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