Stages of the Pathologic Process in Alzheimer Disease: Age Categories From 1 to 100 Years

Abstract

Two thousand three hundred and thirty two nonselected brains from 1- to 100-year-old individuals were examined using immunocytochemistry (AT8) and Gallyas silver staining for abnormal tau; immunocytochemistry (4G8) and Campbell-Switzer staining were used for the detection ofβ-amyloid. A total of 342 cases was negative in the Gallyas stain but when restaged for AT8 only 10 were immunonegative. Fifty-eight cases had subcortical tau predominantly in the locus coeruleus, but there was no abnormal cortical tau (subcortical Stages a-c). Cortical involvement (abnormal tau in neurites) was identified first in the transentorhinal region (Stage 1a, 38 cases). Transentorhinal pyramidal cells displayed pretangle material (Stage 1b, 236 cases). Pretangles gradually became argyrophilic neurofibrillary tangles (NFTs) that progressed in parallel with NFT Stages I to VI. Pretangles restricted to subcortical sites were seen chiefly at younger ages. Of the total cases, 1,031 (44.2%) had β-amyloid plaques. The first plaques occurred in the neocortex after the onset of tauopathy in the brainstem. Plaques generally developed in the 40s in 4% of all cases, culminating in their tenth decade (75%). β-amyloid plaques and NFTs were significantly correlated (p < 0.0001). These data suggest that tauopathy associated with sporadic Alzheimer disease may begin earlier than previously thought and possibly in the lower brainstem rather than in the transentorhinal region.

Impact of tau and amyloid burden on glucose metabolism in Alzheimer's disease

“…Consistent with the literature,16, 17 we found moderate levels of hypometabolism in the hippocampus of AD patients, while hippocampal tau deposition did not differ from normal age‐matched controls. Therefore, hippocampal tau deposition may not be sensitive enough to distinguish normal‐aged individuals from AD patients, as tau is present in medial temporal lobe regions in almost all individuals over the age of 6518 and maybe representative of primary or additive age‐related tauopathy 19…”

Decisive role of Reelin signaling during early stages of Alzheimer’s disease

“…Moreover, the decline in Reelin expression is not only strongly affected by aging and chronic inflammatory conditions in animals (Knuesel et al, 2009), but constitutes also a very early phenomenon of AD pathophysiology in humans (Herring et al, 2012a). Based on the presented evidence we propose that reduction of Reelin-mediated signaling in the olfactory and limbic system accelerates and aggravates the age-associated hyperphosphorylation of Tau (Braak et al, 2011). This in turn is expected to profoundly impair cytoskeletal stability and axonal integrity and would facilitate the formation of NFTs and senile plaques in affected neurons, thereby tipping the balance from healthy to pathological aging and cognitive deterioration (Krstic and Knuesel, 2013).…”

“…Based on the analysis of postmortem human brains in the age range of 1-100 years, Heiko Braak and colleagues recently reported that Tau-related neuronal changes appear first in the locus coeruleus (Braak et al, 2011), a crucial brain stem nucleus implicated in stress response regulation (Valentino and Van Bockstaele, 2008). 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 (Fig.…”

Systematic Literature Review and Meta-Analysis of Commercially Available Computerized Cognitive Training Among Older Adults

“…As individuals age, there is increased risk for cognitive and functional declines (Braak et al 2011). Thus, researchers have explored various interventions to improve cognition and delay the onset of functional decline.…”