Differential effects of APOE and modifiable risk factors on hippocampal volume loss and memory decline in Aβ- and Aβ+ older adults

Document Type

Journal Article

Publication Title



Wolters Kluwer / American Academy of Neurology


School of Medical and Health Sciences / Centre for Precision Health




National Health and Medical Research Council (NHMRC) - Project Grant: APP1161706, APP1191535, APP1197315, APP1152623; APP1140853; APP1132604, GNT1162645.

Grant Number

APP1161706, APP1191535, APP1197315, APP1152623, APP1140853, APP1132604, GNT1162645

Grant Link

http://purl.org/au-research/grants/nhmrc/1191535 http://purl.org/au-research/grants/nhmrc/1197315 https://researchdata.edu.au/big-nhmrc-adnet-app1152623-rowe/1607739/?refer_q=rows=15/sort=score%20desc/class=activity/p=1/q=1152623/ http://purl.org/au-research/grants/nhmrc/1140853 http://purl.org/au-research/grants/nhmrc/1132604


Rosenich, E., Bransby, L., Yassi, N., Fripp, J., Laws, S. M., Martins, R. N., ... & Lim, Y. Y. (2022). Differential Effects of APOE and Modifiable Risk Factors on Hippocampal Volume Loss and Memory Decline in Aβ− and Aβ+ Older Adults. Neurology, 98(17), e1704-e1715. https://doi.org/10.1212/WNL.0000000000200118


Background and Objectives This prospective study sought to determine the association of modifiable/nonmodifiable components included in the Cardiovascular Risk Factors, Aging, and Incidence of Dementia (CAIDE) risk score with hippocampal volume (HV) loss and episodic memory (EM) decline in cognitively normal (CN) older adults classified as brain β-amyloid (Aβ) negative (Aβ−) or positive (Aβ+). Methods Australian Imaging, Biomarkers and Lifestyle study participants (age 58–91 years) who completed ≥2 neuropsychological assessments and a brain Aβ PET scan (n = 592) were included in this study. We computed the CAIDE risk score (age, sex, APOE ε4 status, education, hypertension, body mass index [BMI], hypercholesterolemia, physical inactivity) and a modifiable CAIDE risk score (CAIDE-MR; education, hypertension, BMI, hypercholesterolemia, physical inactivity) for each participant. Aβ+ was classified using Centiloid >25. Linear mixed models assessed interactions between each CAIDE score, Aβ group, and time on HV loss and EM decline. Age, sex, and APOE ε4 were included as separate predictors in CAIDE-MR models to assess differential associations. Exploratory analyses examined relationships between individual modifiable risk factors and outcomes in Aβ− cognitively normal (CN) adults. Results We observed a significant Aβ group × CAIDE × time interaction on HV loss (β [SE] = –0.04 [0.01]; p < 0.000) but not EM decline (β [SE] = –2.33 [9.96]; p = 0.98). Decomposition revealed a significant CAIDE × time interaction in Aβ+ participants only. When modifiable/nonmodifiable CAIDE components were considered separately, we observed a significant Aβ group × CAIDE-MR × time interaction on EM decline only (β [SE] = 3.03 [1.18]; p = 0.01). A significant CAIDE-MR score × time interaction was observed in Aβ− participants only. Significant interactions between APOE ε4 and age × time on HV loss and EM decline were observed in both groups. Exploratory analyses in Aβ− CN participants revealed a significant interaction between BMI × time on EM decline (β [SE] = –3.30 [1.43]; p = 0.02). Discussion These results are consistent with studies showing that increasing age and APOE ε4 are associated with increased rates of HV loss and EM decline. In Aβ− CN adults, lower prevalence of modifiable cardiovascular risk factors was associated with less HV loss and EM decline over ∼10 years, suggesting interventions to reduce modifiable cardiovascular risk factors could be beneficial in this group.



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Research Themes


Priority Areas

Multidisciplinary biological approaches to personalised disease diagnosis, prognosis and management