With much of the research these days focusing on sporadic, late-onset forms of Alzheimer disease (AD), people affected by early onset familial forms (eFAD) often wonder how discoveries apply to them. A case in point is biomarkers. There is strong evidence that levels of amyloid-β (Aβ) in the cerebrospinal fluid (CSF) decline in patients with sporadic AD, or even mild cognitive impairment, but the data link between CSF Aβ and eFAD has been slightly murkier. Tau, another protein biomarker, is elevated in the CSF of AD patients, and a modified form of the protein, phospho-tau, is a specific marker for AD, distinguishing it from normal aging and other forms of dementia. But as with Aβ, it is not clear if tau or phospho-tau are valuable markers in eFAD cases. A paper in print in the July 8 Neurology paints a clearer picture and has been getting some attention in the popular media. John Ringman, Alzheimer’s Disease Research Center at the University of California, Los Angeles, and colleagues report that changes in CSF Aβ and tau are indicative of presymptomatic disease in people carrying eFAD mutations. The researchers also extend the observations to Aβ in the plasma, which appears to fall prior to the onset of symptoms. The findings not only support the idea that these biomarkers are valuable diagnostic tools for eFAD patients but may even help pinpoint disease onset before any overt symptoms appear.

Studying volunteers carrying mutations in genes for amyloid-β precursor protein or presenilin, the enzyme that helps pluck the Aβ peptide from the precursor, the researchers found that in the CSF the ratio of Aβ42 to the slightly shorter Aβ40 is decreased compared to normal controls. This ratio also drops in patients with sporadic forms of the disease, and is generally taken to mean that the more amyloidogenic, or stickier, Aβ42 is getting mopped up in amyloid plaques in the brain. Ringman and colleagues also found that total tau and tau phosphorylated at position 181 (p-tau181) were elevated in the CSF of non-demented mutation carriers, suggesting that these markers are “sensitive indicators of presymptomatic disease,” write the authors.

Interestingly, Ringman and colleagues also found changes in Aβ in the blood in this patient population. They found that plasma Aβ42 and the Aβ42/Aβ40 ratio were higher in presymptomatic eFAD patients compared to normal controls, but when patients began to show the first signs of dementia, the plasma Aβ levels dropped below those seen in symptom-free patients. This suggests that a simple blood test might help pinpoint disease onset in eFAD patients. Plasma Aβ may, therefore, prove to be a more valuable biomarker in familial cases than in sporadic cases, where plasma Aβ levels seem to have questionable value. We discussed this aspect as part of a broader discussion on plasma Aβ when this paper first appeared online (see ARF related news story).

The authors stress that these results need to be repeated in a larger study. These data were based on 21 eFAD patients, 17 with presenilin mutations and four with amyloid precursor protein mutations. This speaks to one of the impediments to studying inherited forms of AD, namely that the patients make up only a very small percentage of cases compared to those with sporadic forms of the disease. Encouraging the inclusion of eFAD patients in research studies and clinical trials will hopefully help improve participation (see related ARF eFAD information).—Tom Fagan


  1. A very elegant and interesting study.

    View all comments by Takaomi Saido

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News Citations

  1. Plasma Aβ Testing Beset by Questions of Assays, Biology, Timing

Other Citations

  1. related ARF eFAD information

Further Reading

Primary Papers

  1. . Biochemical markers in persons with preclinical familial Alzheimer disease. Neurology. 2008 Jul 8;71(2):85-92. PubMed.