Apolipoprotein E ε4 and ε3 alleles associate with cerebrospinal fluid tau and cognition in the presence of amyloid-𝜷 in mild cognitive impairment but not in Alzheimer’s disease

Abstract

Apolipoprotein E is the most well-established genetic risk factor for Alzheimer's disease. However, the associations of apolipoprotein E with tau pathology and cognition remain controversial. The research checks the hypothesis that the relationships between apolipoprotein E alleles and cerebrospinal fluid tau and cognition differ in persons with and without significant amyloid-β deposition. We divided 1119 subjects into cognitively normal (n = 275), mild cognitive impairment (n = 629), and Alzheimer's disease (n = 215), and these subjects were from the Alzheimer's Disease Neuroimaging Initiative database. Linear regression models were used to compare the relationships of apolipoprotein E alleles with cerebrospinal fluid tau and cognition in persons with significant amyloid-β deposition relative to individuals without significant amyloid-β deposition. The associations of apolipoprotein E ε4 and ε3 with total tau (T-tau), phosphorylated tau (P-tau), and Alzheimer's disease assessment scale was significantly substantial among participants with significant amyloid-β deposition. Stratified analyses showed that apolipoprotein E ε4 related to increased concentrations of T-tau, P-tau, and Alzheimer's disease assessment scale and apolipoprotein E ε3 associated with decreased concentrations of T-tau, P-tau, and Alzheimer's disease assessment scale in mild cognitive impairment participants with significant amyloid-β deposition, but not in Alzheimer's disease. Our study shows that the presence of apolipoprotein E ε4 and ε3 alleles is related to tau pathology and cognitive impairment in the presence of amyloid-β in mild cognitive impairment, but not in Alzheimer's disease. This work indirectly provides additional evidence that apolipoprotein E and amyloid-β may not have a role in modulating clinical Alzheimer's disease, and apolipoprotein E ε3 may be supposed to be protective to mild cognitive impairment.

Mesenchymal stem cells and ferroptosis: Clinical opportunities and challenges

“…GPX4 inhibits lipid peroxidation by directly reducing hydroperoxides in membrane lipids [ 80 ], exhibiting direct detoxification. Wang et al [ 68 ]found that in mice with repetitive mild traumatic brain injury (RmTBI), GPX inactivation, decrease in GPX4 levels, increase in lipid peroxidation, abnormal iron metabolism, and mitochondrial ultrastructural changes, are key risk factors for neurodegeneration, characterized by increased deposition of Aβ and tau proteins and cognitive impairment [ 81 ]. By reducing pathological protein deposition after RmTBI and promoting glucose metabolism, MSCs can alleviate neuronal degeneration, effectively regulate protein levels related to iron metabolism, inhibit iron accumulation, reduce RmTBI-induced Fer2+ accumulation, regulate iron metabolism, prevent lipid peroxidation by restoring GPX activity and GPX4 content, and inhibit ferroptosis ( Fig.…”

Predicting amyloid‐PET and clinical conversion in apolipoprotein E ε3/ε3 non‐demented individuals with multidimensional factors

“…In addition, the APOE genotype is also one influencing factor for cognitive decline. Both APOE ε3 and APOE ε4 have impact on cognition of MCI, with APOE ε4 having a more obvious negative effect, the APOE ε3 is also related to cognitive impairment for MCI with Aβ deposition (Xing et al, 2021). Ho and Yang reported a correlation between high Clinical Dementia Rating Sum of Boxes (CDR‐SOB) scores and Aβ‐PET (+) in patients with APOE ε3/ε3 MCI (Ho & Yang, 2020).…”

Bioinformatics-Based Analysis of Circadian Rhythm Regulation Mechanisms in Alzheimer’s Disease

“…closely related to genetics, aging, lifestyle, environmental factors, and nervous system diseases [1][2][3][4], but so far, the etiology and pathogenesis of AD is not clear. Although researchers have proposed the hypothesis of amyloid-␤ (A␤) cascade damage [5], tau hyperphosphorylation [5], cholinergic injury hypothesis [6], the ApoE hypothesis [7], neuroinflammatory hypothesis [8], and mitochondrial dysfunction hypothesis [9] for AD, they have yet to fully explain the complex mechanism of this disease. The prevalence of AD continues to rise, seriously affecting healthcare systems worldwide [10].…”