Olfactory Dysfunction in Alzheimer´s Disease and Mild Cognitive Impairment: A Functional MRI Study. Journal of Alzheimer’s Disease 59 (2017) 359–368. DOI 10.3233/JAD-170310. IOS Press.
The re-analysis of data from a Phase 3 study, in which the active substance aducanumab (antibody against aggregated amyloid-β) had previously had to be declared clinically ineffective (due to different results in two double-blind partial studies), showed in October 2019 that aducanumab could after all lead to an improvement in clinical symptoms. This was achieved by a higher dosage of the active substance and a longer period of administration.
At the beginning of 2020, the developers (Biogen) now intend to submit an application for approval of the drug to the US Food and Drug Administration (FDA). It is hoped that the drug will already be effective during the development of Alzheimer's disease, thereby slowing down the disease process. The slowing of the loss of memory, orientation and speech in Alzheimer's patients has now been shown in the second analysis of data from a phase 3 study.
This news is relevant for the project, because the earliest possible diagnosis, which we want to achieve in the IASON project, will become very important if the drug really does lead to success in slowing down the loss of brain function on a large scale. A diagnosis as early as possible is essential in order to intervene as early as possible in the course of the disease, before there is irreversible damage.
Reference:
Update: for the current status of the approval of Aducanumab see https://www.alzheimer-forschung.de/forschung/aktuell/aducanumab/.
- Written by Dr. Thomas Fritsch und Lenka Wichmann
A previously unknown functional link between amyloid-β and (p-)tau, proteins that both play a major role in the development of Alzheimer's disease, has been demonstrated by a team led by Ising, Heneka et al (2019) in the scientific journal Nature.
In a healthy state, tau proteins are stabilizers for the skeleton of nerve cells. In the development of Alzheimer's disease, these proteins detach from the skeleton and clump together in the nerve cells, so that they can no longer fulfill their actual function of stabilization.
Ising et al (2019) report that they have discovered a “molecular switch” that provides more information about the point in time when the tau proteins begin to change (phosphorylate) and thus detach from the skeleton and clump together. This happens when the molecular switch (consisting of the protein complex NLRP3 inflammasome, which exists within immune cells of the brain) triggers the release of pro-inflammatory substances and causes hyperphosphorylation of tau proteins. The hyperphosphorylation then leads to the detachment of tau proteins from the nerve skeleton and to their aggregation (neurofibrillary tangles).
The study also showed that amyloid-β, which is deposited between nerve cells over years and long before a diagnosis of Alzheimer's disease, activates the molecular switch (NLRP3 inflammasome), which promotes further amyloid-β deposition and leads to the aggregation of Tau. This is new evidence for the currently most popular model “amyloid cascade hypothesis” for the development of Alzheimer's disease.
This publication is relevant to the IASON project as it provides information on the temporal development of Alzheimer's disease. The aim would therefore be to determine the “switching point” by early diagnosis via EEG in order to be able to intervene.
Update: Tau deposition even without previous amyloid-β
Kant & Ossenkoppele have shown that the development of manifest Alzheimer's dementia is not only caused by the deterministic sequence of amyloid-β accumulation with subsequent formation of p-tau, which is predominant in genetic disposition, but also by AD progression with p-tau accumulation independent of amyloid-β. Reference to the different paths of p-tau progression in AD, which Ossenkoppele writes about. The renowned researcher H. Braak has already established in 2011 that tau deposition can also occur in young people without prior amyloid-β agglomeration, see (Braak, 2011):
"In this sample under the age of 30, 41/42 cases did not have amyloid-b plaques or neuritic plaques (Table 1) The absence of amyloid-b deposition in these individuals is not compatible with the amyloid cascade hypothesis, which assumes that amyloid-b drives AD pathogenesis and secondarily induces intraneuronal tau changes “downstream”".
Here we would like to point out the update of the following point "The role of sleep & EEG", where it is shown that already one night of sleep deprivation at any age leads to an increase of the total tau level in the blood.
Reference:
- Ising, C., Venegas, C., Zhang, S., Scheiblich, H., Schmidt, S. V., … & Heneka, M. T. (2019). NLRP3 inflammasome activation drives tau pathology. Nature 575, 669–673. https://doi.org/10.1038/s41586-019-1769-z
- Kant, R.v.d., Goldstein, R. S. B., Ossenkoppele, R. (2020). Amyloid-β-independent regulators of tau pathology in Alzheimer disease. Nature reviews, Neuroscience, Vol. 21. https://www.nature.com/articles/s41583-019-0240-3
- Braak, H., Tredici, K. d., (2011). The pathological process underlying Alzheimer’s disease in individuals under thirty. Acta Neuropathol (2011) 121:171–181. https://doi.org/10.1007/s00401-010-0789-4
- Written by Dr. Thomas Fritsch und Lenka Wichmann
Sleep plays an important role in the consolidation of memories and the removal of amyloid-β deposits via the so-called glymphathic system (GLS, see https://en.wikipedia.org/wiki/Glymphatic_system). It has now been shown by Fultz et al. (2019) that neuronal oscillations, which can be measured with the EEG, cause fluctuations in blood flow, which also set the cerebral fluid in motion. The resulting fluctuating movements of the cerebral fluid are part of the glymphatic system and cleanse the brain of deposits (e.g. amyloid-β) during sleep. Thus, a connection between EEG oscillations during sleep and the activity of the glymphathic system could be shown.
Winer et al (2019) and Lucey et al (2019) also showed that certain properties of EEG oscillations in deep sleep correlated with common Alzheimer's biomarkers (less slow oscillations in deep sleep are correlated with amyloid-β, while a weak “coupling” between slow oscillations and so-called sleep spindles is correlated with tau proteins, see Holth & Fritschi et al. (2019), and that the sleep EEG itself could be used as a biomarker in Alzheimer's disease thus.
This means that certain changes in the sleep EEG (especially in deep sleep) can reveal changes in the function of the glymphatic system. When the GLS is impaired, an increased deposition of amyloid-β takes place, which can lead to Alzheimer's disease in the long term. On the other hand, deposition of amyloid-β and tau can also lead to sleep problems, creating a vicious circle in which poorer sleep and deposition of amyloid-β and tau have a negative influence on each other and promote the development of Alzheimer's disease.
However, these findings could also lead to new treatment options. The teams around Rasch and Born al., see Muehlroth & Rasch et al. (2019) and Ngo & Born et al. (2019) showed an improved consolidation of memories by specifically influencing the subjects in different sleep phases (by cueing with odours, for example) and were able to show a balance of sleep spindles and “slow-wave-oscillations” (SWO).
For the IASON project, this research opens up undreamed-of possibilities. There is now also great interest in the sleep EEG for early diagnosis of Alzheimer's disease. A further research application should be submitted for this, if necessary, as EEG sleep measurements would exceed the resources of the IASON project in terms of time and money.
Update: In support of the above statements by Kant & Ossenkoppele, a recent Swedish study (Ärzteblatt, 2020) showed that even one sleepless night in adolescents causes a significant increase in the total tau level in the blood, see (Benedict, 2020). The consequences of this for the shaping of lifestyle, but also for sleep disturbing diseases such as sleep apnea and depression still need to be clarified in future studies. However, the results of the study may already give an indication of the different pathways of p-tau progression in AD, which Ossenkoppele writes about.
References:
- Fultz, N. E., Bonmassar, G., Setsompop, K., Stickgold, R. A., Rosen, B. R., Polimeni, J. R., & Lewis, L. D. (2019). Coupled electrophysiological, hemodynamic, and cerebrospinal fluid oscillations in human sleep. Science, 366(6465), 628–631. https://doi.org/10.1126/science.aax5440
- Winer, J. R., Mander, B. A., Helfrich, R. F., Maass, A., Harrison, T. M., Baker, S. L., Knight, R. T., Jagust, W. J., & Walker, M. P. (2019). Sleep as a potential biomarker of tau and β-amyloid burden in the human brain. The Journal of Neuroscience, 39(32), 6315–6324. https://doi.org/10.1523/JNEUROSCI.0503-19.2019
- Holth J. K., Fritschi S.K., Wang C., Pedersen N.P., Cirrito J.R., Mahan Th. E., Finn M.B., Manis M., Geerling J.C., Fuller P.M., Lucey B.P., Holtzman D.M. (2019). The sleep-wake cycle regulates brain interstitial fluid tau in mice and CSF tau in humans. Science 363 (6429), 880-884. DOI: 10.1126/science.aav2546 originally published online January 24, 2019. https://science.sciencemag.org/content/363/6429/880
- Muehlroth B.E., Sander M.C., Fandakova Y., Grandy Th. H., Rasch B., Shing Y.-L., Werkle-Bergner M. (2019). Precise slow oscillation–spindle Coupling promotes Memory Consolidation in Younger and older Adults. Scientific Reports (2019) 9:1940. https://doi.org/10.1038/s41598-018-36557-z. www.nature.com/scientificreports
- Ngo H.-V. V., Born J. (2019). Sleep and the Balance between Memory and Forgetting. Cell 179, October 3, 2019. Elsevier Inc. p. 289-291. https://doi.org/10.1016/j.cell.2019.09.007
- Lucey, B., McCullough, A., Landsness, E. C., Toedebusch, C. D., McLeland, J. S., … Holtzman, D. M. (2019). Reduced non-rapid eye movement sleep is associated with tau pathology in early Alzheimer’s disease.Science Translational Medicine, 11(474), doi: https://doi.org/10.1126/scitranslmed.aau6550
- Benedict, C., Blennow, K., Zetterberg, H., Cedernaes, J. (2020). Effects of acute sleep loss on diurnal plasma dynamics of CNS health biomarkers in young men. Neurology, https://n.neurology.org/content/94/11/e1181
There were also new findings with regard to innovative treatment methods for Alzheimer's disease. Research by Iaccarino & Singer et al. (2016), Adaikkan et al. (2019a) and Martorell et al. (2019) from MIT have found a method that could reduce the aggregation of amyloid-β and tau-phosphorylation and thus improve memory. For this purpose, brain waves in the gamma frequency, which are very important in the waking state, are stimulated to synchronize by visual (light flickering at 40 Hz) and auditory (sound waves oscillating at 40 Hz) stimuli. The method has been successfully tested on AD mouse and AD rat models and must now be investigated in humans in the next step. It is particularly remarkable that it could be observed that the immune cells of the brain, the so-called microglia, morphologically changed under the influence of the 40 Hz gamma stimulation and grouped around the amyloid-β as well as neurofibrillary tau-tangles and dissolved them. The rats treated in this way were able to navigate again and “remember” the neural maps stored in their place cells for paths to food and out of labyrinths. This requires revitalisation of their sense of smell. Adaikkan (2019b) speaks of the enormous therapeutic possibilities of the procedure.
For the IASON project, this research is of high relevance as it underlines the importance of brain waves and thus the EEG as a combined diagnostic and treatment tool. This potential combination will be explained in separate communication with the project sponsor. An in-depth literature study is planned for the QI of the 2020 reporting period.
References:
- Adaikkan, C., Middleton, S. J., Marco, A., Pao, P. C., Mathys, H., Kim, D. N., Gao, F., Young, J. Z., Suk, H. J., Boyden, E. S., McHugh, T. J., Tsai, L.-H. (2019a). Gamma entrainment binds higher-order brain regions and offers neuroprotection.Neuron, 102(5), 929-943. doi: https://doi.org/10.1016/j.neuron.2019.04.011
- Martorell, A. J., Paulson, A. L., Suk, H. J., Abdurrob, F., Drummond, G. T., Guan, W., Young, J. Z., Kim, D. N., Kriskiy, O., Barker, S. J., Mangena, V., Prince, S. M., Brown, E. N., Chung, K., Boyden, E. S., Singer, A. C., & Tsai, L. H. (2019). Multi-sensory gamma stimulation ameliorates Alzheimer’s-associated pathology and imrpoves cognition. Cell, 177(2), 256-271. doi: https://doi.org/10.1016/j.cell.2019.02.014
- Iaccarino H.F., Singer A.C., Martorell A. J., Rudenko A., Gao F., Gillingham T.Z., Mathys H., Seo J., Kritskiy O., Abdurrob F., Adaikkan C., Canter R.G., Rueda R. , Brown E. N., Boyden E.S., Tsai L.H. (2016). Gamma frequency entrainment attenuates amyloid load and modifies microglia. Nature. 2016 December 07; 540(7632): 230–235. doi: https://doi.org/10.1038/nature20587.
- Adaikkan C., Tsai L.H. (2019b). Gamma Entrainment: Impact on Neurocircuits, Glia, and Therapeutic Opportunities. Trends in Neurosciences. (2019) https://doi.org/10.1016/j.tins.2019.11.001
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