Abstract
This study aimed to investigate whether the midlife cognitive activity and physical activity moderate the relationship between apolipoprotein Eε4 (APOE4) and in vivo Alzheimer’s disease (AD) pathologies. In total, 287 non-demented older adults (mean age 72 years) from the Korean Brain Aging Study for the Early diagnosis and prediction of Alzheimer’s disease cohort were included. Participants underwent a comprehensive clinical assessment including the evaluation for midlife CA and physical activity, [11C]-Pittsburgh-Compound-B-positron emission tomography (PET), [18F]-fluorodeoxyglucose PET, structural magnetic resonance imaging (MRI), and APOE genotyping. We used linear regression and regression-based mediated-moderation models for statistical analyses. Neither midlife cognitive activity nor physical activity moderated the effect of APOE4 on β-amyloid (Aβ) retention itself. Midlife cognitive activity significantly moderated the effect of APOE4 on hippocampal volume [B (SE) = − 627.580 (252.327), t = −2.488, p = 0.014]: APOE4 carriers had smaller hippocampal volume than non-carriers at relatively high cognitive activity state (p = 0.004), but not at relatively low cognitive activity condition (p = 0.937). Midlife physical activity significantly moderated the effect of Aβ retention, which was closely related to APOE4, on AD-signature region cerebral glucose metabolism [AD-CM; B (SE) = 0.004 (0.002), t = 2.030, p = 0.043]: higher Aβ accumulation was associated with lower AD-CM in relatively low physical activity condition (p < 0.001), whereas no such association was observed in relatively high physical activity state (p = 0.791). The findings suggest that high midlife cognitive activity may accelerate hippocampal atrophy induced by APOE4, whereas high midlife physical activity may delay AD-related cerebral hypometabolism by weakening the influence of APOE4-associated Aβ retention.
Highlights
The apolipoprotein ε4 (APOE4) is the most well-evidenced risk gene for Alzheimer’s disease (AD; Corder et al, 1993) and is related to in vivo AD pathologies such as β-amyloid (Aβ) accumulation (Morris et al, 2010), reduced hippocampal volume (Hashimoto et al, 2001), and decreased AD-signature region cerebral glucose metabolism (AD-CM; Small et al, 1995; Lowe et al, 2014)
We aimed to investigate whether the midlife cognitive activity and physical activity can moderate the effect of APOE4 on in vivo AD pathologies measured by neuroimaging modalities
There were no differences between APOE4 carriers and non-carriers regarding age, sex, education, or midlife cognitive activity or physical activity
Summary
The apolipoprotein ε4 (APOE4) is the most well-evidenced risk gene for Alzheimer’s disease (AD; Corder et al, 1993) and is related to in vivo AD pathologies such as β-amyloid (Aβ) accumulation (Morris et al, 2010), reduced hippocampal volume (Hashimoto et al, 2001), and decreased AD-signature region cerebral glucose metabolism (AD-CM; Small et al, 1995; Lowe et al, 2014). Studies on the in vivo neuropathological mechanisms underlying the association between cognitive activity or physical activity and AD-related cognitive decline have produced controversial findings (Valenzuela et al, 2008; Erickson et al, 2009; Liang et al, 2010; Bugg and Head, 2011; Head et al, 2012; Landau et al, 2012; Vemuri et al, 2012, 2016, 2017; Brown et al, 2013b; Wirth et al, 2014; Gidicsin et al, 2015; Ko et al, 2018) Such modifiable lifestyle activities may change the AD pathophysiological processes associated with APOE4. Their moderation for the influence of APOE4 on AD pathologies remains poorly understood (Kivipelto et al, 2008; Head et al, 2012; Wirth et al, 2014)
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