Synergistic interaction between amyloid and tau predicts the progression to dementia

Abstract

Alzheimer disease (AD) is characterized by the progressive accumulation of extracellular amyloid β (Aβ) plaques, intracellular inclusions of hyperphosphorylated tau in tangles, and neuronal degeneration [ 1 x [1] Jack, C.R. Jr., Knopman, D.S., Jagust, W.J., Petersen, R.C., Weiner, M.W., Aisen, P.S. et al. Tracking pathophysiological processes in Alzheimer's disease: an updated hypothetical model of dynamic biomarkers. Lancet Neurol. 2013; 12: 207–216 Abstract | Full Text | Full Text PDF | PubMed | Scopus (1179) | Google Scholar See all References ] [1] . The most widely accepted model of AD progression proposes a cascade of neuropathological events in which abnormal levels of Aβ, neurofibrillary tangles, and neurodegeneration precede dementia [ 1 x [1] Jack, C.R. Jr., Knopman, D.S., Jagust, W.J., Petersen, R.C., Weiner, M.W., Aisen, P.S. et al. Tracking pathophysiological processes in Alzheimer's disease: an updated hypothetical model of dynamic biomarkers. Lancet Neurol. 2013; 12: 207–216 Abstract | Full Text | Full Text PDF | PubMed | Scopus (1179) | Google Scholar See all References ] [1] . The idea of pathophysiological progression was incorporated by the National Institute on Aging and the Alzheimer's Association criterion for predementia phase of AD, which recognizes that the coexistence of abnormal Aβ and neurodegeneration biomarkers better identify mild cognitive impairment (MCI) patients who will progress to dementia [ 2 x [2] Albert, M.S., DeKosky, S.T., Dickson, D., Dubois, B., Feldman, H.H., Fox, N.C. et al. The diagnosis of mild cognitive impairment due to Alzheimer's disease: recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease. Alzheimers Dement. 2011; 7: 270–279 Abstract | Full Text | Full Text PDF | PubMed | Scopus (3063) | Google Scholar See all References ] [2] . This notion has been supported by recent observations demonstrating that MCI Aβ+ individuals with neurodegenerative changes, measured by brain hypometabolism or atrophy, have higher rates of neuropsychological decline as compared with MCI biomarker negative participants [ 3 x [3] Petersen, R.C., Aisen, P., Boeve, B.F., Geda, Y.E., Ivnik, R.J., Knopman, D.S. et al. Mild cognitive impairment due to Alzheimer disease in the community. Ann Neurol. 2013; 74: 199–208 PubMed | Google Scholar See all References , 4 x [4] Caroli, A., Prestia, A., Galluzzi, S., Ferrari, C., van der Flier, W.M., Ossenkoppele, R. et al. Mild cognitive impairment with suspected nonamyloid pathology (SNAP): prediction of progression. Neurology. 2015; 84: 508–515 Crossref | PubMed | Scopus (53) | Google Scholar See all References , 5 x [5] Wisse, L.E., Butala, N., Das, S.R., Davatzikos, C., Dickerson, B.C., Vaishnavi, S.N. et al. Suspected non-AD pathology in mild cognitive impairment. Neurobiol Aging. 2015; 36: 3152–3162 Abstract | Full Text | Full Text PDF | PubMed | Scopus (26) | Google Scholar See all References ]. Yet, a key question that remains unanswered is whether the highest rate of progression to dementia in MCI Aβ+ individuals with downstream cascade abnormalities is due to a synergistic effect between the coexistent brain pathologies or simply the sum of their deleterious effects. This question is particularly important in the context of the two hallmark proteinopathies underlying AD [ 6 x [6] Selkoe, D.J. Defining molecular targets to prevent Alzheimer disease. Arch Neurol. 2005; 62: 192–195 Crossref | PubMed | Scopus (123) | Google Scholar See all References ] [6] . Although Aβ and phosphorylated tau (p-tau) proteins well characterize AD pathophysiology, brain hypometabolism or atrophy may be found in several other brain disorders associated with neuronal loss [ 2 x [2] Albert, M.S., DeKosky, S.T., Dickson, D., Dubois, B., Feldman, H.H., Fox, N.C. et al. The diagnosis of mild cognitive impairment due to Alzheimer's disease: recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease. Alzheimers Dement. 2011; 7: 270–279 Abstract | Full Text | Full Text PDF | PubMed | Scopus (3063) | Google Scholar See all References , 7 x [7] Blennow, K. and Zetterberg, H. Understanding biomarkers of neurodegeneration: ultrasensitive detection techniques pave the way for mechanistic understanding. Nat Med. 2015; 21: 217–219 Crossref | PubMed | Scopus (22) | Google Scholar See all References ].