Multiple Genetic Factors May Lead to Alzheimer’s Disease

Plasma β-amyloid levels are significantly elevated in first-degree relatives of patients with late-onset Alzheimer’s disease, an increase not attributable to APOE ε4 or to pathogenic coding mutations in the known early-onset Alzheimer’s disease genes, researchers reported in the February 19 Neurology. The increase in plasma β-amyloid levels found in the first-degree relative compared with unrelated controls and married-in spouses suggests strong evidence of unknown genetic risk factors for Alzheimer’s disease, according to Nilufer Ertekin-Taner, MD, PhD, and colleagues.

Dr. Ertekin-Taner’s group measured plasma β-amyloid levels in 217 cognitively healthy, first-degree relatives of patients with late-onset Alzheimer’s disease, as well as in those from 25 extended, multigenerational late-onset Alzheimer’s disease pedigrees, and compared them with appropriate controls. Late-onset Alzheimer’s disease was defined as onset of disease at 60 or older. Participants were screened for pathogenic coding region mutations in early-onset Alzheimer’s disease genes and had their APOE genotypes determined.

The researchers found that plasma β-amyloid levels increased among controls without dementia as the participants aged. “Comparison of control subjects without dementia 20 to 65 years old with those who were over the age of 65 showed highly significant elevations in plasma β-amyloid-40 and β-amyloid-42 in the older age-group,” reported Dr. Ertekin-Taner, Assistant Professor at the Department of Neuroscience, Mayo Clinic, in Jacksonville, Florida, and colleagues. “Analysis of the 20 to 65 age-group was not significant for either β-amyloid-40 or β-amyloid-42 (n = 82), whereas the smaller (n = 67) 65+ age-group did show significant correlations for age for both β-amyloid-40 and β-amyloid-42.”

In the group of young, nondemented first-degree relatives of patients with late-onset Alzheimer’s disease, plasma β-amyloid levels were elevated. “The first-degree relatives have significantly higher plasma β-amyloid-42 levels than controls,” stated Dr. Ertekin-Taner’s group. “Although the mean β-amyloid-40 levels were higher in the late-onset Alzheimer’s disease relatives, [they] did not reach significance.”

The investigators also noted that increased plasma β-amyloid levels in the nondemented first-degree relatives of patients with late-onset Alzheimer’s disease were not due to the APOE genotype. In contrast, they found that the levels in relatives with the ε4 allele were lower than the levels of those who lacked the allele. Also, within this group of nondemented first-degree relatives, the researchers concluded that increased plasma β-amyloid was not due to pathogenic coding mutations in the early-onset familial Alzheimer’s disease genes.

Among first-degree relatives of patients with late-onset Alzheimer’s disease from the 25 late-onset Alzheimer’s disease families and their spouses, Dr. Ertekin-Taner and colleagues said, “both plasma β-amyloid-42 and β-amyloid-40 levels were significantly elevated in the first-degree late-onset Alzheimer’s disease relatives from these families, in comparison to their spouses in the 20 to 65 age-group. We have also performed analyses in the 20 to 55 and 20 to 70 age-groups and determined that both plasma β-amyloid-42 and β-amyloid-40 levels are elevated in the first-degree late-onset Alzheimer’s disease relatives compared with married-in spouses in these age-groups, as well.

NR