Age and sex specific prevalences of cerebral β-amyloidosis, tauopathy and neurodegeneration among clinically normal individuals aged 50-95 years: a cross-sectional study

BACKGROUND: A new descriptive classification scheme for biomarkers used in Alzheimer's and cognitive aging research, labeled ATN, was recently proposed. One implementation of this ATN construct dichotomizes biomarkers of amyloid, tau, and neurodegeneration/neuronal injury as normal or abnormal resulting in 2 × 2× 2=8 possible biomarker profiles. We determined the clinical characteristics and prevalence of each ATN group among clinically normal individuals aged 50 and older from a population based cohort. METHODS: All individuals in this study were participants in the Mayo Clinic Study of Aging, a population-based study of cognitive aging. Potential participants were randomly selected from the Olmsted County, Minnesota population by age- and sex-stratification and invited to participate in cognitive evaluations and undergo multimodality imaging. To be eligible for inclusion in this study, participants must have been judged clinically to have no cognitive impairment and have undergone multi-modality imaging. Imaging studies were obtained from October 11, 2006 to October 5, 2016. All 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 (−) or abnormal (N+) neurodegeneration/neuronal injury using cortical thickness. The cut points used were SUVR 1·42 (centiloid 19) for amyloid PET, 1·23 SUVR for tau PET, and 2·67 mm for MRI cortical thickness. Age- and sex- specific prevalences of the eight ATN biomarker groups were determined using 435 individuals with amyloid PET, tau PET, and MR imaging and 1113 additional clinically normal individuals who underwent amyloid PET and MR imaging, but not tau PET imaging. FINDINGS: There 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+ individuals. Age differed by ATN group (p<0 001) ranging from a median age of 57 in the A−T−N-−and A−T+N− groups to 80 in the A+T−N+ and A+T+N+ groups. The frequency of APOE ε4 carriers differed by ATN group (p=0·04) with ε4 carriers roughly twice as frequent in A+ versus A−. 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 the majority of individuals who would be labeled stage 2/3 preclinical AD (86% at age 65 and 51% at age 80) or suspected non-Alzheimer's pathophysiology (SNAP) (92% at age 65 and 78% at age 80). From age 50, A−T−N− prevalence declines while A+T+N+ and A−T+N+ increase continuously with age. In both men and women, A−T−N− is the most prevalent group until their late 70s. After about age 80, A+T+N+ is the most prevalent group until their late 70s. After about age 80, A+T+N+ is the most prevalent group. The remaining ATN groups reach individual peaks in the 60–90 age range and then decline in prevalence. By age 85 over 90% of men and women have one or more biomarker abnormalities. INTERPRETATION: Biomarkers of fibrillar tau deposition can be included with those of Aβ and neurodegeneration/neuronal injury to more fully characterize the heterogeneous pathological profiles in the population. The prevalence of each ATN group changes substantially with age with progression toward more biomarker abnormalities even among individuals who remain clinically normal. Both abnormal amyloid and normal amyloid pathological profiles can be identified in the clinically normal population.