Brain beta-amyloid measures and magnetic resonance imaging atrophy both predict time-to-progression from mild cognitive impairment to Alzheimer's disease

Abstract

Biomarkers of brain Aβ amyloid deposition can be measured either by cerebrospinal fluid Aβ42 or Pittsburgh compound B positron emission tomography imaging. Our objective was to evaluate the ability of Aβ load and neurodegenerative atrophy on magnetic resonance imaging to predict shorter time-to-progression from mild cognitive impairment to Alzheimer's dementia and to characterize the effect of these biomarkers on the risk of progression as they become increasingly abnormal. A total of 218 subjects with mild cognitive impairment were identified from the Alzheimer's Disease Neuroimaging Initiative. The primary outcome was time-to-progression to Alzheimer's dementia. Hippocampal volumes were measured and adjusted for intracranial volume. We used a new method of pooling cerebrospinal fluid Aβ42 and Pittsburgh compound B positron emission tomography measures to produce equivalent measures of brain Aβ load from either source and analysed the results using multiple imputation methods. We performed our analyses in two phases. First, we grouped our subjects into those who were 'amyloid positive' (n = 165, with the assumption that Alzheimer's pathology is dominant in this group) and those who were 'amyloid negative' (n = 53). In the second phase, we included all 218 subjects with mild cognitive impairment to evaluate the biomarkers in a sample that we assumed to contain a full spectrum of expected pathologies. In a Kaplan-Meier analysis, amyloid positive subjects with mild cognitive impairment were much more likely to progress to dementia within 2 years than amyloid negative subjects with mild cognitive impairment (50 versus 19%). Among amyloid positive subjects with mild cognitive impairment only, hippocampal atrophy predicted shorter time-to-progression (P < 0.001) while Aβ load did not (P = 0.44). In contrast, when all 218 subjects with mild cognitive impairment were combined (amyloid positive and negative), hippocampal atrophy and Aβ load predicted shorter time-to-progression with comparable power (hazard ratio for an inter-quartile difference of 2.6 for both); however, the risk profile was linear throughout the range of hippocampal atrophy values but reached a ceiling at higher values of brain Aβ load. Our results are consistent with a model of Alzheimer's disease in which Aβ deposition initiates the pathological cascade but is not the direct cause of cognitive impairment as evidenced by the fact that Aβ load severity is decoupled from risk of progression at high levels. In contrast, hippocampal atrophy indicates how far along the neurodegenerative path one is, and hence how close to progressing to dementia. Possible explanations for our finding that many subjects with mild cognitive impairment have intermediate levels of Aβ load include: (i) individual subjects may reach an Aβ load plateau at varying absolute levels; (ii) some subjects may be more biologically susceptible to Aβ than others; and (iii) subjects with mild cognitive impairment with intermediate levels of Aβ may represent individuals with Alzheimer's disease co-existent with other pathologies.

Figure 1

Illustrative images. Left: Mild cognitive impairment progressor, Top: positive PIB PET. Bottom: MRI illustrating atrophic hippocampi and ventricular enlargement. Right: Mild cognitive impairment non-progressor. Top: negative PIB PET with non-specific white matter retention but no cortical retention. Bottom: MRI illustrating normal hippocampi and no ventricular enlargement.

Figure 2

Risk profile as a function of increasing biomarker severity among all 218 subjects with mild cognitive impairment. Log hazard of progressing to dementia as a function of (A) increasing hippocampal volume (adjusting for total intercranial volumes) and (B) increasing brain Aβ amyloid load within all 218 subjects with mild cognitive impairment. Hash marks at the bottom of the plot indicate the hippocampal volume and Aβ load measures of individual subjects with mild cognitive impairment, with APOE genotype (ε4 carrier gold, non-carrier blue) and progressor versus non-progressor status indicated.

Figure 3

Hypothetical effects of pure Alzheimer’s pathology versus mixed pathology on time-to-progression from mild cognitive impairment to dementia. Clinical disease stage is indicated on the horizontal axis with vertical lines indicating the time at which diagnoses of mild cognitive impairment and dementia are reached. The severity of Aβ load (red curve) and brain atrophy (blue curve) on the vertical axis range from normal to maximally abnormal. (A) [modified from Jack et al. (2010)], illustrates the hypothetical biomarker curves of Subject A, who progresses from normal to mild cognitive impairment to dementia and who has pure Alzheimer’s pathology. Over the time a subject traverses the horizontal ‘clinical distance’ from time-of diagnosis of mild cognitive impairment to time-of diagnosis of dementia (indicated by the horizontal red and blue arrows), the vertical ‘distance travelled’ along the Aβ load biomarkers curve is small as indicated by the red vertical arrow in (A). In contrast, over this same ‘clinical distance travelled’ on the horizontal axis, the vertical distance travelled along the MRI biomarker is substantial as indicated by the blue vertical arrow in (A). (B) illustrates the hypothetical curve of Subject B, who has mixed pathology. The effect of the coexistent second pathology is to shift the blue atrophy curve, time-of diagnosis of mild cognitive impairment, and time-of diagnosis of dementia closer to the Aβ curve. Consequently Subject B reaches a diagnosis of dementia with a lower level of Aβ in situ than Subject A. AD = Alzheimer’s disease; MCI = mild cognitive impairment.