Several genes relating to plasma proteins—particularly those involved in the immune system—have been linked for the first time with Alzheimer’s disease.
The proteome-wide association study (PWAS) strengthens the link between dementia and the immune system.
It also highlights potential therapeutic targets outside the traditional confines of the central nervous system (CNS) brain and spinal cord.
Genes relating to both the innate and adaptive immune system were linked with the neurodegenerative disease in the Science Translational Medicine study.
“The present PWAS, which modeled circulating protein abundance, identified potential candidate genes, many of which are expressed broadly or predominantly outside the CNS,” reported Keenan Walker, PhD, from the National Institute on Aging in Baltimore.
“These genes exhibited a higher enrichment for adaptive immunity compared with GWAS [genome-wide association study] candidates, implying distinct mechanistic pathways operating outside the CNS.”
Data on the plasma proteome and protein quantitative trait loci (pQTLs)—genetic variants that control the expression of proteins—are increasingly becoming available.
These offer the opportunity to identify disease-related genes through their effect on protein levels. Proteins are highly relevant to diseases and the development of therapeutic targets, given their role as effectors of cellular biology.
Walker and team compared genetic and proteomic changes associated with Alzheimer’s disease by studying GWAS results from tens of thousands of cases of Alzheimer’s disease, related dementias and control individuals.
They then compared this information with genetic models of 1348 circulating proteins derived from European Americans and 1385 circulating proteins from African Americans.
Plasma cis-pQTL data identified genes associated with the neurodegenerative disease through the cis regulation of plasma protein abundance. It also highlighted several plasma proteins with potential links with dementia.
The research revealed 18 genes with potentially causal relationships with the risk of Alzheimer’s disease among people with European ancestry, six of which had not been previously identified through GWAS.
Leukocyte immunoglobulin-like receptor (LILR)B1 and signal regulatory protein alpha (SIRPA), two immunoregulatory proteins not previously implicated in GWAS, showed the strongest mechanistic link to Alzheimer’s disease in the European Americans.
“We demonstrated that a subset of the plasma proteins encoded by PWAS candidate genes may function as biomarkers, given their association with dementia risk over 8- and 20-year follow-up periods, as early as middle adulthood,” the researchers reported.
“These same plasma proteins were associated with biomarkers of [Alzheimer’s disease] pathology and a broad set of cerebrospinal fluid (CSF) proteins enriched for immune and metabolic processes relevant to [Alzheimer’s disease].
“The present PWAS, which modeled circulating protein abundance, identified potential candidate genes, many of which are expressed broadly or predominantly outside the CNS.
“These genes exhibited a higher enrichment for adaptive immunity compared with GWAS candidates, implying distinct mechanistic pathways operating outside the CNS.”
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