Alzheimer's disease and non-demented high pathology control nonagenarians: Comparing and contrasting the biochemistry of cognitively successful aging

MAAROUF CL; DAUGS ID; KOKJOHN TA; WALKER DG; HUNTER JM; KRUCHOWSKY JC; WOLTJER R; KAYE J; CASTAÑO EM; SABBAGH MN; BEACH TG; ROHER AE

PLOS ONE

PUBLIC LIBRARY SCIENCE

Lugar: San Francisco; Año: 2011 vol. 6 p. 1 - 17

1932-6203

The amyloid cascade hypothesis provides an economical mechanistic explanation for Alzheimer’s disease (AD) dementiaand correlated neuropathology. However, some nonagenarian individuals (high pathology controls, HPC) remain cognitivelyintact while enduring high amyloid plaque loads for decades. If amyloid accumulation is the prime instigator ofneurotoxicity and dementia, specific protective mechanisms must enable these HPC to evade cognitive decline. Weevaluated the neuropathological and biochemical differences existing between non-demented (ND)-HPC and an agematchedcohort with AD dementia. The ND-HPC selected for our study were clinically assessed as ND and possessed highamyloid plaque burdens. ELISA and Western blot analyses were used to quantify a group of proteins related to APP/Ab/taumetabolism and other neurotrophic and inflammation-related molecules that have been found to be altered inneurodegenerative disorders and are pivotal to brain homeostasis and mental health. The molecules assumed to be criticalin AD dementia, such as soluble or insoluble Ab40, Ab42 and tau were quantified by ELISA. Interestingly, only Ab42demonstrated a significant increase in ND-HPC when compared to the AD group. The vascular amyloid load which was notused in the selection of cases, was on the average almost 2-fold greater in AD than the ND-HPC, suggesting that a higherdegree of microvascular dysfunction and perfusion compromise was present in the demented cohort. Neurofibrillarytangles were less frequent in the frontal cortices of ND-HPC. Biochemical findings included elevated vascular endothelialgrowth factor, apolipoprotein E and the neuroprotective factor S100B in ND-HPC, while anti-angiogenic pigment epitheliumderived factor levels were lower. The lack of clear Ab-related pathological/biochemical demarcation between AD and NDHPCsuggests that in addition to amyloid plaques other factors, such as neurofibrillary tangle density and vascular integrity,must play important roles in cognitive failure.