Homozygous loss-of-function mutations in the microglial receptor TREM2 cause Nasu-Hakola disease, an early onset form of dementia thought to be unrelated to Aβ amyloidosis. Now, researchers led by Laura Ghezzi and Tiziana Carandini at the University of Milan describe amyloid accumulation in the cortex of a 39-year-old woman with a homozygous TREM2 mutation. Writing in the November 15 Neurology, they report the patient had profound dementia but tested negative for mutations in 43 dementia-related genes. They did not specify if familial AD genes were sequenced. The TREM2 mutation introduces a stop codon, Q33X, recently found in another Italian patient and a Turkish family. If confirmed, the findings would suggest a closer relationship between Alzheimer’s and Nasu-Hakola disease than previously suspected, and strengthen the link between TREM2 dysfunction and amyloid pathology.

Several scientists raised concerns about the interpretation. “[It is] really difficult to make a statement as to whether the dementia was caused by the supposed underlying pathology,” wrote Anne Fagan, Washington University, St. Louis, in an email to Alzforum. Many people have amyloid in the brain and show no overt signs of dementia, but they are usually much older than this 39-year-old.

The study is not the first to link amyloid plaques to Nasu-Hakola. Thomas Bird, University of Washington, Seattle, reported senile plaques and neurofibrillary tangles in a 48-year-old from a family carrying the D134G TREM2 mutation (Bird et al., 1983; Bird, 2013; Paloneva et al., 2002). However, as noted by Jason Ulrich at WashU, amyloid deposition is not widely accepted as a facet of the disease, making the new findings by Ghezzi and colleagues unexpected.

The woman had rapidly deteriorating dementia, scoring a 7 on the Mini-Mental State Examination one year after diagnosis. Rapid deterioration is not typical for AD. MRI scans showed diffuse cortical atrophy and severely reduced white matter, while F18-fluorodeoxyglucose-PET indicated reduced glucose metabolism, particularly in temporal and parietal cortex. Ghezzi and colleagues measured moderately low levels of Aβ in the spinal fluid (597 pg/mL), but did not describe the assay used, nor its normal range.

Florbetapir-PET indicated accumulation of Aβ in the gray matter of the inferior frontal and occipital lobes. The patient’s parents, aged 72 with no cognitive impairment, both carried a single Q33X mutation and they also had Aβ accumulation in the cortex, which is common among people that age. Brian Gordon, also from WashU, noted that while the amyloid is probably elevated in the patient, the PET imaging is not interpretable. “They provide no quantitative data anywhere in the paper,” he said. William Klunk from the University of Pennsylvania Medical Center, Philadelphia, agreed. “It is really hard to judge the florbetapir scans with just these images,” he wrote, but noted they could be positive. “The FDG imaging is more convincingly AD-like,” he added.

The authors detected cystic bone lesions in the patient’s hands and feet characteristic of Nasu-Hakola disease, but whether the Q33X mutation caused the purported amyloidosis is uncertain, noted Henrik Zetterberg, University of Gothenburg, Sweden. “I find this very hard to judge. Additional patients in that family would have made for a stronger case,” he wrote. The authors agree. “Further studies in larger populations are needed to test whether the Q33X variant plays a role in the deposition of amyloid,” they write.—Marina Chicurel 


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Paper Citations

  1. . Lipomembranous polycystic osteodysplasia (brain, bone, and fat disease): a genetic cause of presenile dementia. Neurology. 1983 Jan;33(1):81-6. PubMed.
  2. . TREM2 and neurodegenerative disease. N Engl J Med. 2013 Oct 17;369(16):1568. PubMed.
  3. . Mutations in two genes encoding different subunits of a receptor signaling complex result in an identical disease phenotype. Am J Hum Genet. 2002 Sep;71(3):656-62. Epub 2002 Jun 21 PubMed.

Further Reading

Primary Papers

  1. . Evidence of CNS β-amyloid deposition in Nasu-Hakola disease due to the TREM2 Q33X mutation. Neurology. 2017 Dec 12;89(24):2503-2505. Epub 2017 Nov 15 PubMed.