journal articles
AMYLOID PATHOLOGY AND MODIFIABLE RISK FACTORS IN COGNITIVE DECLINE AMONG COGNITIVELY UNIMPAIRED OLDER ADULTS
Ying-Hsin Hsu, Chih-Kuang Liang, Ming-Yueh Chou, Jaysón Davidson, Yu-Chun Wang, Mike A. Nalls, Luigi Ferrucci, Mark Cookson, Hirotaka Iwaki
BACKGROUND: Alzheimer’s disease (AD) pathology, particularly amyloid-β (Aβ) deposition, occurs years before clinical symptoms. Modifiable risk factors may influence cognitive trajectories during this preclinical stage, but whether amyloid status alters their effects remains unclear.
OBJECTIVES: To investigate interactions between amyloid pathology and modifiable risk factors in predicting longitudinal cognitive decline among cognitively unimpaired older adults.
DESIGN AND SETTING: This study was a secondary analysis of data derived from two large multicenter longitudinal cohort studies, the Anti-Amyloid Treatment in Asymptomatic Alzheimer Disease (A4) Study and the Longitudinal Evaluation of Amyloid Risk and Neurodegeneration (LEARN) Study.
PARTICIPANTS: A total of 1707 cognitively unimpaired adults aged 65–85 years were included, comprising 1169 amyloid-positive participants from the A4 Study (Aβ+) and 538 amyloid-negative participants from the LEARN Study (Aβ–).
MEASUREMENTS: Cognitive function was assessed every six months using the Preclinical Alzheimer’s Cognitive Composite (PACC) over a mean follow-up of 4.9 years. Eight established modifiable risk factors—low education, alcohol use, diabetes, high cholesterol, high blood pressure, obesity, depressive symptoms, and physical inactivity—were evaluated. Linear mixed-effects models were applied to examine associations between each risk factor and longitudinal PACC decline, and to test interactions with amyloid status, adjusting for demographic and genetic covariates.
RESULTS: Significant interactions between amyloid status and modifiable risk factors were observed for diabetes (adjusted β = −0.206, p = 0.032), high cholesterol (adjusted β = −0.155, p < 0.001), and physical inactivity (adjusted β = −0.161, p = 0.046), indicating combined effects rather than additive effects on cognitive decline among Aβ+ individuals. In the A4 study (Aβ+), low education, diabetes, high cholesterol, and physical inactivity were independently associated with accelerated cognitive decline, whereas obesity was linked to slower decline. In contrast, in the LEARN study (Aβ-), these associations were not statistically significant.
CONCLUSIONS: In conclusion, the significant interactions with amyloid status were observed for diabetes, high cholesterol, and physical inactivity, indicating that these risk factors were associated with faster cognitive decline specifically in Aβ+ individuals. The results suggest that consideration of amyloid status may be important when evaluating the potential role of metabolic and lifestyle risk factors in preclinical cognitive decline. In Aβ+ individuals, obesity was associated with slower cognitive decline, while low education was linked to lower baseline cognition or a reduced symptom threshold, without a significant interaction with amyloid status. Future studies should incorporate amyloid status and longitudinal biomarkers to assess whether modifying these factors can slow preclinical cognitive decline.
CITATION:
Ying-Hsin Hsu ; Chih-Kuang Liang ; Ming-Yueh Chou ; Jaysón Davidson ; Yu-Chun Wang ; Mike A. Nalls ; Luigi Ferrucci ; Mark Cookson ; Hirotaka Iwaki (2025): Amyloid pathology and modifiable risk factors in cognitive decline among cognitively unimpaired older adults. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100574