data published by Braak and colleagues. Based on their analysis of postmortem human brains in the age range of 1–100 years, they reported that tau-related neuronal changes appear first in the locus coeruleus, a crucial brain stem nucleus implicated in stress response regulation. The following area to be affected with increasing age is the transentorhinal cortex with its axonal projections from Reelin-expressing cells located in the olfactory bulb. The reduction of Reelin, as a consequence of cumulative environmental injury/disease/infection-induced chronic inflammation [1], accelerates the age-dependent phosphorylation of tau and the instability of interneuronal connections. This will in turn result in a more pronounced synaptic loss and wide-spread formation of neurofibrillary tangles, a correlate of disease progression and dementia severity in patients with AD. Further, reduced Reelinmediated signaling will lead to impairments in NMDAtype of glutamate receptor modulation that might initially affect olfactory information processing, followed by hippocampus-dependent cognitive dysfunctions. In parallel, chronic neuroinflammatory processes presumably provoke axonal stress in long projection neurons, leading to the formation of amyloid plaques and neurofibrillary tangles in cortical association areas, and might, in addition, impair the innate immune system of the brain to adequately support the vulnerable neurons. In addition, ApoE4 potently competes with Reelin for receptor binding and affects its downstream signaling and function. This view positions Reelin and its signaling members in the aging brain as a protective factor against cognitive decline. Accordingly, the reduction in Reelin may shift the balance from healthy to pathological aging. In conclusion, the distinct pathology in the limbicolfactory brain areas and its consistent progression along interconnected neurons as the disease advances has recently received much attention. Here, we highlight the importance of the Reelin-mediated signaling pathway that is maintained in the adult brain and instrumental to modulate synaptic functions and protect neuronal connectivity and integrity. Inflammation/injury-induced dysfunctions of this crucial neurodevelopmental program may indeed underlie the apparent “spread” of the neuropathology across brain networks in patients diagnosed with AD.