Alzheimer’s Study Reveals 13 Variants as Possible New Drug Targets

563
Close Up of DNA Sequencing on a Computer Monitor From a DNA Analysis Machine
[Source: Monty Rakusen/Getty Images]

Researchers have identified genomic variants associated with Alzheimer’s disease in what they say is the first study to use whole-genome sequencing (WGS) to discover such markers. They also report that the study establishes new genetic links between AD and the function of synapses and the ability of neurons to reorganize the brain’s neural network.

“This paper brings us to the next stage of disease-gene discovery by allowing us to look at the entire sequence of the human genome and assess the rare genomic variants, which we couldn’t do before,” says Dmitry Prokopenko, PhD, of MGH’s McCance Center for Brain Health, who is lead author of the study.

The field of Alzheimer’s drug development has been at a virtual standstill, with formerly widely accepted theories about the disease’s cause now being challenged. The amyloid protein that accumulates in AD patient’s brains has been a favorite target for drug developers. This study could provide new targets aimed at enhancing neuroplasticity and synapse stability.

The work was co-led by Rudolph Tanzi, Ph.D., vice chair of Neurology and director of the hospital’s Genetics and Aging Research Unit. The team included researchers at Massachusetts General Hospital (MGH), the Harvard T. H. Chan School of Public Health, and Beth Israel Deaconess Medical Center. These findings are reporter the current issue of Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association.

Alzheimer’s disease (AD) is a growing global problem. In the US alone, the number of AD patients is expected to grow to 14 million by 2050.  Meanwhile, the failure rate of AD drug development is 99%. (Cummings, J. et al. Alzheimers Dement, 2018).

The researchers performed WGS analyses on the genomes of 2,247 individuals from 605 families that include multiple members who have been diagnosed with AD. They also analyzed WGS datasets on 1,669 unrelated individuals. The study identified 13 previously unknown rare gene variants associated with AD. These gene variants were associated with functioning of synapses, development of neurons, and neuroplasticity.

Tanzi, Prokopenko, and colleagues previously co-discovered genes that cause early onset (prior to age 60) familial AD, including the amyloid protein (A4) precursor (APP), and the presenilin genes (PSEN1 and PSEN2). Mutations in these genes lead to accumulation of amyloid plaques in the brain.

The next 30 AD gene variants discovered are primarily linked to chronic neuroinflammation, which also increases the risk for AD. However, loss of synapses is the neurological change that is most closely correlated with the severity of dementia in Alzheimer’s disease, yet no clear genetic links between the disease and these vital connections had previously been identified. “It was always kind of surprising that whole-genome screens had not identified Alzheimer’s genes that are directly involved with synapses and neuroplasticity,” says Tanzi.

Prior to this paper, the genome-wide association study (GWAS) was the primary tool used for identifying AD genes. But to date, common Alzheimer’s-associated gene variants have accounted for less than half of the heritability of AD. A standard GWAS misses the rare gene variants (those occurring in less than 1% of the population), a problem solved by the WGS, which scans every bit of DNA in a genome.

Tanzi says less-common gene mutations that increase the risk for AD may hold critical information about the biology of the disease. “Rare gene variants are the dark matter of the human genome,” he says, and there are lots of them: Of the three billion pairs of nucleotide bases that form a complete set of DNA, each person has 50 to 60 million gene variants–and 77% are rare.

“With this study, we believe we have created a new template for going beyond standard GWAS and association of disease with common genome variants, in which you miss much of the genetic landscape of the disease,” says Tanzi. In future studies, he plans to use “Alzheimer’s in a dish”–three-dimensional cell culture models and brain organoids he and his colleagues have developed over the past decade–to explore what happens when the rare mutations this paper identified are inserted in neurons. “That could help guide us in novel drug discovery,” he says.

This site uses Akismet to reduce spam. Learn how your comment data is processed.