Prevalence and prognosis of Alzheimer’s disease at the mild cognitive impairment stage

Abstract

Three sets of research criteria are available for diagnosis of Alzheimer's disease in subjects with mild cognitive impairment: the International Working Group-1, International Working Group-2, and National Institute of Aging-Alzheimer Association criteria. We compared the prevalence and prognosis of Alzheimer's disease at the mild cognitive impairment stage according to these criteria. Subjects with mild cognitive impairment (n = 1607), 766 of whom had both amyloid and neuronal injury markers, were recruited from 13 cohorts. We used cognitive test performance and available biomarkers to classify subjects as prodromal Alzheimer's disease according to International Working Group-1 and International Working Group-2 criteria and in the high Alzheimer's disease likelihood group, conflicting biomarker groups (isolated amyloid pathology or suspected non-Alzheimer pathophysiology), and low Alzheimer's disease likelihood group according to the National Institute of Ageing-Alzheimer Association criteria. Outcome measures were the proportion of subjects with Alzheimer's disease at the mild cognitive impairment stage and progression to Alzheimer's disease-type dementia. We performed survival analyses using Cox proportional hazards models. According to the International Working Group-1 criteria, 850 (53%) subjects had prodromal Alzheimer's disease. Their 3-year progression rate to Alzheimer's disease-type dementia was 50% compared to 21% for subjects without prodromal Alzheimer's disease. According to the International Working Group-2 criteria, 308 (40%) subjects had prodromal Alzheimer's disease. Their 3-year progression rate to Alzheimer's disease-type dementia was 61% compared to 22% for subjects without prodromal Alzheimer's disease. According to the National Institute of Ageing-Alzheimer Association criteria, 353 (46%) subjects were in the high Alzheimer's disease likelihood group, 49 (6%) in the isolated amyloid pathology group, 220 (29%) in the suspected non-Alzheimer pathophysiology group, and 144 (19%) in the low Alzheimer's disease likelihood group. The 3-year progression rate to Alzheimer's disease-type dementia was 59% in the high Alzheimer's disease likelihood group, 22% in the isolated amyloid pathology group, 24% in the suspected non-Alzheimer pathophysiology group, and 5% in the low Alzheimer's disease likelihood group. Our findings support the use of the proposed research criteria to identify Alzheimer's disease at the mild cognitive impairment stage. In clinical settings, the use of both amyloid and neuronal injury markers as proposed by the National Institute of Ageing-Alzheimer Association criteria offers the most accurate prognosis. For clinical trials, selection of subjects in the National Institute of Ageing-Alzheimer Association high Alzheimer's disease likelihood group or the International Working Group-2 prodromal Alzheimer's disease group could be considered.

A Cochrane review on brain [18F]FDG PET in dementia: limitations and future perspectives

“…This position is also in line with published guidelines explicitly requiring the presence of neuronal injury markers to come to a conclusion of Bintermediate probability^or Bhigh probability^MCI/AD [46]. Furthermore, recently the validity of this approach has been further confirmed by a large retrospective multicentre study showing that, in the clinical setting, the combined use of both amyloid and neuronal injury markers offers the most accurate prognosis in MCI patients [47].…”

Amyloidosis and neurodegeneration result in distinct structural connectivity patterns in mild cognitive impairment

“…In accordance with this hypothesis of heterogeneity of MCI A-N+ etiologies, we found that among all MCI A-N+, only 20% were positive by both biomarkers, whereas they were 47% in the MCI A+N+ (supplementary Table S4). However, it has been also proposed that MCI A-N+ may reflect a proportion of AD individuals with subthreshold Aß SUVr (Vos et al, 2016(Vos et al, , 2015. We SUVr in MCI A-N+ classified using CSF Aβ 42 as amyloid biomarker (Wisse et al, 2015).…”

“…In particular, MCI A+N-did not display alteration of the fornix, showing that even though fornix alterations have been described at the MCI stage, they are not present in all MCI patients (Madhavan et al, 2015;Metzler-Baddeley et al, 2012). term of conversion rate and cognitive deterioration, but discrepancies appear between studies (Caroli et al, 2015;Petersen et al, 2013;Vos et al, 2015;Wisse et al, 2015). Our study is consistent with this prior knowledge, showing that MCI A+N-white matter is less altered than MCI A+N+ but more altered than MCI A-N.…”

“…These indicators include biomarkers of β-amyloidosis (reductions in CSF Aβ 42 and increased amyloid PET tracer retention) and biomarkers of neuronal injury and neurodegeneration (increased CSF tau, decrease of fluorodeoxyglucose uptake on PET, structural MRI measures of hippocampal atrophy) . Biomarkers have improved the characterization of the heterogeneity of the MCI phenotype by distinguishing patients with and without abnormal biomarkers of amyloidosis and neurodegeneration (Caroli et al, 2015;Petersen et al, 2013;Vos et al, 2015;Wisse et al, 2015). In particular, two subgroups of patients are of high interest.…”

Dual-phase amyloid PET: hitting two birds with one stone

“…In this frame, NIA-AA criteria relate the number of abnormal biomarkers to the likelihood that MCI is due to AD [2]. Although a prospective comparison between these two different approaches (IWG2 and NIA-AA) is still lacking, the validity of this NIA-AA model has been confirmed by a large retrospective multicenter study showing that, in the clinical setting, the combined use of both amyloid and neuronal injury markers offers the most accurate prognosis in MCI patients [5]. Similarly, in a recent survey, neurologists working in European Alzheimer's Disease Consortium Centres agreed that only a combination of amyloidosis and neuronal injury biomarkers is a strong indicator of an underlying AD [6].…”