THE APOE-ε4 ALLELE AND AGE SYNERGISTICALLY DRIVE DISEASE PROGRESSION IN ALZHEIMER'S DISEASE. (8th November 2019)

• Record Type: Journal Article
• Authors: Kleineidam, Luca; Zammit, Andrea R; DeVito, Alyssa; Lipton, Richard B; Peters, Oliver; Ramirez, Alfredo; Wagner, Michael; Terrera, Graciela Muniz
• Is Part Of: Innovation in aging. Volume 3(2019)Supplement 1
• Page Start: S943
• Page End: S943
• Publication Date: 2019-11-08
• Subjects: Aging -- Periodicals; Gerontology -- Periodicals; 612.67
• DOI: 10.1093/geroni/igz038.3427
• Languages: English
• ISSNs: 2399-5300

Abstract

Abstract: The Apolipoprotein E (APOE)-ε4 allele is the strongest genetic risk factor for Alzheimer's disease (AD) and other neurodegenerative dementias. Cross-sectional case-control studies suggest that the effect of APOE-ε4 decreases in old age. However, since APOE- ε4 is associated with mortality, these studies might be prone to bias due to selective survival. Therefore, we used multi-state-modeling in longitudinal cohort studies to examine the effect of APOE-ε4 on the transition through cognitive states (i.e. cognitively normal, mild cognitive impairment (MCI) and dementia) while taking death as a competing risk into account. Results from the German AgeCoDe study (n=3000, aged 75-101 years) showed that APOE-ε4 increases the risk for cognitive deterioration in all disease stages. Contrary to results from cross-sectional studies, the effect of APOE-ε4 on the transition from MCI to dementia increased with increasing age (HR=1.044, 95%-CI=1.001-1090). The direction of this effect was confirmed in a smaller sample from the Einstein Aging Study (n=744, HR=1.032, 95%-CI=0.949-1.122). To examine the pathophysiological basis of these results, generalized additive models were used to study AD biomarkers in the liquor of 1045 patients with MCI or AD-dementia. Here, increased amyloid (Abeta1-42) pathology was associated with increased tau pathology (pTau181), consistent with the amyloid-cascade-hypothesis. Interestingly, higher age and presence of the APOE-ε4 synergistically lowered the amount of amyloid required to exacerbate tau pathology (interaction p=0.012). Taken together, our results suggest that the effect of APOE-ε4 on disease progression increases with advancing age. An altered neuroinflammatory response to neurodegeneration should be further explored as potential underlying mechanism.