Unlike infectious diseases that typically have a single pathological origin, disorders such as Alzheimer’s tend to be much more complex and multifactorial in nature. Stratifying patients into groups based on clinical symptomology and genetic backgrounds could help drug developers create new treatment options to better treat this debilitating disease. In that vein, a group of investigators, led by scientists at the University of Washington School of Medicine have created a new approach to classify patients with Alzheimer’s disease, a finding that may open the door for personalized treatments.
“Alzheimer’s, like breast cancer, is not one disease,” explained lead study investigator and lead author Shubhabrata Mukherjee, Ph.D., a research assistant professor in general internal medicine at the University of Washington School of Medicine. “I think a good drug might fail in a clinical trial because not all the subjects have the same kind of Alzheimer’s.
Findings from the new study were published recently in Molecular Psychiatry through an article titled “Genetic data and cognitively defined late-onset Alzheimer’s disease subgroups. ”
In the current study, researchers put 4,050 people with late-onset Alzheimer’s disease into six groups based on their cognitive functioning at the time of diagnosis and then used genetic data to find biological differences across these groups.
“The implications are exciting,” noted senior study investigator Paul Crane, M.D., a professor of general internal medicine at the University of Washington School of Medicine. “We have found substantial biological differences among cognitively defined subgroups of Alzheimer’s patients.”
The identification of cognitive subgroups related to genetic differences is an important step toward developing a precision medicine approach for Alzheimer’s disease. For the current study, the participants received cognitive scores in four domains: memory, executive functioning, language, and visuospatial functioning.
Interestingly, the research team found that the largest group (39%) had scores in all four domains that were close to each other. The next largest group (27%) had memory scores substantially lower than their other scores. Smaller groups had language scores substantially lower than their other scores (13%), visuospatial functioning scores substantially lower than their other scores (12%), and executive functioning scores substantially lower than their other scores (3%). There were 6% who had two domains that were substantially lower than their other scores.
Participants came from five studies, and it took more than two years to standardize the neuropsychological test scores across all the studies in order to detect meaningful patterns. The mean age was 80, 92% self-reported white race, and 61% were female.
Using genome-wide genetic data to find out if the subgroups are biologically distinct, the investigators found 33 single nucleotide polymorphisms (SNPs)—specific locations throughout the genome—where the genetic association was very strong for one of the subgroups. These genetic relationships were stronger than the strongest effects found by an earlier and much larger international consortium study where Alzheimer’s disease was treated as a single homogeneous condition.
Moreover, the current study also found a particularly strong relationship between a variant of the APOE gene and risk for the memory subgroup. The APOE e4 allele is a very strong risk factor for developing Alzheimer’s disease for people with European ancestry, and it also appears to influence which cognitive subtype of Alzheimer’s a person is likely to develop.
People can currently find out if they have an APOE e4 allele with direct-to-consumer testing—however, the researchers note that many people with an APOE e4 allele never develop Alzheimer’s disease and many who don’t carry any known genetic risk factor nevertheless end up with the condition.
While world leaders want to find a cure for Alzheimer’s by 2025, so far no one has been able to develop an effective treatment let alone a cure. But this study suggests that thinking of Alzheimer’s disease as six distinct conditions may provide a way forward.
“This study is not the end, it’s a start,” concluded Dr. Mukherjee.