title: Age-specific population frequencies of cerebral β-amyloidosis and neurodegeneration among people with normal cognitive function aged 50-89 years: a cross-sectional study.
abstract: 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, (18)F-fluorodeoxyglucose ((18)F-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 (11)C Pittsburgh compound B. Neurodegeneration status (positive [N(+)] or negative [N(-)]) was determined by an Alzheimer's disease signature (18)F-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 ɛ4 status (assessed with DNA extracted from blood) and sex by including these covariates in the multinomial models.
  
  
  RESULTS
  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 ɛ4 carriers than in non-carriers and that A(+)N(+) was more, and A(+)N(-) less frequent in men than in women.
  
  
  CONCLUSIONS
  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 ɛ4 and sex, suggest that pathophysiological sequences might differ between individuals.
  
  
  BACKGROUND
  US National Institute on Aging and Alexander Family Professorship of Alzheimer's Disease Research.
authors.affiliation: Department of Radiology, Mayo Clinic and Foundation, Rochester, MN, USA. Electronic address: jack.clifford@mayo.edu.
authors.forename: Clifford R
authors.initials: CR
authors.lastname: Jack
authors.affiliation: Department of Health Sciences Research, Mayo Clinic and Foundation, Rochester, MN, USA.
authors.forename: Heather J
authors.initials: HJ
authors.lastname: Wiste
authors.affiliation: Department of Health Sciences Research, Mayo Clinic and Foundation, Rochester, MN, USA.
authors.forename: Stephen D
authors.initials: SD
authors.lastname: Weigand
authors.affiliation: Department of Health Sciences Research, Mayo Clinic and Foundation, Rochester, MN, USA; Department of Neurology, Mayo Clinic and Foundation, Rochester, MN, USA.
authors.forename: Walter A
authors.initials: WA
authors.lastname: Rocca
authors.affiliation: Department of Neurology, Mayo Clinic and Foundation, Rochester, MN, USA.
authors.forename: David S
authors.initials: DS
authors.lastname: Knopman
authors.affiliation: Department of Health Sciences Research, Mayo Clinic and Foundation, Rochester, MN, USA.
authors.forename: Michelle M
authors.initials: MM
authors.lastname: Mielke
authors.affiliation: Department of Radiology, Mayo Clinic and Foundation, Rochester, MN, USA.
authors.forename: Val J
authors.initials: VJ
authors.lastname: Lowe
authors.affiliation: Department of Radiology, Mayo Clinic and Foundation, Rochester, MN, USA.
authors.forename: Matthew L
authors.initials: ML
authors.lastname: Senjem
authors.affiliation: Department of Radiology, Mayo Clinic and Foundation, Rochester, MN, USA.
authors.forename: Jeffrey L
authors.initials: JL
authors.lastname: Gunter
authors.affiliation: Department of Radiology, Mayo Clinic and Foundation, Rochester, MN, USA.
authors.forename: Gregory M
authors.initials: GM
authors.lastname: Preboske
authors.affiliation: Department of Health Sciences Research, Mayo Clinic and Foundation, Rochester, MN, USA.
authors.forename: Vernon S
authors.initials: VS
authors.lastname: Pankratz
authors.affiliation: Department of Radiology, Mayo Clinic and Foundation, Rochester, MN, USA.
authors.forename: Prashanthi
authors.initials: P
authors.lastname: Vemuri
authors.affiliation: Department of Neurology, Mayo Clinic and Foundation, Rochester, MN, USA.
authors.forename: Ronald C
authors.initials: RC
authors.lastname: Petersen
mesh_terms: D017677:Age Distribution; D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000453:epidemiology / Q000523:psychology; D000686:Amyloidosis / Q000000981:diagnostic imaging / Q000453:epidemiology* / Q000523:psychology*; D000814:Aniline Compounds; D001057:Apolipoproteins E / Q000235:genetics; D003071:Cognition / Q000502:physiology*; D015331:Cohort Studies; D003430:Cross-Sectional Studies; D004247:DNA / Q000235:genetics / Q000302:isolation & purification; D004522:Educational Status; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D019636:Neurodegenerative Diseases / Q000000981:diagnostic imaging / Q000453:epidemiology* / Q000523:psychology*; D009483:Neuropsychological Tests; D049268:Positron-Emission Tomography; D019275:Radiopharmaceuticals; D013844:Thiazoles; D014706:Verbal Learning
chemical_list: C475519:2-(4'-(methylamino)phenyl)-6-hydroxybenzothiazole; D000814:Aniline Compounds; D001057:Apolipoproteins E; D019275:Radiopharmaceuticals; D013844:Thiazoles; D004247:DNA