LOAD is the most common form of Alzheimer's disease, occurring in individuals age 65 and older. It is not well understood, but there are heritable aspects that can increase risk. The neuropathologic hallmarks of the disease are Amyloid-β (Aβ) plaques and neurofibrillary tangles (NFTs) composed of Tau proteins.

The complexity of the human genome and shortcomings of extant sequence characterization methods are limiting factors that have previously prevented researchers from fully understanding the genomic impact of the disease. Recent advances in sequencing technologies have enables more comprehensive genotype-phenotype association studies. For example, the Sequence Kernel Association Test (SKAT) can be used to test for association between rare variants and a phenotype of interest.

In the current study, researchers analyzed whole-exome sequencing data from the Alzheimer's Disease Sequencing Project, a collaborative effort comprised of two large, independent genetic consortia and four large-scaled genome sequencing and analysis centers. The data was derived from over 10,000 individuals. The goal of the study was to identify novel genetic variations associated with the LOAD phenotype.

The team focused their research efforts on a highly polymorphic variable number tandem repeat VNTR region within the Mucin 6 (MUC6) gene, which was associated with Adaptor Related Protein Complex 2 Subunit Alpha 2 (AP2A2) expression in the human brain of individuals with LOAD. The researchers found that variations in this genomic region are relevant to neocortical neurofibrillary degeneration. The VNTR region contains many tandem repeated sequences, which makes it a difficult region to sequence. Another repeat-rich region, Ap2A2, was found to be associated with neurofibrillary tangles, more specifically, pTau proteinopathy. They found that LOAD-linked genetic variation within an exon of the MUC6 gene, and ∼4000 base pairs downstream from another gene that encodes AP2A2.

Corresponding author, Peter Nelson said of this study, "Our findings were made in a group of patients that is relatively small for a genetics study--some recent studies included hundreds of thousands of research subjects! That small sample size means two things: first, we should exercise caution and we need to make sure the phenomenon can be replicated in other groups; and second, it implies that there is a very large effect size--the genetic variation is strongly associated with the disease."

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