title: Alzheimer's disease and non-demented high pathology control nonagenarians: comparing and contrasting the biochemistry of cognitively successful aging.
abstract: The amyloid cascade hypothesis provides an economical mechanistic explanation for Alzheimer's disease (AD) dementia and correlated neuropathology. However, some nonagenarian individuals (high pathology controls, HPC) remain cognitively intact while enduring high amyloid plaque loads for decades. If amyloid accumulation is the prime instigator of neurotoxicity and dementia, specific protective mechanisms must enable these HPC to evade cognitive decline. We evaluated the neuropathological and biochemical differences existing between non-demented (ND)-HPC and an age-matched cohort with AD dementia. The ND-HPC selected for our study were clinically assessed as ND and possessed high amyloid plaque burdens. ELISA and Western blot analyses were used to quantify a group of proteins related to APP/Aβ/tau metabolism and other neurotrophic and inflammation-related molecules that have been found to be altered in neurodegenerative disorders and are pivotal to brain homeostasis and mental health. The molecules assumed to be critical in AD dementia, such as soluble or insoluble Aβ40, Aβ42 and tau were quantified by ELISA. Interestingly, only Aβ42 demonstrated a significant increase in ND-HPC when compared to the AD group. The vascular amyloid load which was not used in the selection of cases, was on the average almost 2-fold greater in AD than the ND-HPC, suggesting that a higher degree of microvascular dysfunction and perfusion compromise was present in the demented cohort. Neurofibrillary tangles were less frequent in the frontal cortices of ND-HPC. Biochemical findings included elevated vascular endothelial growth factor, apolipoprotein E and the neuroprotective factor S100B in ND-HPC, while anti-angiogenic pigment epithelium derived factor levels were lower. The lack of clear Aβ-related pathological/biochemical demarcation between AD and ND-HPC suggests that in addition to amyloid plaques other factors, such as neurofibrillary tangle density and vascular integrity, must play important roles in cognitive failure.
authors.affiliation: The Longtine Center for Neurodegenerative Biochemistry, Banner Sun Health Research Institute, Sun City, Arizona, United States of America.
authors.forename: Chera L
authors.initials: CL
authors.lastname: Maarouf
authors.forename: Ian D
authors.initials: ID
authors.lastname: Daugs
authors.forename: Tyler A
authors.initials: TA
authors.lastname: Kokjohn
authors.forename: Douglas G
authors.initials: DG
authors.lastname: Walker
authors.forename: Jesse M
authors.initials: JM
authors.lastname: Hunter
authors.forename: Jane C
authors.initials: JC
authors.lastname: Kruchowsky
authors.forename: Randy
authors.initials: R
authors.lastname: Woltjer
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Kaye
authors.forename: Eduardo M
authors.initials: EM
authors.lastname: Castaño
authors.forename: Marwan N
authors.initials: MN
authors.lastname: Sabbagh
authors.forename: Thomas G
authors.initials: TG
authors.lastname: Beach
authors.forename: Alex E
authors.initials: AE
authors.lastname: Roher
mesh_terms: D000369:Aged, 80 and over; D000375:Aging / Q000473:pathology*; D000544:Alzheimer Disease / Q000503:physiopathology*; D016229:Amyloid beta-Peptides / Q000032:analysis; D016564:Amyloid beta-Protein Precursor / Q000032:analysis; D016022:Case-Control Studies; D003072:Cognition Disorders / Q000209:etiology; D003704:Dementia / Q000209:etiology*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D008297:Male; D016874:Neurofibrillary Tangles; D016875:tau Proteins / Q000032:analysis
chemical_list: C545487:APP protein, human; D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D016875:tau Proteins
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