APOE ε4 allele accelerates age-related multi-cognitive decline and white matter damage in non-demented elderly

Abstract

Advanced age and apolipoprotein E ( APOE ) ε4 allele are both associated with increased risk of the Alzheimer’s disease (AD). However, the extent of the joint contribution of APOE ε4 allele and age on the brain white matter integrity, cognition and their relationship are unclear. We assessed the age-related variation differences of major cognitions in 846 non-demented elderly, and brain major white matter tracts in an MRI sub-cohort of 111 individuals between ε4 carriers and noncarriers. We found that: (i) carriers showed a steeper age-related decline after age 50 in general mental status, attention, language, and executive function and performed worse than noncarriers at almost all ages; (ii) main effect of age on anterior fibers, but main effect of APOE ε 4 on posterior fibers, and the interactive effect of them existed on anterior and posterior fibers; (iii) carriers showed an accelerated age-related integrity reduction of these fibers compared to noncarriers who had a slight decrease but not significant; and (iv) significant associations of the higher white matter integrity with better multi-cognitive performance in old ε4 carriers. Overall, combining APOE status with age may be useful in assessing possible mechanisms of disease development in AD.

White matter injury, cholesterol dysmetabolism, and APP/Abeta dysmetabolism interact to produce Alzheimer’s disease (AD) neuropathology: A hypothesis and review

“…In 10.3389/fnagi.2023.1096206 contrast APOE2 elderly cognitively normal carriers have robust white matter by DTI (Chiang et al, 2012). Even one APOE4 allele increases cognitive decline and white matter damage in non-demented elderly (Sun et al, 2020). ApoE4 is associated with atherosclerosis, amyloid angiopathy, and WM damage in AD (Tian et al, 2004) and likely accounts at least in part for the frequent co-occurrence of these conditions in AD patients (Sweeney et al, 2019).…”

“…There is now a considerable literature on how cholesterol and ApoE interact with Abeta synthesis and transport, APP metabolism, amyloid formation and tau phosphorylation (Michikawa, 2006;Carter, 2007;Popp et al, 2013;Allinquant et al, 2014;Gamba et al, 2015;Sun et al, 2015;Fanaee-Danesh et al, 2019;Loera-Valencia et al, 2019;Chew et al, 2020;Chai et al, 2021;Nanjundaiah et al, 2021;Wu et al, 2022). In general higher plasma and brain cholesterol and its metabolites correlate with higher brain Abeta levels and lower CSF Abeta levels (Reed et al, 2014;Iriondo et al, 2020).…”

Genetic mutations of APOEε4 carriers in cardiovascular patients lead to the development of insulin resistance and risk of Alzheimer's disease

“…amyloid-β PP, amyloid-β precursor protein; APP, amyloid protein precursor; PSEN1, presenilin-1; PSEN2, presenilin-2; ROS, reactive oxygen species repair process after neuronal cell death and/or injury. [35,36] However, ε4 inhibits synaptic plasticity in the cortex and hippocampus as compared to ε3 and ε2 alleles. APOE ε4 has also been reported to have inhibitory effects on micro-tubular assembly (Figure 3), on the other hand, ε3 can stimulate the formation of microtubules and polymerization of β-tubulin.…”

APOE4 allele-specific associations between diet, multimodal biomarkers, and cognition among Puerto Rican adults in Massachusetts

“…Stratifying the sample into relatively younger ( n = 78) and older ( n = 78) individuals, based on mean age (68 years) showed lower WM ND in bilateral ILF (Left: p = 0.03, Right: p = 0.04) and bilateral SLFT (Left: p = 0.03, Right: p = 0.01) in carriers <68 years. Model 2 additionally accounted for interaction between age×APOE4 and showed lower ND in carriers in bilateral ILF (Left: p = 0.03, Right: p < 0.05) and right SLFT ( p = 0.04) ( Figure 1B ), as well as higher OD in right ILF and left SLFT ( Table 3 ) ( Operto et al, 2019 ; Sun et al, 2020 ). In model 3, the same tracts remained clearly different after adjusting education and CVR ( Figure 1C ).…”