DOI: 10.1002/alz.079078 ISSN: 1552-5260

Association between APOE‐ε4 allele and cognitive function is mediated by Alzheimer’s disease pathology: a population‐based autopsy study in an admixed sample

Regina Silva Paradela, Vitor Ribeiro Paes, Alberto Fernando Oliveira Justo, Renata Elaine Paraizo Leite, Carlos Augusto Pasquallucci, Lea T. Grinberg, Michel S Naslavsky, Mayana Zatz, Ricardo Nitrini, Wilson Jacob‐Filho, Claudia Kimie Suemoto
  • Psychiatry and Mental health
  • Cellular and Molecular Neuroscience
  • Geriatrics and Gerontology
  • Neurology (clinical)
  • Developmental Neuroscience
  • Health Policy
  • Epidemiology



Apolipoprotein E ε4 allele (APOE‐ε4) is the main genetic risk factor for dementia. APOE‐ε4 is also associated with Alzheimer’s disease (AD) pathology, cerebrovascular disease, and non‐AD neurodegenerative pathologies. Although APOE‐ε4 may influence cognitive impairment through these pathways, less evidence is available from diverse populations, considering that APOE genotype associations seem to vary by race. Therefore, we aimed to evaluate the pathways linking APOE‐ε4 to cognition through AD and non‐AD neuropathology in an autopsy study with an admixed sample.


We used data from the Biobank for Aging Studies of the University of Sao Paulo Medical School. Participants were classified into APOE‐ε4 carriers (at least one ε4 allele) and non‐carriers. Cognitive function was evaluated by the Clinical Dementia Rating Scale sum of boxes. Mediation analyses were conducted to assess the APOE‐ε4 association with cognition through direct and indirect pathways. Indirect pathways included the following mediators: AD‐type pathology, lacunar infarcts, hyaline arteriosclerosis, cerebral amyloid angiopathy (CAA), Lewy body disease (LBD), and TAR DNA‐binding protein 43 (TDP‐43). We used immunohistochemistry to detect AD pathology, CAA, LBD, and TDP‐43. AD pathology was scored using the Braak staging for neurofibrillary tangles and the Consortium to Establish a Registry for AD criteria for β‐amyloid plaque. Lacunar infarcts and hyaline arteriosclerosis were evaluated microscopically using hematoxylin and eosin‐stained. All analyses were adjusted for demographic and clinical cofounders.


We included 648 participants (mean age 75±12 y, 52% women, 69% white, and 28% APOE‐ε4 carriers). The association between APOE‐ε4 and cognitive abilities was mediated by the burden of neurofibrillary tangles (β = 0.78, 95% CI = 0.39; 1.22, p<0.001) and β‐amyloid plaques (β = 0.87, 95% CI = 0.39; 1.40, p<0.001). Lacunar infarcts, hyaline arteriosclerosis, CAA, LBD, and TDP‐43 were not mediators in the pathway from APOE‐ε4 to cognitive function. Direct pathways remained significant in the presence of all mediators except TDP‐43 (p = 0.09) and β‐amyloid plaques (p = 0.07).


The influence of APOE‐ε4 on cognitive abilities was partially mediated by AD pathology. However, cerebrovascular lesions and non‐AD pathologies were not mediators in the pathway linking APOE‐ε4 to cognition.

More from our Archive