A new family-based study has confirmed what many researchers have long suspected: having multiple relatives with late-onset Alzheimer’s increases a person’s chances of coming down with the disease themselves. Results drawn from two separate cohorts of families tracked for more than a decade reveal that unaffected people with a heavy burden of AD in their family have more than three times the chance of ultimately getting the disease as does the general population. For those of Caribbean Hispanic descent, the chances could be nearly twice as high again, researchers reported in the January 13 JAMA Neurology.
“This confirms that individuals with prominent family histories of dementia are at higher risk than the rest of the population,” Claudia Kawas of the University of California, Irvine, who was not involved in the study, told Alzforum. “But we still need to do more work to understand how much of this increased risk is genetic versus other shared factors.”
While known variants in three genes play a strong role in early onset AD, the genetic factors behind the far more common late-onset AD (LOAD) are more varied and subtle, and intense genomic research aims to uncover them (see July 2013 conference news). Genome-wide association studies (GWAS) are useful for identifying common genetic variants shared among unrelated people but lack the power to unearth rare variants, first author Badri Vardarajan at Columbia University in New York told Alzforum. The best way to increase the number of these “needles in the genetic haystack” is to start with families with a high incidence of LOAD, Vardarajan said.
Cohorts of such families are the subject of multiple ongoing studies, including the newly launched Alzheimer’s Disease Sequencing Project (ASDP) and the Alzheimer's Genome Project (see Dec 2013 news story). Yet few studies have looked at incidence rates of AD in family-based cohorts, making it difficult to know just how much enrichment researchers might expect, Vardarajan said.
Led by Richard Mayeux at Columbia University, Vardarajan and colleagues decided to nail down the LOAD incidence rates in unaffected people from two cohorts of families commonly studied in genetic research, which make up the majority of samples used in the ADSP. One cohort, going by the mouthful the National Institute on Aging Genetics Initiative for Late-Onset Alzheimer Disease/National Cell Repository for Alzheimer Disease (NIA-LOAD/NCRAD) Family Study, started in 2002 to recruit families with two or more members with LOAD with the aim of identifying new genes associated with LOAD. “The NIA group is the most frequently used data set for GWAS and now for sequencing,” Mayeux told Alzforum. “Most researchers share the hypothesis that these families are enriched for additional cases because they have a high frequency of disease, but nobody’s ever tested that.”
The scientists defined the familial risk by monitoring unaffected relatives for onset of dementia or AD. They regularly examined 943 people from 396 families in the NIA group, calculated annual incidence rates, and compared those to incidence rates of the general population based on data collected from a 1990-1994 population sample in Rochester, Minnesota (see Knopman et al., 2006). The NIA group showed an 18 percent cumulative incidence of progression to AD throughout the course of the study, and more than triple the incidence of LOAD as the general population.
“The overall findings that the incidence rates are higher in these families are not surprising,” Lindsay Farrer of Boston University told Alzforum. “It confirms a lot of what we already knew.”
Vardarajan agrees, but thinks confirmation was necessary. “It confirms the hypothesis that the family-based design is powerful, especially when you have extended families,” he said.
The investigators also tracked participants from the Estudio Familiar de Influencia Genetica en Alzheimer. EFIGA included 683 at-risk family members from 242 AD-affected families of Caribbean Hispanic descent. Initiated in 1998, the study recruited participants from the Taub Institute for Research on Alzheimer’s Disease and the Aging Brain in New York as well as from clinics in the Dominican Republic, with the goal of rooting out genetic variants that elevate LOAD risk in this ethnic group. At 26 percent, members from the EFIGA group showed 1.4 times the cumulative incidence of progression to LOAD as those in the NIA group.
The EFIGA cohort results came as no surprise either, as a previous population study conducted by Mayeux’s group had showed that Caribbean Hispanic and African-American populations in Manhattan had nearly twice the cumulative incidence of LOAD as a white population living in the same area (see Tang et al., 2001). AD risk factors such as diabetes mellitus, obesity, hypertension, low levels of education, and an unhealthy diet also occur at a higher frequency in the Caribbean Hispanic population than in Caucasian populations, and researchers have yet to tease out the relative contributions of each to disease onset.
As a result of the slave trade, much of the Caribbean Hispanic population, especially from the Dominican Republic and Puerto Rico, bears a strong African ancestry and a high degree of genetic homogeneity, Vardarajan said. Therefore, Africans and Caribbean Hispanics may share common genetic risk factors for AD. In line with this hypothesis, an earlier study conducted by Mayeux’s group on the same Manhattan cohort determined that the ApoE4 risk variant allele was less of a risk factor in African-American or Caribbean Hispanic carriers than whites (see Tang et al., 1998; Reitz et al., 2013). Similarly, other researchers have reported that ApoE4 has little influence on AD risk in Yoruba people in Africa (see Gureje et al., 2006).
To see if the ApoE4 effect on LOAD risk would hold up in family-based groups, the investigators genotyped unaffected members of both the NIA and EFIGA groups. In the NIA group, which consists predominantly of Caucasians, ApoE4 carriers had a two- to threefold higher LOAD incidence rate than non-carriers, which is in line with many previous studies. In the EFIGA group, the ApoE4 allele had a slightly weaker influence on LOAD incidence, especially in the oldest age groups. However, Farrer noted that the sample sizes were too small to draw strong comparisons between the two cohorts.
If it’s not ApoE4 that explains the high incidence in the EFIGA cohort, what is it? This question is for ongoing exome and whole-genome sequencing to answer. “These results speak to the family-based study design, where you have more power to detect rare variants for future genetic studies,” Vardarajan said. He hopes the results will provide support for the continued use of these cohorts in genetic studies.—Jessica Shugart
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