Relationship Between Amyloid-β Positivity and Progression to Mild Cognitive Impairment or Dementia over 8 Years in Cognitively Normal Older Adults

Christa Dang; Karra D Harrington; Yen Ying Lim; David Ames; Jason Hassenstab; Simon M Laws; Nawaf Yassi; Martha Hickey; Stephanie Rainey-Smith; Joanne Robertson; Hamid R Sohrabi; Olivier Salvado; Michael Weinborn; Victor L Villemagne; Christopher C Rowe; Colin L Masters; Paul Maruff; AIBL Research Group

doi:10.3233/JAD-180507

Relationship Between Amyloid-β Positivity and Progression to Mild Cognitive Impairment or Dementia over 8 Years in Cognitively Normal Older Adults

J Alzheimers Dis. 2018;65(4):1313-1325. doi: 10.3233/JAD-180507.

Authors

Christa Dang^{1

2}, Karra D Harrington^{2

3}, Yen Ying Lim², David Ames^{4

5}, Jason Hassenstab^{6

7

8}, Simon M Laws^{3

9

10}, Nawaf Yassi^{2

11}, Martha Hickey¹, Stephanie Rainey-Smith^{12

13}, Joanne Robertson², Hamid R Sohrabi^{12

14}, Olivier Salvado¹⁵, Michael Weinborn^{12

13

16}, Victor L Villemagne^{2

17

18}, Christopher C Rowe^{17

18}, Colin L Masters², Paul Maruff^{2

19}; AIBL Research Group

Affiliations

¹ Department of Obstetrics and Gynaecology, Melbourne Medical School, The University of Melbourne, Parkville, VIC, Australia.
² The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, VIC, Australia.
³ Cooperative Research Centre for Mental Health, Parkville, VIC, Australia.
⁴ Department of Psychiatry, Academic Unit for Psychiatry of Old Age, The University of Melbourne, Parkville, VIC, Australia.
⁵ National Ageing Research Institute, Parkville, VIC, Australia.
⁶ Charles F. and Joanne Knight Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, MO, USA.
⁷ Department of Neurology, Washington University School of Medicine, St. Louis, MO, USA.
⁸ Department of Psychological and Brain Sciences, Washington University, St. Louis, MO, USA.
⁹ Collaborative Genomics Group, Centre of Excellence for Alzheimer's Disease Research and Care, School of Medical and Health Sciences, Edith Cowan University, Perth, Western Australia, Australia.
¹⁰ School of Pharmacy and Biomedical Sciences, Faculty of Health Sciences, Curtin Health Innovation Research Institute, Curtin University, Western Australia, Australia.
¹¹ Department of Medicine and Neurology, Royal Melbourne Hospital, Melbourne, VIC, Australia.
¹² Centre of Excellence for Alzheimer's Disease Research and Care, School of Exercise, Biomedical and Health Sciences, Edith Cowan University, Perth, Western Australia, Australia.
¹³ Australian Alzheimer's Disease Research Unit, Hollywood Private Hospital, Perth, Western Australia, Australia.
¹⁴ School of Psychiatry and Clinical Neurosciences, University of WA, Nedlands, Western Australia, Australia.
¹⁵ CSIRO Health and Biosecurity, the Australian eHealth Research Centre, Brisbane, QLD, Australia.
¹⁶ School of Psychological Science, University of Western Australia, Crawley, WA, Australia.
¹⁷ Department of Molecular Imaging and Therapy, Austin Health, Melbourne, VIC, Australia.
¹⁸ Department of Medicine, Austin Health, The University of Melbourne, Melbourne, VIC, Australia.
¹⁹ CogState Ltd., Melbourne, VIC, Australia.

PMID: 30149452
DOI: 10.3233/JAD-180507

Abstract

Background: Preclinical Alzheimer's disease (AD) is defined by cerebral amyloid-β positivity (Aβ+) in cognitively normal (CN) older adults.

Objective: To estimate the risk of progression to the symptomatic stages of AD due to PET Aβ+ and the extent that progression was influenced by other demographic, genetic, and clinical characteristics in a large prospective study.

Methods: Fine-Gray subdistribution modeling was used to examine the risk of progression from CN to MCI/dementia due to Aβ+, APOEɛ4 carriage, and their interaction in the Australian Imaging, Biomarkers and Lifestyle (AIBL) flagship study of aging CN cohort (n = 599) over 8 years.

Results: 17.7% Aβ+ and 8.1% Aβ-progressed over 8 years (OR: 2.43). Risk of progression for Aβ+ was 65-104% greater than Aβ-. Aβ+ APOEɛ4 carriers were at 348% greater risk than all other participants. Significant risk factors of progression in Aβ+ were age (HR: 1.05), PET SUVR (HR: 2.49) and APOE ɛ4 carriage (HR: 2.63); only age was a significant risk factor in Aβ-(HR: 1.09). Aβ-progressors were not near the threshold for Aβ+. These relationships were not moderated by hypertension, diabetes, obesity, or stroke/TIA.

Conclusion: Aβ+ is an important prognostic marker for progression from CN to MCI/dementia in older adults and APOEɛ4 carriage provides further predictive value in the presence of Aβ+. These data suggest that Aβ-associated clinical progression is consistent with clinical-pathological models of AD, whereas progression in the absence of elevated Aβ deposition may be the result of neuropathological processes other than AD that accumulate with age.

Keywords: APOEɛ4; Alzheimer’s disease; biomarkers; dementia; mild cognitive impairment.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Aged
Aged, 80 and over
Aging / pathology*
Amyloid beta-Peptides / metabolism*
Apolipoprotein E4 / genetics
Cerebral Cortex / diagnostic imaging
Cerebral Cortex / metabolism*
Cognitive Dysfunction / diagnostic imaging
Cognitive Dysfunction / genetics
Cognitive Dysfunction / pathology*
Dementia / diagnostic imaging
Dementia / genetics
Dementia / pathology*
Disease Progression*
Female
Humans
Longitudinal Studies
Male
Middle Aged
Positron-Emission Tomography
Statistics, Nonparametric
Survival Analysis

Substances

Amyloid beta-Peptides
Apolipoprotein E4