Skip to main content
Premium Trial:

Request an Annual Quote

Dementia Contributors Uncovered Using Neuropathy Endophenotype-Focused Strategies

NEW YORK – By focusing on distinct neuropathy endophenotypes, a team led by investigators at the University of Kentucky has identified loci linked to different forms of a set of dementia-related conditions collectively known as Alzheimer's disease and related dementias (ADRD).

"Sharpening the endophenotypes enabled the discovery of new hit genes that did not reach genome-wide significance in previous studies oriented toward studying [Alzheimer's disease (AD)] clinical phenotypes," co-senior and corresponding author David Fardo, a biostatistics researcher at the University of Kentucky, and his colleagues wrote in a paper published in Nature Genetics on Tuesday.

Using genotypes generated on autopsy samples collected from 7,804 individuals for the National Alzheimer's Coordinating Center, the Religious Orders Study and Rush Memory and Aging Project, and the Adult Changes in Thought study, the researchers performed genome-wide association and GWAS meta-analyses searching for variants linked to 11 ADRD-related neuropathy endophenotypes.

"Genome-wide association studies have identified [more than 80 ADRD]-associated genetic loci," the authors explained. "However, the clinical outcomes used in most previous studies belie the complex nature of underlying neuropathologies."

With that in mind, the team began by using autopsy and genotype data from the large research cohorts to come up with more precise neuropathology endophenotype classifications, uncovering four known loci and four new loci with significant ADRD associations, including sites in or around the COL4A1, PIK3R5, LZTS1, and APOC2 genes that appeared to either bump up or tamp down ADRD risk.

The researchers unearthed a variant in an intron of LZTS1 that appeared to protect against brain arteriolosclerosis, for example, though they noted that the current study did not lead to genome-wide significant associations for the gross infarct, microinfarct, or Lewy body pathology forms of neuropathology endophenotypes.

When they focused on loci previously implicated in ADRD, on the other hand, the investigators saw 19 loci with significant ties to one or more of the neuropathology phenotypes considered.

"These results provide an autopsy-based complement to previous studies based on clinical diagnoses and expand on the findings of previous genetic studies of dementias and neuropathologies," the authors explained, noting that their findings "improve our collective understanding of the complex nature of ADRD and its genetic bases."

From there, the team performed a series of follow-up functional analyses, including variant annotation, gene set enrichment, co-localization, and methylation analyses, informed by quantitative trait locus profiles for the brain prefrontal cortex and dozens of other tissue types.

Those efforts provided a look at gene expression and methylation profiles coinciding with specific neuropathy endophenotypes considered — from higher-than-usual expression of TMEM106B in severe "limbic-predominant age-related TDP-43 encephalopathy-neuropathological change" cases to diminished methylation at APOC2 adjacent methylation quantitative trait loci in cases marked by severe cerebral amyloid angiopathy pathology.

Together, the authors suggested, the work "demonstrates the importance of studying genetic risk factors of [neuropathy endophenotypes] as a complement to studies of clinical and proxy phenotypes of [late-onset Alzheimer's disease]."