ArticlesAge-specific population frequencies of cerebral β-amyloidosis and neurodegeneration among people with normal cognitive function aged 50–89 years: a cross-sectional study
Introduction
Recognition that biomarker evidence of Alzheimer's disease pathophysiology is present long before clinical symptoms become apparent1 has motivated the formulation of research criteria for preclinical Alzheimer's disease.2, 3 In 2011, the authors of the National Institute on Aging–Alzheimer's Association (NIA–AA) criteria described a method for defining and staging preclinical Alzheimer's disease, defining stage 1 as cerebral amyloidosis, stage 2 as amyloidosis plus neurodegeneration, and stage 3 as amyloidosis, neurodegeneration, and subtle cognitive decline.2 Although the NIA–AA method probably accurately reflects the onset and staged progression of biomarkers in the pathophysiology of Alzheimer's disease,1, 4, 5, 6 Alzheimer's disease pathological changes do not typically occur in isolation in elderly people, but rather co-occur with other age-related degenerative processes.7 Structural MRI and 18F-fluorodeoxyglucose (18F-FDG) PET are sensitive approaches to the measurement of neurodegeneration or brain injury; however, even signature Alzheimer's disease topographic measures on these modalities (eg, hippocampal atrophy on MRI) are not specific for Alzheimer's disease.8, 9, 10
A two-feature biomarker classification system based on both β-amyloidosis and neurodegeneration, described previously,11, 12 expands the NIA–AA staging of preclinical Alzheimer's disease.2 This system can be used to classify all individuals, rather than only those who are exclusively in the Alzheimer's disease pathophysiological pathway, thereby accommodating the facts that Alzheimer's disease and non-Alzheimer's disease degenerative processes occur with ageing and that techniques for the imaging of neurodegeneration are sensitive to various degenerative processes. Every individual is assigned to one of four groups in this scheme: 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+).11, 12 A–N– corresponds to NIA–AA stage 0, A+N– to NIA–AA stage 1, A–N+ to suspected non-Alzheimer's pathophysiology (SNAP),13 and A+N+ to NIA–AA stages 2 and 3.
Our classification system11, 12 also operationalises the 2014 International Working Group (IWG) research criteria (the IWG-2 criteria) for the stage of asymptomatic at risk for Alzheimer's disease.3 Asymptomatic at risk for Alzheimer's disease is defined by the absence of a clinical phenotype consistent with typical or atypical Alzheimer's disease and the presence of a pathophysiological biomarker consistent with the presence of Alzheimer's disease pathophysiology. A positive amyloid PET scan is the only currently available imaging finding that is diagnostic of Alzheimer's disease pathophysiology.11 Structural MRI and 18F-FDG PET abnormalities in topographic areas characteristic of Alzheimer's disease are used to stage disease severity, but not as diagnostic measures.3 Thus, framed in terms of the IWG-2 criteria, A+N– and A+N+ individuals with normal cognitive function would be designated as asymptomatic at risk for Alzheimer's disease, with A+N+ individuals at a more advanced stage of the disease process. According to the IWG-2 criteria, A–N– and A–N+ individuals would not be regarded as having evidence of Alzheimer's disease pathophysiology.
From a clinical standpoint, typical ageing blends imperceptibly with preclinical Alzheimer's disease in the population. Our objective was to characterise amyloidosis and neurodegeneration in people with normal cognitive function, a population that includes both typical ageing and preclinical Alzheimer's disease (asymptomatic at risk for Alzheimer's disease). We aimed to estimate age-specific frequencies of the four groups based on amyloidosis and neurodegeneration status in a large sample of individuals with normal cognitive function aged 50–89 years from a population-based cohort.
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Study design and participants
We studied participants with normal cognitive function in the Mayo Clinic Study of Aging (MCSA), a population-based study of cognitive ageing among residents of Olmsted County (MN, USA).14 The Rochester Epidemiology Project15 medical records linkage system was used to enumerate all Olmsted County residents aged 50–89 years. All residents from the population count were randomly ordered in lists and stratified by age and sex; we selected potential participants from these ordered lists (by taking
Results
985 individuals met the criteria for inclusion in the present analysis. The median age increased by group in the order A–N–, A+N–, A–N+, then A+N+ (p<0·0001 for all pairwise comparisons apart from A–N+ vs A+N+ [p=0·013]; table 1). The proportion of men was higher in the A–N+ group than in the A+N– group (p=0·006). The proportion of men was higher in the A+N+ group than in the A–N– group (p=0·010) or the A+N– group (p=0·0007). The proportion of APOE ɛ4 carriers was higher in the A+N– and A+N+
Discussion
In our cross-sectional study among individuals with normal cognitive function aged 50–89 years, the frequency of A–N– fell monotonically with age from 100% at age 50 years to 17% at age 89 years. The frequency of A–N+ and A+N– increased monotonically with age. The pattern for A+N– was different, with the frequency increasing until age 74 years and decreasing thereafter. Sex and APOE4 ɛ4 status seemed to modify these age trends.
Various processes that can be detrimental to brain structure and
References (39)
- et al.
Amyloid β deposition, neurodegeneration, and cognitive decline in sporadic Alzheimer's disease: a prospective cohort study
Lancet Neurol
(2013) - et al.
Toward defining the preclinical stages of Alzheimer's disease: recommendations from the National Institute on Aging–Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease
Alzheimers Dement
(2011) - et al.
Advancing research diagnostic criteria for Alzheimer's disease: the IWG-2 criteria
Lancet Neurol
(2014) - et al.
Generalizability of epidemiological findings and public health decisions: an illustration from the Rochester Epidemiology Project
Mayo Clin Proc
(2012) - et al.
Restriction isotyping of human apolipoprotein E by gene amplification and cleavage with HhaI
J Lipid Res
(1990) - et al.
Associations between cognitive, functional, and FDG-PET measures of decline in AD and MCI
Neurobiol Aging
(2011) Vulnerable neural systems and the borderland of brain aging and neurodegeneration
Neuron
(2013)- et al.
Amyloid imaging results from the Australian Imaging, Biomarkers and Lifestyle (AIBL) study of aging
Neurobiol Aging
(2010) - et al.
Preclinical Alzheimer's disease and its outcome: a longitudinal cohort study
Lancet Neurol
(2013) - et al.
Prevalence, incidence and duration of Braak's stages in the general population: can we know?
Neurobiol Aging
(1997)