Elsevier

The Lancet Neurology

Volume 12, Issue 4, April 2013, Pages 357-367
The Lancet Neurology

Articles
Amyloid β deposition, neurodegeneration, and cognitive decline in sporadic Alzheimer's disease: a prospective cohort study

https://doi.org/10.1016/S1474-4422(13)70044-9Get rights and content

Summary

Background

Similar to most chronic diseases, Alzheimer's disease (AD) develops slowly from a preclinical phase into a fully expressed clinical syndrome. We aimed to use longitudinal data to calculate the rates of amyloid β (Aβ) deposition, cerebral atrophy, and cognitive decline.

Methods

In this prospective cohort study, healthy controls, patients with mild cognitive impairment (MCI), and patients with AD were assessed at enrolment and every 18 months. At every visit, participants underwent neuropsychological examination, MRI, and a carbon-11-labelled Pittsburgh compound B (11C-PiB) PET scan. We included participants with three or more 11C-PiB PET follow-up assessments. Aβ burden was expressed as 11C-PiB standardised uptake value ratio (SUVR) with the cerebellar cortex as reference region. An SUVR of 1·5 was used to discriminate high from low Aβ burdens. The slope of the regression plots over 3–5 years was used to estimate rates of change for Aβ deposition, MRI volumetrics, and cognition. We included those participants with a positive rate of Aβ deposition to calculate the trajectory of each variable over time.

Findings

200 participants (145 healthy controls, 36 participants with MCI, and 19 participants with AD) were assessed at enrolment and every 18 months for a mean follow-up of 3·8 (95% CI CI 3·6–3·9) years. At baseline, significantly higher Aβ burdens were noted in patients with AD (2·27, SD 0·43) and those with MCI (1·94, 0·64) than in healthy controls (1·38, 0·39). At follow-up, 163 (82%) of the 200 participants showed positive rates of Aβ accumulation. Aβ deposition was estimated to take 19·2 (95% CI 16·8–22·5) years in an almost linear fashion—with a mean increase of 0·043 (95% CI 0·037–0·049) SUVR per year—to go from the threshold of 11C-PiB positivity (1·5 SUVR) to the levels observed in AD. It was estimated to take 12·0 (95% CI 10·1–14·9) years from the levels observed in healthy controls with low Aβ deposition (1·2 [SD 0·1] SUVR) to the threshold of 11C-PiB positivity. As AD progressed, the rate of Aβ deposition slowed towards a plateau. Our projections suggest a prolonged preclinical phase of AD in which Aβ deposition reaches our threshold of positivity at 17·0 (95% CI 14·9–19·9) years, hippocampal atrophy at 4·2 (3·6–5·1) years, and memory impairment at 3·3 (2·5–4·5) years before the onset of dementia (clinical dementia rating score 1).

Interpretation

Aβ deposition is slow and protracted, likely to extend for more than two decades. Such predictions of the rate of preclinical changes and the onset of the clinical phase of AD will facilitate the design and timing of therapeutic interventions aimed at modifying the course of this illness.

Funding

Science and Industry Endowment Fund (Australia), The Commonwealth Scientific and Industrial Research Organisation (Australia), The National Health and Medical Research Council of Australia Program and Project Grants, the Austin Hospital Medical Research Foundation, Victorian State Government, The Alzheimer's Drug Discovery Foundation, and the Alzheimer's Association.

Introduction

The increasing age of the population is leading to an increased prevalence of Alzheimer's disease (AD). Identification of individuals at risk for developing sporadic AD and estimation of the timing of dementia onset is a fundamental prerequisite for testing therapeutic interventions. The increased awareness of the difficulty in altering the rates of cognitive decline in fully established AD1, 2 has fostered the growing consensus that intervention at the earliest possible phase, perhaps even at the asymptomatic stage, is desirable.3

It is widely assumed that amyloid β (Aβ) deposition precedes cerebral atrophy and cognitive decline4, 5, 6 since results from both post-mortem7, 8 and Aβ PET studies9, 10, 11 show that about 20–40% of cognitively normal individuals aged 60–90 years have high levels of Aβ deposition in the brain. Furthermore, cognitively normal elderly individuals with high Aβ deposition show significantly faster rates of grey matter atrophy and memory decline than those with low Aβ deposition.12, 13

On the basis of preliminary evidence from prospective Aβ imaging studies,14, 15 the rate of Aβ accumulation has been estimated to be very slow. Cross-sectional data from studies of dominantly inherited AD have provided the first quantitative insights into rates of biomarker change in preclinical AD, showing that changes start decades before onset of clinical symptoms.16

To understand how Aβ accumulation is related to cerebral atrophy and the clinical manifestations of AD, it is necessary to prospectively estimate how each of these aspects of the disease change over time. Here we report rates of Aβ deposition, cerebral atrophy, and cognitive impairment in people aged 55–89 years classified as being healthy or who met clinical criteria for mild cognitive impairment (MCI)17 or AD.18

Section snippets

Study design and participants

This prospective cohort study started in Sept 17, 2004, and was designed to assess all participants every 18 months.

Healthy controls were recruited by advertisement in the community or were spouses of the participants with MCI or AD recruited from tertiary Memory Disorders Clinics or from primary care physicians who specialise in dementia care in Melbourne, VIC, and Perth, WA, Australia. Irrespective of their classification at baseline, the clinical and neuropsychological performance of all

Results

Of the 366 participants who were initially assessed, 200 (145 healthy controls, 36 participants with MCI, and 19 patients with AD) were assessed at enrolment and 1·5 and 3 years later. Up to Nov 15, 2012, 72 participants were also assessed at 4·5 years, and 12 participants at 6 years. The mean follow-up for the cohort was 3·8 (95% CI 3·6–3·9) years.

Table 1 shows the characteristics of the participants included in the analyses. While the group of healthy controls not included in the study had a

Discussion

New proposed diagnostic criteria for AD incorporate the use of biomarkers,27, 28, 29, 30 which show either the underlying pathogenesis by assessing Aβ in the brain or CSF, or synaptic and neuronal damage as indicated in reduced glucose metabolism, grey matter atrophy, or tau in CSF. Intra-individual changes in Aβ deposition, brain atrophy, and cognitive decline provide a more accurate estimation of disease progression than inter-individual comparisons of groups. This approach is crucial in the

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