TY  - JOUR
AU  - Simons, Mikael
AU  - Levin, Johannes
AU  - Dichgans, Martin
TI  - Tipping points in neurodegeneration.
JO  - Neuron
VL  - 111
IS  - 19
SN  - 0896-6273
CY  - New York, NY
PB  - Elsevier
M1  - DZNE-2023-01024
SP  - 2954 - 2968
PY  - 2023
AB  - In Alzheimer's disease (AD), Aβ deposits form slowly, several decades before further pathological events trigger neurodegeneration and dementia. However, a substantial proportion of affected individuals remains non-demented despite AD pathology, raising questions about the underlying factors that determine the transition to clinical disease. Here, we emphasize the critical function of resilience and resistance factors, which we extend beyond the concept of cognitive reserve to include the glial, immune, and vascular system. We review the evidence and use the metaphor of 'tipping points' to illustrate how gradually forming AD neuropathology in the preclinical stage can transition to dementia once adaptive functions of the glial, immune, and vascular system are lost and self-reinforcing pathological cascades are unleashed. Thus, we propose an expanded framework for pathomechanistic research that focuses on tipping points and non-neuronal resilience mechanisms, which may represent previously untapped therapeutic targets in preclinical AD.
KW  - Humans
KW  - Alzheimer Disease: pathology
KW  - Neuroglia: pathology
KW  - Amyloid beta-Peptides
KW  - Alzheimer's disease (Other)
KW  - glia (Other)
KW  - inflammation (Other)
KW  - neurodegeneration (Other)
KW  - vasculature (Other)
KW  - Amyloid beta-Peptides (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:37385247
DO  - DOI:10.1016/j.neuron.2023.05.031
UR  - https://pub.dzne.de/record/265749
ER  -