Published estimates of LOAD incidence rates in the literature have been variable owing to underlying differences in populations, varying case ascertainment, or different study designs.26
Unaffected members of families multiply affected by LOAD are assumed to have an increased risk of dementia. Family studies tend to be biased because recruitment strategies favor large, multiplex families. Most previous studies of familial risk of LOAD have included a small number of families or families with specific genetic variants, making it difficult or impossible to estimate incidence rates. The goal of this study was to determine whether the incidence rate for new-onset dementia, specifically LOAD, in multiplex families exceeded that in the general population.
The results here suggest that the incidence rate of LOAD in the NIA-LOAD/NCRAD families, who are multiply affected by the disease, exceed published population incidence rates18–23
by 3-fold or more. Despite the lack of comparable studies, we elected to contrast the AD incidence rate estimates calculated from a family-based study design with those from population-based studies to emphasize and quantify the importance of familial aggregation studies. As expected, the incidence in the NIA-LOAD/NCRAD families was also higher than has been observed in families ascertained through a single individual with LOAD, owing to multiple NIA-LOAD/NCRAD individuals who have had LOAD. Higher rates of incidence in such families could be partially attributed to relatives of affected individuals who might be recruited with early signs of mild cognitive impairment and who might be more likely to develop dementia or AD in subsequent visits. The increased incidence rate may result from enrichment for the rare and common variants currently the subject of large-scale investigations in these families. Alternatively, these families may also have an increased frequency of certain environmental exposures or behaviors associated with increased risk. We also observed no differences in rates between men and women, but the incidence increased with advancing age.
The EFIGA began 20 years ago to identify the cause or causes of the high frequency of LOAD among Caribbean Hispanics living in New York and the Dominican Republic. Compared with white populations residing in the same communities, the incidence rate of LOAD is approximately twice as high in Caribbean Hispanics, leading to a considerable burden is this population group.6
The increased incidence rate of LOAD could be explained by common ancestry and inbreeding within the isolated population. In addition, common risk factors that are known to be associated with LOAD risk, such as diabetes mellitus, obesity, hypertension, low levels of education, and an unhealthy diet, are also more frequent in this ethnic group.6
Although recently identified genetic associations in non-Hispanic populations have been replicated in Caribbean Hispanics, the specific single-nucleotide polymorphism variants can differ.27
This variation results in part from differences in allele frequency and linkage disequilibrium structure. The population-based estimates of incidence rates among African Americans have been reported to be 2-fold greater than those for whites and are comparable to but slightly higher than those for Caribbean Hispanics.6
Dominicans and Puerto Ricans share strong genetic African ancestry,28
which resulted from the large influx of African slaves into the islands of the Caribbean basin after the mid-16th century, when European settlers imported them for agricultural production. We also estimated a strong African ancestry in Caribbean Hispanics from genome-wide single-nucleotide polymorphism data.27
These observations suggest that Caribbean Hispanics who are most closely related to Western Africans among the broad Hispanic populations might share common risk factors for LOAD with African Americans.
The incidence rate among unaffected family members in the EFIGA was at least twice as high as that observed in the NIA-LOAD/NCRAD families. The frequency of APOE
alleles in the NIA-LOAD/NCRAD individuals at risk is similar to that of EFIGA individuals () but substantially enriched compared with some population estimates among the white individuals. The higher incidence of AD in Caribbean Hispanics is not attributable to enrichment of APOE
ε4 alleles and could be due to familial clustering or other genetic risk variants. Socioeconomic factors, such as low rates of literacy and occupational attainment, have been shown to increase the risk of developing AD.29
However, results relating AD risk to educational level are inconclusive in the literature,29–33
which might indicate that educational level captures the effect of yet unknown early life factors. The educational levels attained among individuals in the NIA-LOAD/NCRAD and EFIGA families are significantly different (P
< 2 × 10−16
) (), which could increase the risk of LOAD in the EFIGA cohort.
The sex bias in AD has conflicting evidence in the literature. An increased prevalence of AD among women has been reported in many studies.34–41
However, incidence studies have generally found no significant sex difference,18,23,42–44
which could be explained by lack of sample size and by low recruitment at the highest ages of incidence for men. Remarkably, we observed a more than 2-fold increase in the incidence of AD in men in the group aged 75 to 84 years within the NIA-LOAD/ NCRAD data set, but the incidence rates were similar in the other age categories. We believe that this estimate might be biased by a limited number of observations and requires replication in other studies. In the EFIGA data set, we observed small sex differences in incidence rates within the 3 age groups, with overlapping 95% confidence intervals consistent with the previous findings in the literature. This study suggests that the family-based incident rates of dementia and AD are higher than in the general population and that Caribbean Hispanics have significantly a higher rate than the white population.