Journal ArticleDOI
Amyloid β deposition, neurodegeneration, and cognitive decline in sporadic Alzheimer's disease: a prospective cohort study.
Victor L. Villemagne,Samantha C. Burnham,Pierrick Bourgeat,Belinda M. Brown,Kathryn A. Ellis,Olivier Salvado,Cassandra Szoeke,S. Lance Macaulay,Ralph N. Martins,Paul Maruff,David Ames,Christopher C. Rowe,Colin L. Masters +12 more
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TLDR
These projections suggest a prolonged preclinical phase of AD in which Aβ deposition reaches the authors' 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).Abstract:
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 ( 11 C-PiB) PET scan. We included participants with three or more 11 C-PiB PET follow-up assessments. Aβ burden was expressed as 11 C-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 11 C-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 11 C-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.read more
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Journal ArticleDOI
Enduring Elevations of Hippocampal Amyloid Precursor Protein and Iron Are Features of β-Amyloid Toxicity and Are Mediated by Tau
Xuling Li,Xuling Li,Peng Lei,Qingzhang Tuo,Qingzhang Tuo,Scott Ayton,Qiao-Xin Li,Steve Moon,Irene Volitakis,Rong Liu,Colin L. Masters,David Finkelstein,Ashley I. Bush +12 more
TL;DR: The results from this study support the amyloid cascade hypothesis and suggest that downstream effectors of Aβ, which propagate toxicity after Aβ has been cleared, may be tractable therapeutic targets.
Journal ArticleDOI
BACE1 as a therapeutic target in Alzheimer's disease: rationale and current status.
Genevieve Evin,Christopher Hince +1 more
TL;DR: Potential side effects of BACE1 inhibitors that will require further evaluation to provide a safe therapy for AD are alerted.
Journal ArticleDOI
Evidence For and Against a Pathogenic Role of Reduced γ-Secretase Activity in Familial Alzheimer’s Disease
Tanya Jayne,Morgan Newman,Giuseppe Verdile,Giuseppe Verdile,Giuseppe Verdile,Greg T. Sutherland,Gerald Münch,Ian F. Musgrave,Seyyed Hani Moussavi Nik,Michael Lardelli +9 more
TL;DR: A case for an alternative interpretation of published data on the role of γ-secretase activity and fAD-associated mutations in AD pathology is presented and evidence supports a "PSEN holoprotein multimer hypothesis" where PSEN fAD mutations generate mutant PSEN Holoproteins that multimerize with wild type holop protein and dominantly interfere with an AD-critical function such as autophagy or secretion of Aβ.
Journal ArticleDOI
Amyloid imaging: Past, present and future perspectives.
TL;DR: Functional and molecular neuroimaging techniques such as positron emission tomography (PET) using functional and molecular tracers, in conjuction with other Aβ and tau biomarkers in CSF, are proving valuable in the differential diagnosis of AD, as well as in establishing disease prognosis.
Journal ArticleDOI
Cognitive Variability during Middle-Age: Possible Association with Neurodegeneration and Cognitive Reserve.
Daniel Ferreira,Daniel Ferreira,Alejandra Machado,Alejandra Machado,Yaiza Molina,Antonieta Nieto,Rut Correia,Rut Correia,Eric Westman,José Barroso +9 more
TL;DR: Variability in cognition during middle-age is associated with neurodegeneration in the parietal–temporal–occipital association cortex and white matter tracts connecting this to the prefrontal dorsolateral cortex and the hippocampus.
References
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Information Theory and an Extension of the Maximum Likelihood Principle
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The diagnosis of dementia due to Alzheimer’s disease: Recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer's disease
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