Appraisal of cognition in preclinical Alzheimer's disease: a conceptual review

Abstract

Biomarker evidence and clinical observations support the hypothesis that there is a diagnosable condition termed preclinical Alzheimer's disease (AD). Recently, a workgroup convened under the auspices of the National Institute on Aging and the Alzheimer's Association proposed a framework for defining preclinical AD. The definition was based on the presence of biomarkers that are indicative of the AD pathophysiological process. In the context of abnormal AD biomarkers, the workgroup postulated that 'subtle cognitive changes' occurred as well. Based on studies of genetically at-risk individuals and those destined to become demented, who were observed while still cognitively normal, low performance on learning and memory functions may be the earliest cognitive manifestations of preclinical AD, at the group level at least. It is not clear whether subtle cognitive decline can be detected reliably on an individual basis. Preclinical AD cognitive changes could be diagnosed by traditional neuropsychological testing, computerized testing, assessments of subjective memory loss, assessments of levels of participation in cognitively stimulating activities and direct measurement of activity using recently developed monitoring technology. Confounding effects of normal aging, test-retest variability, variations in educational attainment, as well as the presence of other brain diseases make diagnosing cognitive decline due to preclinical AD challenging.

Figure 1. A graphic depiction of the National Institute on Aging and the Alzheimer Association model of preclinical Alzheimer’s disease

The size of the circles should not be construed as representing the relative proportions of subjects meeting the criteria. Stage 1 represents β-amyloidosis. Stage 2 represents neurodegeneration in the setting of β-amyloidosis. Stage 3 represents cognitive decline in the setting of both β-amyloidosis and neurodegeneration. The Venn diagram depicts how neurodegeneration in Stage 2 is conditioned on the presence of abnormal levels of β-amyloidois, and how cognitive decline denoting Stage 3 is conditioned on the joint presence of abnormalities of both amyloid and neurodegeneration biomarkers. Data taken from [14].

Figure 2. Incidence of Alzheimer’s disease dementia

Solid line shows incidence rates; dashed lines represent the 95% CIs. The same rates of preclinical Alzheimer’s disease would be seen 15–20 years earlier. The point estimates of incidence (per 1000 person-years) by 5-year age brackets are: 0.58 (60–64 years); 1.86 (65–69 years); 5.06 (70–74 years); 11.74 (75–79 years); 23.1 (80–84 years); 38.58 (85–89 years); 54.88 (90–94 years); and 66.85 (95+ years). Data taken from a meta-analysis [24].

Figure 3. Normative data from the delayed recall assessment of the auditory verbal learning test from Mayo’s Older Adults Normative Study

The solid line represents the mean of delayed recall raw scores, and the dashed lines represent one standard deviation. Adapted with permission from [33].