Fig. 2.

Mechanisms in “normal” aging, AD and NDAN. Organ level: Shrinkage of grey matter in frontal and parietal volume over time in normal aging. Overall grey matter volume shrinks in AD but increases in NDAN brain. In NDAN the cingulate gyrus is thicker, and the hippocampus is spared, or increased in some cases. Neurons: Neurogenesis is decreased, and brain plasticity is increased in normal aging. In AD, NSCs proliferate less in the subventricular zone and hippocampus and VEN cells degenerate. NSC proliferation in the hippocampus of NDAN brain is increased, as well as VEN density. Inflammation: Microglia and astrocyte response to pro-inflammatory cytokines is increased in normal aging hippocampus. Microglia and astrocytes become more (re)active in AD, due to increased levels of pro-inflammatory cytokines (IL-1, IL-6, and TNF-α). Glial activation is decreased in superior temporal sulcus of NDAN, as anti-inflammatory cytokines (IL-4 and IL-10) are increased. Aβ: The molecular composition of Aβ molecules in normal aging is different than in AD and not distributed to specific areas. In AD, Aβ oligomers bind to synapses and induce synaptotoxicity. In NDAN, postsynaptic binding of Aβ oligomers is prevented by neuromodulators (Zn²⁺ [230] and Reelin [232]), Insulin [235] and specific APP miRNAs [182]. Tau: NFT distribution in normal aging is restricted to specific areas: entorhinal cortex, olfactory nucleus, and parahippocampal gyrus [49]. NFT levels in these areas are elevated in AD and also spread to the neocortex. In NDAN, NFT formation is inhibited in the temporal cortex, due to lower 0N3R expression [236]. A proposed mechanism for NDAN is to investigate the composition and location of different tau species.