The Brazilian population is highly admixed, with >90% of its ancestry derived from African slaves and European immigrants, which makes it ideal for ancestry-related studies. Moreover, Brazilian law mandates that autopsies be performed in all persons without a death certificate, which provides a large recruitment base for populational studies in neuropathology, without bias toward demented persons. The University of São Paulo alone performs more than 14 000 autopsies per year, encompassing the full range of demographic variation of the city. The centering of all samples in a single institution also greatly reduced inter-rater variation in both interviews and pathology.

Contrary to previous studies, our results show that African ancestry is highly protective of Alzheimer's disease neuropathology (neuritic plaques), with an adjusted OR of 0.43. This suggests that unknown genetic variants or environmental factors associated with African ancestry reduce the accumulation of β-amyloid or increase its clearance. The results are robust and are not altered when studying only those who self-defined themselves as whites, when adjusting for APOE4 status only or when adjusting for age and sex only.

Previous studies with the United States population reported a significantly higher prevalence of dementia in African Americans when compared with Caucasians.8, 9, 10, 11, 12 These differences could be due to cultural differences in the performance on cognitive screening tests, such as the Mini Mental Status Examination, genetic differences between races, environmental differences or likely a combination of factors.13, 14, 15, 16 In a study comparing dementia in Nigerians and African Americans, the former had significantly lower disease rates. Our data suggest that these results might be explained not only by environmental differences, but also by the European admixture present in African Americans.39 Further studies are needed to confirm this.

Cardiovascular disease risk and stroke also vary between races, but statistical significance often disappears when adjustments for socioeconomic levels are applied.14, 40, 41 Lower educational and socioeconomic levels in those with higher African ancestry may create important differences in disease susceptibility, which is independent of genetics, but confounds the analysis.

To our knowledge, few studies have compared autopsy-diagnosed cases in different races and none used AIMs.17, 18, 19 The growing clinical use of AIMs was recently shown by Kumar et al21 as a tool for improved lung-function prediction in African Americans, although this should only be considered an intermediary step toward the use of specific disease-related variants in personalized medicine.42, 43 Furthermore, dementia is a complex clinical phenotype that may be caused by widely diverse pathologies, and post-mortem diagnosis remains the gold-standard. The specific neuropathology of Alzheimer's disease, Lewy body dementia and vascular dementia may have different underlying biological and genetic causes, and should therefore be studied separately.

A few notes of caution regarding this study should be pointed out. First, although we adjusted for multiple environmental and social factors as well as APOE genotype, other untested environmental factors may be confounding our ancestry results. Second, African populations are highly variable (more so than Europeans), and therefore we cannot state from our data that this effect is applicable to all African populations.13 It is unknown if there are population subgroups within Africa with different risk profiles for neuropathological alterations. Actually, our results reinforce the need for more Alzheimer's disease studies in the developing world, for trends identified in the United States may not be universal. Third, we have adjusted our analysis using known cardiovascular risk factors, to focus on unknown genetic factors, but many authors have suggested that ethnic/racial differences in dementia prevalence may in fact be derived from differences in these factors (for example, hypertension, diabetes). A future expansion of this data set is required to answer these questions with confidence, especially regarding vascular dementia.

In conclusion, our study shows, for the first time, that Alzheimer's neuropathological findings depend on the ancestral genetic background. It clearly demonstrates that the presence of neuritic plaques are reduced in persons with African ancestry in a population-based sample, independently of known confounding factors. This should serve as a basis for future genetic studies of Alzheimer's disease, as well as alert against overinterpreting epidemiological studies using race and clinically diagnosed dementia.