Association of APOE e2 genotype with Alzheimer's and non-Alzheimer's neurodegenerative pathologies

Abstract

The apolipoprotein E (APOE) gene contains both the major common risk variant for late onset Alzheimer's disease (AD), e4, and the major neuroprotective variant, e2. Here we examine the association of APOE e2 with multiple neurodegenerative pathologies, leveraging the NACC v. 10 database of 1557 brains that included 130 e2 carriers and 679 e4 carriers in order to examine potential neuroprotective effects. For AD-related pathologies of amyloid plaques and Braak stage, e2 had large and highly significant protective effects contrasted with e3/e3 and e4 carriers with odds ratios of about 0.50 for e3 contrasts and 0.10 for e4 contrasts. When we separately examined e2/e4 carriers, risk for AD pathologies was similar to that of e4 carriers, not e2 carriers. For multiple fronto-temporal lobar pathologies and tauopathies, e2 was not significantly associated with pathology. In sum, we found that e2 was associated with large but circumscribed protective effects.

Fig. 1. Associations of APOE genotype with amyloid and tau neuropathologies.

a Association of APOE genotype and diffuse amyloid plaque distribution. Within each APOE genotype column, colored rows represent the relative proportion of cases in each severity stage. These proportions are expressed as percentages and add to 100. There are increasing proportions of the most severe pathology (plaque stage 5) from the e2 to e4/e4 genotype groups in stepwise fashion. Amyloid stage 0 = no pathology; stage 5 = severe. b Association of APOE genotype and Braak stage. Within each APOE genotype column, colored rows represent the relative proportion of cases in each severity stage. These proportions are expressed as percentages and add to 100. There are increasing proportions of the most severe pathology (Braak stages v and vi) from the e2 to e4/e4 genotype groups in stepwise fashion. Braak stage 0 = no pathology; stage vi = severe neocortical pathology. c Association of APOE genotype and neuritic amyloid plaque density level. Within each APOE genotype column, colored rows represent the relative proportion of cases in each severity stage. These proportions are expressed as percentages and add to 100. There are increasing proportions of the most severe pathology (plaque stages v and vi) from the e2 to e4/e4 genotype groups in stepwise fashion. Neuritic plaque stage 0 = no pathology; stage 3 = severe pathology.

Fig. 2. Mediation analysis of APOE e2 versus e3 showing both direct and indirect effects (via neuritic plaques) on Braak stage.

Values represent beta weights after adjustment.

Fig. 3. Association of APOE e2/e4 genotype with Braak stage.

Within each APOE genotype column, colored rows represent the relative proportion of cases in each severity stage. These proportions are expressed as percentages and add to 100. Note the similarity of e2/e4 cases to e3/e4 cases with respect to high levels of tau pathology. Braak stage 0 = no pathology; stage 6 = severe neocortical pathology.

Fig. 4. Association of APOE genotype with Lewy body pathology.

Within each APOE genotype column, colored rows represent the relative proportion of cases in each severity stage. These proportions are expressed as percentages and add to 100. Note the high proportion of e4 cases with limbic and neocortical pathology and the paucity of e4 cases with pathology restricted to the midbrain. Lewy body stage 0 = no pathology; stage 1 = midbrain; stage 2 = limbic; stage 3 = neocortical.