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Alzheimer's Disease Subgroups Identified

December 19, 2018

By Marilynn Larkin 

NEW YORK—Researchers have categorized Alzheimer's disease into six distinct conditions based on cognitive function at the time of diagnosis and genetic data demonstrating biological differences across groups.

The findings represent "an important result on the road to personalized medicine," write Dr. Paul Crane of the University of Washington School of Medicine in Seattle and colleagues in a report online December 4 in Molecular Psychiatry.

"Clinicians have noted a lot of variation in the cognitive profiles of people presenting with Alzheimer's disease for many years," Dr. Crane told Reuters Health by email. "A 'relative deficits' approach to differential diagnosis has characterized typical clinical neuropsychological practice."

"We were curious as to whether this clinical framework could prove useful in characterizing heterogeneity among people with typical late-onset Alzheimer's disease," he said.

In previous studies, the group used cognitive tests to subdivide people with late-onset Alzheimer's disease into different groups. The current study "looks specifically at genetic data to see whether there is genetic (biological) support for this particular way of categorizing people with typical late-onset Alzheimer's disease," Dr. Crane said.

The researchers studied information from five studies involving 4,050 patients with late-onset Alzheimer's (mean age, 80; 61% women), including 2,431 with single nucleotide polymorphism (SNP) data.

Individuals were assigned to cognitively defined subgroups on the basis of their relative performance in memory, executive functioning, visuospatial functioning, and language at the time of diagnosis. Genotype frequencies for each subgroup were compared with those from cognitively normal elderly controls.

The team focused on the APOE gene and SNPs with more extreme odds ratios than those previously reported for Alzheimer's disease. They found substantial variation across studies in the proportions of people in each subgroup. However, in each study, higher proportions of people in the subgroup with isolated substantial relative memory impairment had at least one APOE-e4 allele.

Overall, across subgroups, "we found 33 SNPs scattered through the genome with a strong association with one of the cognitively defined subgroups," Dr. Crane said. "Few of these SNPs had previously been identified as being interesting in Alzheimer's disease."

"These data provide strong support for the biological coherence of subgroups produced by our categorization scheme," the authors state. "Each subgroup we analyzed has extreme ORs at novel SNPs that were consistent across multiple independent samples."

"Even with the relatively small sample sizes from these studies, the large effect sizes at common SNPs produced p values that are close to genome-wide significance," they concluded.

"A lot more work needs to happen downstream of our initial findings," Dr. Crane noted, "but each of these 33 SNPs represents some underlying biology that makes people susceptible to one specific subtype of Alzheimer's disease," he said. "Each one thus represents a possible novel target for future work."

In the future, he said, clinicians "may see different treatments recommended on the basis of cognitively-defined subgroups, but we are not there yet."

Dr. Keith Fargo, Alzheimer's Association Director of Scientific Programs and Outreach, commented, "This seems to be a reasonable approach -- trying to identify subgroups of people with Alzheimer's who have different clinical presentations, and associate those with specific genetic variants."

"Whether it is clinically useful or not remains to be seen," he said, after the findings have been replicated and additional studies have been done in larger, more diverse populations.

"Looking to the future, it is possible that we may soon be able to treat people with Alzheimer's disease based on their unique combination of genetics, medical history, risk factors and more," he said. "This kind of research may be getting us closer to this future of precision medicine for Alzheimer's and other dementias."

SOURCE: https://www.nature.com/articles/s41380-018-0298-8

Mol Psych 2018.

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