Effect of apolipoprotein genotype and educational attainment on cognitive function in autosomal dominant Alzheimer’s disease

Abstract

Autosomal dominant Alzheimer’s disease (ADAD) is genetically determined, but variability in age of symptom onset suggests additional factors may influence cognitive trajectories. Although apolipoprotein E (APOE) genotype and educational attainment both influence dementia onset in sporadic AD, evidence for these effects in ADAD is limited. To investigate the effects of APOE and educational attainment on age-related cognitive trajectories in ADAD, we analyzed data from 675 Presenilin-1 E280A mutation carriers and 594 non-carriers. Here we show that age-related cognitive decline is accelerated in ADAD mutation carriers who also have an APOE e4 allele compared to those who do not and delayed in mutation carriers who also have an APOE e2 allele compared to those who do not. Educational attainment is protective and moderates the effect of APOE on cognition. Despite ADAD mutation carriers being genetically determined to develop dementia, age-related cognitive decline may be influenced by other genetic and environmental factors.

Genetic modifiers of cognitive decline in PSEN1 E280A Alzheimer's disease

“…Recently, in a larger sample of PSEN1 E280A carriers, an association between APOE ε4 allele and faster cognitive decline was identified. 12 Sample size could be considered a limitation of the present study. For that finding, we did not identify an association between slope of cognitive decline and APOE alleles (Table S10 in supporting information).…”

“… 9 In both cases, rate of decline can be affected by other factors such as years of education 10 or apolipoprotein E ( APOE ) haplotype. 11 , 12 Not all cognitive domains decline at the same rate, and more rapidly declining domains can be disease specific, with memory, language, and executive function showing faster decline rates in AD. 13 Some attempts have been made to find genetic markers for cognitive decline progression in AD, with variable success.…”

Early- and Late-Onset Alzheimer’s Disease: Two Sides of the Same Coin?

“…However, articles show great heterogeneity in their results. Regarding AoO, De Luca et al, 2016 and Valdez-Gaxiola et al, 2023 [ 167 , 168 ] showed that the presence of APOEε4 retards the appearance of EOAD symptoms, while studies like Langella et al, 2023 [ 169 ] suggest that it decreases AoO and accelerates cognitive decline in PSEN1 E280A carriers (related to fAD). Nonetheless, Ryan et al, 2016 [ 170 ], studying a fAD population, found no effect of APOEε4 over AoO nor cognitive symptoms.…”

A Toxicogenic Interaction between Intracellular Amyloid-β and Apolipoprotein-E

“…Apolipoprotein E (ApoE), particularly the ApoE4 allele, is the strongest non-Aβ risk factor associated with late-onset of AD . Aβ and p-tau aggregates are directly observable in AD patients’ brains, but their interaction with ApoE (if any) remains less well established. − A plausible interaction of ApoE with Aβ has been a focus of multiple solution-state and intracellular studies .…”