How does apolipoprotein E genotype influence the relationship between physical activity and Alzheimer’s disease risk? A novel integrative model

de Frutos Lucas, Jaisalmer; Sewell, Kelsey R.; García-Colomo, Alejandra; Markovic, Shaun; Erickson, Kirk I.; Brown, Belinda M.

doi:10.1186/s13195-023-01170-4

Table 1 Suggestions for prospective studies. Abbreviations: Aβ amyloid-beta, APOE apolipoprotein E—gene, ApoE apolipoprotein E—protein, BBB brain-blood barrier, CNS central nervous system, PA physical activity, p-tau phosphorylated tau, TLR toll-like receptor

From: How does apolipoprotein E genotype influence the relationship between physical activity and Alzheimer’s disease risk? A novel integrative model

Identified testable hypotheses
1. In APOE ε4 carriers, PA, via downregulation of pro-inflammatory cytokines and preservation of the BBB, will reduce the negative effects of pro-inflammatory molecules on Aβ burden 2. In APOE ε4 carriers, PA, via downregulation of pro-inflammatory cytokines and preservation of the BBB, will reduce the negative effects of pro-inflammatory molecules on tau hyperphosphorylation 3. PA-induced Aβ clearance by means of protease upregulation will be more efficient in APOE ε4 non-carriers 4. Immunosenescence and age-related downregulation of neurotrophic factors reduce the ability of PA to counteract the detrimental effects of APOE ε4 carriage 5. PA will less efficiently contribute to the preservation of capillary pericytes, small vessels and the BBB in the presence of the APOE ε4 allele 6. Alternatively, greater levels of PA might be required for APOE ε4 carriers to show improvements in the integrity of the BBB 7. PA will improve insulin signalling and glucose metabolism in the CNS even in the presence of the APOE ε4 allele 8. Midlife PA will reduce the risk of brain insulin resistance in late life, even in the presence of the APOE ε4 allele
Relevant exploratory questions
1. Can PA counteract the increased Aβ oligomerization driven by ApoE4 presence? 2. Does PA, through increased expression of neurotrophic factors, still promote neurogenesis and synaptogenesis despite the detrimental effects of APOE ε4 carriage on lipid transport? 3. How does APOE genotype modulate the neurotrophic response to PA in clinical subgroups at various stages of disease progression? 4. Does PA improve glucose metabolism, glucose transporter levels, insulin receptor and transporter levels and mitochondrial function in the presence of the APOE ε4 allele? 5. Can PA revert brain insulin signalling and glucose metabolism impairments regardless of APOE genotype?

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