Age-specific and sex-specific prevalence of cerebral β-amyloidosis, tauopathy, and neurodegeneration in cognitively unimpaired individuals aged 50-95 years: a cross-sectional study

Abstract

Background: A new classification for biomarkers in Alzheimer's disease and cognitive ageing research is based on grouping the markers into three categories: amyloid deposition (A), tauopathy (T), and neurodegeneration or neuronal injury (N). Dichotomising these biomarkers as normal or abnormal results in eight possible profiles. We determined the clinical characteristics and prevalence of each ATN profile in cognitively unimpaired individuals aged 50 years and older.

Methods: All participants were in the Mayo Clinic Study of Aging, a population-based study that uses a medical records linkage system to enumerate all individuals aged 50-89 years in Olmsted County, MN, USA. Potential participants are randomly selected, stratified by age and sex, and invited to participate in cognitive assessments; individuals without medical contraindications are invited to participate in brain imaging studies. Participants who were judged clinically as having no cognitive impairment and underwent multimodality imaging between Oct 11, 2006, and Oct 5, 2016, were included in the current study. Participants were classified as having normal (A-) or abnormal (A+) amyloid using amyloid PET, normal (T-) or abnormal (T+) tau using tau PET, and normal (N-) or abnormal (N+) neurodegeneration or neuronal injury using cortical thickness assessed by MRI. We used the cutoff points of standard uptake value ratio (SUVR) 1·42 (centiloid 19) for amyloid PET, 1·23 SUVR for tau PET, and 2·67 mm for MRI cortical thickness. Age-specific and sex-specific prevalences of the eight groups were determined using multinomial models combining data from 435 individuals with amyloid PET, tau PET, and MRI assessments, and 1113 individuals who underwent amyloid PET and MRI, but not tau PET imaging.

Findings: The numbers of participants in each profile group were 165 A-T-N-, 35 A-T+N-, 63 A-T-N+, 19 A-T+N+, 44 A+T-N-, 25 A+T+N-, 35 A+T-N+, and 49 A+T+N+. Age differed by ATN group (p<0·0001), ranging from a median 58 years (IQR 55-64) in A-T-N- and 57 years (54-64) in A-T+N- to a median 80 years (75-84) in A+T-N+ and 79 years (73-87) in A+T+N+. The number of APOE ε4 carriers differed by ATN group (p=0·04), with carriers roughly twice as frequent in each A+ group versus the corresponding A- group. White matter hyperintensity volume (p<0·0001) and cognitive performance (p<0·0001) also differed by ATN group. Tau PET and neurodegeneration biomarkers were discordant in most individuals who would be categorised as stage 2 or 3 preclinical Alzheimer's disease (A+T+N-, A+T-N+, and A+T+N+; 86% at age 65 years and 51% at age 80 years) or with suspected non-Alzheimer's pathophysiology (A-T+N-, A-T-N+, and A-T+N+; 92% at age 65 years and 78% at age 80 years). From age 50 years, A-T-N- prevalence declined and A+T+N+ and A-T+N+ prevalence increased. In both men and women, A-T-N- was the most prevalent until age late 70s. After about age 80 years, A+T+N+ was most prevalent. By age 85 years, more than 90% of men and women had one or more biomarker abnormalities.

Interpretation: Biomarkers of fibrillar tau deposition can be included with those of β-amyloidosis and neurodegeneration or neuronal injury to more fully characterise the heterogeneous pathological profiles in the population. Both amyloid- dependent and amyloid-independent pathological profiles can be identified in the cognitively unimpaired population. The prevalence of each ATN group changed substantially with age, with progression towards more biomarker abnormalities among individuals who remained cognitively unimpaired.

Funding: National Institute on Aging (part of the US National Institutes of Health), the Alexander Family Professorship of Alzheimer's Disease Research, the Mayo Clinic, and the GHR Foundation.

Figure 1. Plots of ATN group characteristics

Box plots of continuous variables and bar charts summarizing percentages of categorical variables from table 1 by ATN biomarker group. The box plots and estimated percentages reflect weighting the sample to match the age and sex distribution of Olmsted County, Minnesota residents who are clinically normal. Box and bar widths reflect relative sample sizes. As in Table 1, the 8 groups are sorted left-right hierarchically first on the basis of A- vs A+, then T- vs T+, then N- vs N+.

Figure 2. Estimated prevalence of the ATN biomarker groups by age and sex

Panel A shows the estimated prevalence curves by age and sex for all ATN groups. Panel B shows the same curves as panel A (except for the A−T−N−, A−T+N+, and A+T+N+) on an enlarged scale with the estimated peak for each curve shown with a square and a 95% confidence interval.

Figure 3. Venn diagram of the estimated prevalence of each ATN group at age 65 and age 80

These estimates are averaged over men and women. Since estimates are for a given age among clinically normal individuals, weighting to the population is not necessary. 95% confidence intervals for the estimates are also shown.