Does Progranulin Play Both Sides in AD and FTD?

Mutations that cause frontotemporal dementia may also predispose carriers to Alzheimer’s dementia, according to a paper in the April 22 JAMA Neurology online. Previous genetic studies have suggested that progranulin mutations increase risk for AD (Brouwers et al., 2008; Fenoglio et al., 2009; Lee et al., 2011); the current study solidifies the association by confirming amyloid pathology in two cases. Nonetheless, the possibility remains that their Alzheimer’s is unrelated to progranulin genotype. In small studies such as this, it is difficult to prove beyond a doubt that a genetic association with disease is truly the cause of symptoms.

Researchers led by Gil Rabinovici of the University of California, San Francisco, identified the cases. One was a man who developed typical AD symptoms at age 62; the other a woman whose speech impairment, of a type often associated with Alzheimer’s, began when she was 53. Both carried one copy of ApoE4, as well as a progranulin mutation. While progranulin is more commonly linked to frontotemporal dementia (FTD), Alzheimer’s is not entirely uncommon in mutation carriers, said first author David Perry, also at UCSF. According to the literature, 9-17 percent of people with progranulin mutations have AD-like symptoms (Le Ber et al., 2008; Rademakers et al., 2007). Both people in the study also had family histories of FTD.

An Alzheimer’s diagnosis requires amyloid in the brain, while FTD frequently means inclusions of the protein TDP-43. On autopsy of the woman, who died at age 55, both pathologies were present. In the man, imaging with the amyloid tracer Pittsburgh Compound B confirmed cortical amyloid. Since he still lives, the researchers do not know if he has TDP-43 pathology as well. “Their clinical syndrome, and their imaging and pathology data, are consistent with Alzheimer’s disease,” Perry said. “I think the progranulin mutation may be increasing their risk of getting Alzheimer’s.”

Then again, it could be that the participants would have developed Alzheimer’s regardless of their progranulin genotype. Some purported genetic links turn out to be wrong (see ARF Webinar). However, the young age of the people in the study argues against coincidence, commented Rita Guerreiro of University College London in the U.K., who was not involved in this work (see comment below). The likelihood of amyloid pathology and sporadic AD symptoms in people in their fifties and sixties is quite low, Perry said, even given their ApoE status.

Guerreiro noted that she often finds mismatches between genetics and diagnosis. For example, she and her colleagues recently discovered that homozygous mutations in TREM2, which cause a rare bone disease, also cause FTD (see ARF related news story on Guerreiro et al., 2012), while mutations in one copy of the gene boost the risk for AD (see ARF related news story on Guerreiro et al., 2013; Jonsson et al., 2013). “These diseases all seem to be related somehow,” she said (see ARF related news story). She recommends sequencing several genes, or better yet, the whole exome, to find the genetic root for a person’s disease.

Progranulin mutations lead to a 50 percent drop in the protein’s concentration. How could that cause AD or FTD? Perry suspects that the deficiency promotes inflammation, rendering the brain prone to degeneration and dementia in general (see ARF related news story on Martens et al., 2012). Inflammation and activation of TNF-α has been linked to cognitive decline, extra amyloid production, and less microglial engulfment of amyloid in mice (Holmes, 2012; Yamamoto et al., 2007; see ARF related news story on Hickman et al., 2008). Which specific dementia arises might be determined by other genetic factors, suggested Mikko Hiltunen of the University of Eastern Finland in Kuopio, who was not involved in the study (see comment below). Perry added that if AD and FTD do share molecular roots, then they might share treatment targets as well.

Perry DC, Lehmann M, Yokoyama JS, Karydas A, Lee JJ, Coppola G, Grinberg LT, Geschwind D, Seeley WW, Miller BL, Rosen H, Rabinovici G. Progranulin mutations as risk factors for Alzheimer Disease. JAMA Neurol. 2013 Apr 22. Abstract

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