Abstract
IMPORTANCE: It remains unclear which risk factors accelerate brain atrophy along with a progression from normal cognition to mild cognitive impairment (MCI). OBJECTIVE: To examine risk factors associated with the acceleration of brain atrophy and progression from normal cognition to MCI based on long-term longitudinal data for middle-aged and older adults. DESIGN, SETTING, AND PARTICIPANTS: Data for this cohort study were extracted from the Biomarkers for Older Controls at Risk for Dementia (BIOCARD) cohort, initiated at the National Institutes of Health from January 1, 1995, to December 31, 2005, and continued at Johns Hopkins University from January 1, 2015, to October 31, 2023. All participants were cognitively normal at baseline. The participants whose structural magnetic brain imaging (MRI) of the brain and cerebrospinal fluid (CSF) measures were available for over 10 years were included. EXPOSURES: Longitudinal structural MRI of the brain and measurement of CSF biomarkers for Alzheimer disease pathology (ratio of amyloid β peptide 42 [Aβ42] to Aβ40, tau phosphorylated at threonine 181, and total tau). MAIN OUTCOMES AND MEASURES: Annual change rates of segmental brain volumes, Kaplan-Meier survival curves plotting time to event for progression to MCI symptom onset, and hazard ratios (HRs) determined by Cox proportional hazards regression models. RESULTS: A total of 185 participants (mean [SD] age, 55.4 [8.4] years; 116 women [63%]) were included and followed up for a maximum of 27 years (median, 20 [IQR, 18-22] years). The groups with high levels of atrophy in the white matter and enlargement in the ventricles had an earlier progression from normal cognition to MCI symptom onset (HR for white matter, 1.86 [95% CI, 1.24-2.49]; P = .001; HR for ventricles, 1.71 [95% CI, 1.19-2.24]; P = .009). Diabetes was associated with progression to MCI (HR, 1.41 [95% CI, 1.06-1.76]; P = .04), as was a low CSF Aβ42:Aβ40 ratio (HR, 1.48 [95% CI, 1.09-1.88]; P = .04), and their combination had a higher HR of 1.55 (95% CI, 1.13-1.98]; P = .03), indicating a synergic association of diabetes and amyloid pathology with MCI progression. CONCLUSIONS AND RELEVANCE: In this cohort study of middle-aged and older adults, higher rates of volume change in the white matter and ventricles, along with the presence of diabetes and a low CSF Aβ42:Aβ40 ratio, were identified as important risk factors for the progression to MCI. These results support the importance of identifying individuals who have accelerated brain atrophy to optimize preventive strategies for progression to MCI.