18 June 2008. Genetic variants in MAPT, the gene that encodes the microtubule-associated protein tau, are associated with an earlier age of onset, but not with overall risk of Alzheimer disease. That result comes from a genetic association study carried out by Alison Goate and colleagues at Washington University in St. Louis, where they looked at the effects of MAPT variation on the level of tau and phosphorylated tau in cerebrospinal fluid. Writing in the June 9 PNAS online, Goate and colleagues present evidence that tau variants are associated with increased CSF tau only in people who show evidence of amyloid deposition. The results suggest that ongoing amyloid accumulation stimulates the expression of tau, and that MAPT alleles that support higher tau expression levels can accelerate the progression of AD.
Last year, first author John Kauwe, Goate, and colleagues published a paper looking at genetic influences on levels of CSF Aβ, a promising biomarker for AD. That study found that a family with hereditary, late-onset AD and CSF Aβ levels in the extreme low end of the scale actually carried a mutation in the presenilin gene (see ARF related news story). Now the same group report an analysis on CSF tau and variants in the tau gene, MAPT. In the work, Kauwe and colleagues correlated CSF tau and phospho-tau (p-tau181) from 313 adults with 21 single nucleotide polymorphisms (SNPs) in and around the MAPT gene. The subjects were mostly nondemented, with 28 percent classified as having very mild to mild dementia. The researchers found that the variation in CSF tau and p-tau181 was 10-fold across the subjects. Four SNPs, which broke out into two pairs of two linked SNPs, were significantly associated with tau and/or p-tau181 levels. For both SNP pairs, the minor alleles were associated with increased CSF tau. The association was confirmed for two tested SNPs in an independent set of 49 CSF samples.
To determine if the SNPs were associated with brain amyloid, the investigators stratified their sample by CSF Aβ levels. In previous work, coauthors Anne Fagan and David Holtzman used PIB-PET scans to establish that low Aβ is a sign of amyloid deposition in the brain (see ARF related news story), whereas high Aβ suggests a lack of brain amyloid. The researchers found that the SNPs associated with tau levels only in subjects with low Aβ (who comprised 45 percent of the sample). These results indicated that the effects of tau genotype on tau levels are dependent on previous Aβ deposition.
The results suggested to Goate and colleagues that the MAPT variations might not be associated with disease risk. Instead, because CSF tau levels correlate with dementia, the researchers hypothesized that MAPT variants associated with higher tau levels in the presence of amyloid might affect age onset of disease. To test this, they chose a SNP (rs3785883) that showed the strongest association with CSF tau and p-tau181, and looked for association with age of onset in a case-control sample of roughly 650 subjects. Previous work from Goate had shown that MAPT variations were not associated with risk for AD (Mukherjee et al., 2007), and this result was confirmed. However, in the present study, they found that the SNPs were associated with an earlier age at onset (AAO).
To see if the effects of rs3785883 variants were associated with higher expression of tau in the brain, the investigators genotyped 33 cases and 37 controls where tau mRNA had been measured in postmortem brain tissue. They found elevated mRNA in carriers of the minor allele among AD cases, but not controls. “Our data indicate that Aβ deposition directly or indirectly leads to an induction of MAPT gene expression, leading to increased CSF tau levels and increased neurodegeneration as evidenced by earlier AAO of LOAD,” the authors write.
The researchers also looked for evidence of elevated CSF tau in carriers of the H1 sub-haplotype H1C, which has been suggested to confer a higher risk for late-onset AD (see ARF related news story). H1 homozygotes also show higher tau mRNA expression in the cortex compared to H2 (see ARF related news story). In this study, H1C showed no association with CSF tau levels, but two rare H1 sub-haplotypes did (H1U and H1H). None of the haplotypes showed a significant association with age at onset or risk of LOAD. With the caveat that the H1C sample size was small, the authors conclude that elevation in tau associated with the H1 haplotype probably results from a few sub-haplotypes of H1.
Previous work showed varying results on the association of tau with AD (see Alzgene), and work from Goate's own lab showed no clear evidence for association with disease risk. The new study supports that result, but still shows a role for tau in AD as a modulator of progression. The finding that tau levels are tied to disease onset raises the possibility that lowering tau, even in the presence of amyloid, might slow the disease.—Pat McCaffrey.
Kauwe JS, Cruchaga C, Mayo K, Fenoglio C, Bertelsen S, Nowotny P, Galimberti D, Scarpini E, Morris JC, Fagan AM, Holtzman DM, Goate AM. Variation in MAPT is associated with cerebrospinal fluid tau levels in the presence of amyloid-beta deposition.
Proc Natl Acad Sci U S A. 2008 Jun 10;105(23):8050-4. Epub 2008 Jun 9. Abstract