Lifetime and 10-year absolute risk of cognitive impairment in relation to amyloid PET severity: a retrospective, longitudinal cohort study.

BACKGROUND: A key knowledge gap concerns the lifetime risk of developing cognitive impairment among individuals who are cognitively unimpaired with abnormal Alzheimer's disease biomarkers. Our aim was to compute lifetime and 10-year absolute risk of cognitive impairment as a function of continuous amyloid PET. METHODS: In this retrospective, longitudinal cohort study of data from participants of the population-based Mayo Clinic Study of Aging (Olmsted County, MN, USA), we computed lifetime and 10-year absolute risk of cognitive impairment in participants who were cognitively unimpaired and aged 50 years or older at enrolment. The primary predictor of interest was biological Alzheimer's disease severity, based on amyloid PET centiloid value. Starting age, sex, and APOE ε4 carriership status were also predictors. Outcomes were incident mild cognitive impairment (MCI), dementia, and death, which were ascertained or estimated via multistate hidden Markov modelling both in study and out of study. FINDINGS: Between Nov 29, 2004, and Dec 2, 2024, 5158 participants (2623 [51%] women and 2535 [49%] men) who are cognitively unimpaired and 700 (307 [44%] women and 393 [56%] men) with MCI were included for analysis. Lifetime risk of MCI and dementia increased monotonically with increasing centiloid value (p<0·0001), which was the predictor with the largest effect. Lifetime risk of MCI for male APOE ε4 carriers who are cognitively unimpaired at a starting age of 75 years was 56·2% (95% CI 50·5-61·9) for centiloid 5, 60·2% (54·9-65·6) for centiloid 25, 71·0% (65·2-76·7) for centiloid 50, 75·2% (69·1-81·2) for centiloid 75, and 76·5% (70·5-82·4) for centiloid 100. Lifetime risk of MCI for female APOE ε4 carriers who are cognitively unimpaired at a starting age of 75 years was 68·9% (63·7-74·1) for centiloid 5, 71·3% (66·6-76·0) for centiloid 25, 77·6% (72·5-82·7) for centiloid 50, 81·2% (76·7-85·7) for centiloid 75, and 83·8% (78·5-89·1) for centiloid 100. Within each centiloid group, and for both men and women, lifetime and 10-year absolute risk for MCI and dementia was greater for APOE ε4 carriers than for non-carriers (p<0·0001). Biological severity of Alzheimer's disease was a predictor of 10-year absolute risk of MCI and dementia (p<0·0001); however, starting age (p<0·0001) had a more prominent effect. The rate of incident dementia was two times greater among individuals who had previously left the study than those who remained in the study. INTERPRETATION: Lifetime and 10-year absolute risk for MCI and dementia among individuals who are currently cognitively unimpaired increase with increasing biological severity of Alzheimer's disease. This information should be important for risk-benefit evaluation of therapeutic interventions in the future. The high lifetime risk in participants with higher centiloid values addresses academic controversies concerning risk of future impairment associated with biomarkers of Alzheimer's disease among individuals who are cognitively unimpaired. Ascertainment and modelling of out-of-study outcomes are necessary for accurate lifetime risk estimates. FUNDING: US National Institutes of Health, GHR Foundation, and the Alexander Family.