Maxwell_2022_Chem.Biol.Interact__110065

A subset of octogenarians and older maintain normal cognitive function (CNOO) despite high prevalence and incidence of cognitive decline attributed to neurodegeneration or aging in the population. The rostral prefrontal cortex (rPFC) and hippocampal formation are brain regions integral to cognition, namely attention and memory, facilitated in part by cholinergic innervation. We hypothesized that preserved cholinergic neurotransmission in these regions contributes to intact cognition in the CNOO. To test this, we evaluated the burden of neuropathological and cholinesterase-associated protein aggregates in the rPFC and hippocampal formation. Tissues from age- and sex-matched CNOO and Alzheimer's disease (AD) rPFC and hippocampal formation were stained for beta-amyloid (Abeta), tau, alpha-synuclein, phosphorylated TAR DNA-binding protein 43 (pTDP-43), acetylcholinesterase (AChE), and butyrylcholinesterase (BChE). The relative abundance of neuropathological aggregates was semi-quantitatively scored. Deposition of Abeta plaques, tau neurofibrillary tangles (NFT) and pTDP-43 inclusions were comparable between CNOO and AD cases. Intraneuronal Abeta and tau-positive thorny astrocytes consistent with aging-related tau astrogliopathy, were also noted in the rPFC. Abundance of BChE-positive plaque pathology was significantly higher in AD than in CNOO cases in most regions of interest, followed closely by abundance of AChE-positive plaque pathology. BChE- and AChE-activities were also associated with varied NFT morphologies. CNOO cases maintained cognition despite a high neuropathological burden in the rPFC and hippocampal formation. BChE-positive and, to a lesser extent, AChE-positive pathologies were significantly lower in most regions in the CNOO compared to AD. This suggests a specificity of cholinesterase-associated neuropathology with AD. We conclude that while CNOO have cholinesterase-associated neuropathology in the rPFC and hippocampal formation, abundance in this population is significantly lower compared to AD which may contribute to their intact cognition.