Underlying Biological Processes in Mild Cognitive Impairment: Amyloidosis Versus Neurodegeneration

Issue title: Alzheimer’s Disease: New Beginnings

Guest editors: G. Perry, J. Avila, P.I. Moreira, A.A. Sorensen and M. Tabaton

Article type: Research Article

Authors: Santana, Isabel^{a; b; c; *} | Baldeiras, Inês^{b; c; d} | Santiago, Beatriz^a | Duro, Diana^{a; b} | Freitas, Sandra^{c; e} | Pereira, Miguel Tábuas^a | Almeida, Maria Rosário^c | Oliveira, Catarina Resende^{b; c; d}

Affiliations: [a] Department of Neurology, Dementia Clinic, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal | [b] Faculty of Medicine, University of Coimbra, Coimbra, Portugal | [c] Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal | [d] Department of Neurology, Laboratory of Neurochemistry, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal | [e] Faculty of Psychology and Educational Sciences, University of Coimbra, Coimbra, Portugal

Correspondence: [*] Correspondence to: Isabel Santana, Dementia Clinic, Neurology Department, Hospitais da Universidade de Coimbra, Praceta Mota Pinto, 3000-075 Coimbra, Portugal. Tel.: +351 239 836244; Fax: +351 239 822637; E-mail: isabeljsantana@gmail.com.

Abstract: The amyloid cascade hypothesis proposes amyloid-β (Aβ) as the earliest and key pathological hallmark of Alzheimer’s disease (AD), but this mandatory “amyloid-first pathway” has been contested. Longitudinal studies of mild cognitive impairment (MCI) patients represent an opportunity to investigate the intensity of underlying biological processes (amyloidosis versus neurodegeneration) and their relevance for progression to AD. We re-examined our cohort of amnestic MCI, grouped according to cerebrospinal fluid (CSF) biomarkers, aiming at establishing their prognostic value for Alzheimer-type dementia and testing the hypothetical model of biomarkers sequence, based on the amyloid cascade. Our baseline population consisted of 217 MCI patients, 63% with neurodegeneration markers and 47% with amyloidosis. Within the longitudinal study-group (n = 165), 85 progressed to AD and 80 remained cognitively stable. Age, CSF Aβ42, and t-Tau were identified as the best single predictors of conversion to AD. Regarding MCI classification according to the NIA-AA criteria, the high-AD-likelihood group (HL-both amyloid and neurodegeneration markers) was the most frequent (42%); followed by the Suspected Non-Alzheimer Pathophysiology group (SNAP-26%), the low-AD-likelihood group (LL-negative biomarkers-22%), and the Isolated Amyloid Pathology group (IAP-10%). Risk of progression to AD was higher in HL in relation to the LL group (HR = 6.1, 95% CI = 2.1–18.0, p = 0.001). SNAP and IAP groups were equivalent in terms of risk of progression to AD (IAP: HR = 2.6, 95% CI = 0.7–9.3, p = 0.141; SNAP: HR = 3.1, 95% CI = 1.1–9.6; p = 0.046), but only SNAP was significantly different from the LL group. These results support different neurobiological pathways to AD beyond the amyloid hypothesis, highlighting the alternative “neurodegeneration-first pathway” for further investigation.

Keywords: Alzheimer’s disease, amyloid, cerebrospinal fluid biomarkers, mild cognitive impairment, neurodegeneration

DOI: 10.3233/JAD-179908

Journal: Journal of Alzheimer's Disease, vol. 64, no. s1, pp. S647-S657, 2018