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.

Keywords: Alzheimer’s disease; MCI; biomarkers; diagnostic criteria; prognosis.

Vos et al. compare the prevalence and prognosis of Alzheimer’s disease at the mild cognitive impairment stage based on the IWG-1, IWG-2 and NIA-AA criteria. All three aid identification of early Alzheimer’s disease, but combining amyloid and neuronal injury markers according to the NIA-AA criteria offers the most accurate prognosis.

Figure 1

Alzheimer’s disease-type dementia survival probability by the IWG-1, IWG-2 and NIA-AA criteria. The graphs represent the Alzheimer’s disease-type dementia survival probability according to the IWG-1 (left), IWG-2 (middle), and NIA-AA (right) criteria, adjusted for age, gender, education and centre. IWG-1: The group without prodromal Alzheimer’s disease represents subjects without memory impairment and/or abnormal biomarker(s). The prodromal Alzheimer’s disease group represents subjects with memory impairment and at least one abnormal biomarker. IWG-2: The group without prodromal Alzheimer’s disease represents subjects with normal CSF amyloid-β_1-42 and/or tau. The prodromal Alzheimer’s disease group represents subjects with abnormal CSF amyloid-β_1-42 and tau. NIA-AA: The low Alzheimer’s disease likelihood group represents subjects with normal amyloid and neuronal injury markers, the high Alzheimer’s disease likelihood group represents subjects with both abnormal amyloid and neuronal injury markers, the IAP group is a conflicting biomarker group with an abnormal amyloid marker and normal neuronal injury marker, the SNAP group is a conflicting biomarker group with an abnormal neuronal injury marker and normal amyloid marker, the intermediate Alzheimer’s disease likelihood group represents subjects with an abnormal neuronal injury marker without information on amyloid pathology, the inconclusive group represents subjects with a normal neuronal injury marker without information on amyloid pathology. AD = Alzheimer’s disease.

Figure 2

CSF amyloid-β_1-42 levels above the cut-off in the SNAP group by outcome. Results are CSF amyloid-β_1-42 levels above the cut-off of subjects with SNAP who had Alzheimer’s disease-type dementia, no dementia or non-Alzheimer’s disease dementia at follow-up. As amyloid-β_1-42 cut-offs were different for different studies, we compared the amyloid-β_1-42 levels above the cut-off (deviation from the cut-off) and not overall amyloid-β_1-42 levels. The bold line represents the mean CSF amyloid-β_1-42 levels above the cut-off. AD = Alzheimer’s disease, Aß = amyloid-β.