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. Author manuscript; available in PMC: 2020 Jul 2.
Published in final edited form as: Ann Integr Mol Med. 2020;2(1):90–114. doi: 10.33597/aimm.02-1007

Figure 5: Dynamics of Alzheimer’s disease in two paradigms.

Figure 5:

Left panels: Dynamics of Aβ production; Right panels: Dynamics of neurodegeneration. Blue lines: Levels of beta-amyloid; Red lines: Extent of neurodegeneration; Black lines: Indicator lines, no significant neurodegeneration; Red blocks: Manifestation of Alzheimer’s disease. T: Threshold of symptomatic manifestation of AD (reflects levels of Aβ and consequent extent of neurodegeneration); T1: Threshold of activation of RNA-dependent βAPP mRNA amplification (reflects not only Aβ levels but also the extent of Aβ−coupled mitochondrial dysfunction and related stresses, possibly including ER stress); Numerous genetic factors such as, for example, the occurrence of various alleles of ApoE gene, as well as certain epigenetic factors, influence the age when thresholds T and T1 are reached, hence, the fanning lines. T2: Threshold of symptomatic occurrence of AD (reflects levels of Aβ and consequent extent of neurodegeneration). Panels A, B: View of the dynamics of AD prevailing until now (A: Dynamics of SAD; B: Dynamics of FAD). Levels of Aβ increase, neurodegeneration starts early and accumulates throughout the life. When threshold T is reached, AD symptoms manifest. Panels C, D: The outlook on the dynamics of Alzheimer’s disease envisioned in the present study (C: Dynamics of SAD; D: Dynamics of FAD). Levels of Aβ increase, the extent of mitochondrial dysfunction and related stresses reach threshold T1 and RNA-dependent βAPP mRNA amplification is activated. There is no significant neurodegeneration until after a lag period (when amplified RNA encoding C99 fragment of βAPP accrues and Aβ further accumulates) following the crossing of T1 threshold and activation of βAPP mRNA amplification; when the extent of neurodegeneration reaches threshold T2, AD symptoms manifest. Panel E: Dynamics of Aβ production and neurodegeneration in non-human mammals in light of the present study: T1 threshold is crossed but βAPPP mRNA is not amplified because it is not eligible for RNA-dependent amplification process. There is no significant neurodegeneration; T2 threshold is not reached, no AD symptoms manifest, no disease occurs. Note: Scenario depicted in panel (E) would occur in humans not susceptible to Alzheimer’s disease due to variations in βAPP TSSs utilization or when activation of βAPP mRNA amplification is blocked by therapeutic intervention.