TY - JOUR
T1 - Age-specific population frequencies of cerebral β-amyloidosis and neurodegeneration among people with normal cognitive function aged 50-89 years
T2 - A cross-sectional study
AU - Jack, Clifford R.
AU - Wiste, Heather J.
AU - Weigand, Stephen D.
AU - Rocca, Walter A.
AU - Knopman, David S.
AU - Mielke, Michelle M.
AU - Lowe, Val J.
AU - Senjem, Matthew L.
AU - Gunter, Jeffrey L.
AU - Preboske, Gregory M.
AU - Pankratz, Vernon S.
AU - Vemuri, Prashanthi
AU - Petersen, Ronald C.
N1 - Funding Information:
This study was supported by the US National Institute on Aging and the Alexander Family Professorship of Alzheimer's Disease Research.
Funding Information:
CRJ has provided consulting services for Janssen Research and Development. He receives research funding from the US National Institutes of Health (NIH; R01-AG011378, U01-HL096917, U01-AG024904, RO1 AG041851, R01 AG37551, R01AG043392, and U01-AG06786) and the Alexander Family Alzheimer's Disease Research Professorship of the Mayo Foundation. WAR receives research support from the NIH (R01 AG034676, U01 AG006786, and P50 AG044170). DSK serves on a data safety monitoring board for Eli Lilly; is an investigator in a clinical trial sponsored by Janssen Pharmaceuticals; and receives research support from the NIH (R01-AG11378, P50 AG16574, U01 AG 06786, AG 29550, AG32306, and U01 96917). VJL is a consultant for Bayer Schering Pharma and Piramal Imaging and receives research support from GE Healthcare, Siemens Molecular Imaging, AVID Radiopharmaceuticals, the NIH, the Elsie and Marvin Dekelboum Family Foundation, the MN Partnership for Biotechnology and Medical Genomics, and the Leukemia and Lymphoma Society. VSP is funded by the NIH (R01AG040042, U01AG06786, P50AG16574/Core C, and R01AG32990). RCP serves on scientific advisory boards for Elan Pharmaceuticals, Wyeth Pharmaceuticals, and GE Healthcare, and receives research support from the NIH (P50-AG16574, U01-AG06786, R01-AG11378, and U01–24904). HJW, SDW, MMM, MLS, JLG, GMP, and PV declare no competing interests.
Publisher Copyright:
© 2014 Elsevier Ltd.
PY - 2014/10/1
Y1 - 2014/10/1
N2 - Background: As preclinical Alzheimer's disease becomes a target for therapeutic intervention, the overlap between imaging abnormalities associated with typical ageing and those associated with Alzheimer's disease needs to be recognised. We aimed to characterise how typical ageing and preclinical Alzheimer's disease overlap in terms of β-amyloidosis and neurodegeneration. Methods: We measured age-specific frequencies of amyloidosis and neurodegeneration in individuals with normal cognitive function aged 50-89 years. Potential participants were randomly selected from the Olmsted County (MN, USA) population-based study of cognitive ageing and invited to participate in cognitive and imaging assessments. To be eligible for inclusion, individuals must have been judged clinically to have no cognitive impairment and have undergone amyloid PET, 18F-fluorodeoxyglucose (18F-FDG) PET, and MRI. Imaging results were obtained from March 28, 2006, to Dec 3, 2013. Amyloid status (positive [A+] or negative [A-]) was determined by amyloid PET with 11C Pittsburgh compound B. Neurodegeneration status (positive [N+] or negative [N-]) was determined by an Alzheimer's disease signature 18F-FDG PET or hippocampal volume on MRI. We determined age-specific frequencies of the four groups (amyloid negative and neurodegeneration negative [A-N-], amyloid positive and neurodegeneration negative [A+N-], amyloid negative and neurodegeneration positive [A-N+], or amyloid positive and neurodegeneration positive [A+N+]) cross-sectionally using multinomial regression models. We also investigated associations of group frequencies with APOE e4 status (assessed with DNA extracted from blood) and sex by including these covariates in the multinomial models. Findings: The study population consisted of 985 eligible participants. The population frequency of A-N- was 100% (n=985) at age 50 years and fell to 17% (95% CI 11-24) by age 89 years. The frequency of A+N- increased to 28% (24-32) at age 74 years, then decreased to 17% (11-25) by age 89 years. The frequency of A-N+ increased from age 60 years, reaching 24% (16-34) by age 89 years. The frequency of A+N+ increased from age 65 years, reaching 42% (31-52) by age 89 years. The results from our multinomial models suggest that A+N- and A+N+ were more frequent in APOE e4 carriers than in non-carriers and that A+N+ was more, and A+N- less frequent in men than in women. Interpretation: Accumulation of amyloid and neurodegeneration are nearly inevitable by old age, but many people are able to maintain normal cognitive function despite these imaging abnormalities. Changes in the frequency of amyloidosis and neurodegeneration with age, which seem to be modified by APOE e4 and sex, suggest that pathophysiological sequences might differ between individuals. Funding: US National Institute on Aging and Alexander Family Professorship of Alzheimer's Disease Research.
AB - Background: As preclinical Alzheimer's disease becomes a target for therapeutic intervention, the overlap between imaging abnormalities associated with typical ageing and those associated with Alzheimer's disease needs to be recognised. We aimed to characterise how typical ageing and preclinical Alzheimer's disease overlap in terms of β-amyloidosis and neurodegeneration. Methods: We measured age-specific frequencies of amyloidosis and neurodegeneration in individuals with normal cognitive function aged 50-89 years. Potential participants were randomly selected from the Olmsted County (MN, USA) population-based study of cognitive ageing and invited to participate in cognitive and imaging assessments. To be eligible for inclusion, individuals must have been judged clinically to have no cognitive impairment and have undergone amyloid PET, 18F-fluorodeoxyglucose (18F-FDG) PET, and MRI. Imaging results were obtained from March 28, 2006, to Dec 3, 2013. Amyloid status (positive [A+] or negative [A-]) was determined by amyloid PET with 11C Pittsburgh compound B. Neurodegeneration status (positive [N+] or negative [N-]) was determined by an Alzheimer's disease signature 18F-FDG PET or hippocampal volume on MRI. We determined age-specific frequencies of the four groups (amyloid negative and neurodegeneration negative [A-N-], amyloid positive and neurodegeneration negative [A+N-], amyloid negative and neurodegeneration positive [A-N+], or amyloid positive and neurodegeneration positive [A+N+]) cross-sectionally using multinomial regression models. We also investigated associations of group frequencies with APOE e4 status (assessed with DNA extracted from blood) and sex by including these covariates in the multinomial models. Findings: The study population consisted of 985 eligible participants. The population frequency of A-N- was 100% (n=985) at age 50 years and fell to 17% (95% CI 11-24) by age 89 years. The frequency of A+N- increased to 28% (24-32) at age 74 years, then decreased to 17% (11-25) by age 89 years. The frequency of A-N+ increased from age 60 years, reaching 24% (16-34) by age 89 years. The frequency of A+N+ increased from age 65 years, reaching 42% (31-52) by age 89 years. The results from our multinomial models suggest that A+N- and A+N+ were more frequent in APOE e4 carriers than in non-carriers and that A+N+ was more, and A+N- less frequent in men than in women. Interpretation: Accumulation of amyloid and neurodegeneration are nearly inevitable by old age, but many people are able to maintain normal cognitive function despite these imaging abnormalities. Changes in the frequency of amyloidosis and neurodegeneration with age, which seem to be modified by APOE e4 and sex, suggest that pathophysiological sequences might differ between individuals. Funding: US National Institute on Aging and Alexander Family Professorship of Alzheimer's Disease Research.
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U2 - 10.1016/S1474-4422(14)70194-2
DO - 10.1016/S1474-4422(14)70194-2
M3 - Article
C2 - 25201514
AN - SCOPUS:84908009018
VL - 13
SP - 997
EP - 1005
JO - The Lancet Neurology
JF - The Lancet Neurology
SN - 1474-4422
IS - 10
ER -