Research Brief: More Evidence That CSF Aβ Changes Precede AD

The longest study yet to correlate Alzheimer’s disease biomarkers in cerebrospinal fluid (CSF) with disease progression confirms that β amyloid levels bottom out at pathological levels up to 10 years before the clinical onset of disease. In contrast, CSF tau levels are higher the closer people are to developing dementia, implying that tau continues to rise as cognitive impairment progresses, report researchers led by Oskar Hansson at Skåne University Hospital, Malmö, Sweden. The data lend further support to current models of biomarker progression (see ARF Webinar). Writing in the January Archives of General Psychiatry, the authors also note that the ratio of β amyloid to phosphorylated tau in the CSF can predict with high accuracy which people will progress from mild cognitive impairment (MCI) to AD, making this biomarker potentially useful for selecting participants in clinical trials.

To study biomarker progression, first author Peder Buchhave analyzed a cohort of 137 patients with MCI who donated CSF samples at baseline. The authors previously reported on the first five years of data from this cohort (see Hansson et al., 2006); the new work extends the longitudinal data to nearly a decade. Clinical assessments on the cohort found that, at an average follow-up period of nine years, about 40 people remained stable, around 70 progressed to AD, and about 20 developed other forms of dementia.

At baseline, CSF Aβ42 was equally reduced in the MCI patients who developed AD within a year or two and in those who were diagnosed 10 years later, suggesting Aβ levels plateau long before disease develops. These low Aβ42 levels (around 350 ng/L) contrast with average levels of 600 ng/L in people who remained stable or developed other dementias, and around 700 ng/L in healthy controls. However, elevated total tau and phosphorylated tau at baseline distinguished people who converted to AD within the next five years from those who converted later. The baseline total tau levels hovered around 800 ng/L in early converters, versus 500 ng/L in late converters, and around 300 ng/L in controls and those who stayed stable. The data imply that CSF tau continues to rise in the years immediately before the onset of clinical symptoms, as progression models predict. Recent work by Cliff Jack and colleagues at the Mayo Clinic in Rochester, Minnesota, also provided evidence in support of this model (see ARF related news story on Jack et al., 2011).

In addition, the authors report that an Aβ42:p-tau ratio of less than about 6 in MCI patients predicted the development of AD within nine years with a sensitivity and specificity of around 90 percent. To put it another way, MCI patients with pathological Aβ42:p-tau ratios developed AD with an incidence of almost 30 percent per year, compared to 2 percent per year in MCI patients with normal ratios. This marker could be useful in selecting patients for clinical trials, but is not good enough for clinical diagnosis, Hansson noted, pointing out that, for a useful clinical tool, accuracy would need to be nearly 100 percent.

“Not only do [the data] support the proposed trajectory of specific biomarker changes very early in the course of the disease, but they also provide support for the importance of assigning an underlying etiology to the construct of MCI,” Anne Fagan at Washington University School of Medicine, St. Louis, Missouri, wrote to ARF, noting that MCI with AD biomarkers should be considered early AD. “I predict that longer clinical follow-up in cognitively normal individuals who exhibit AD biomarker profiles will provide support for the utility of such biomarkers to identify individuals with the disease even earlier, before the onset of any clinical symptoms.” (See full comment below.)

For his part, Hansson is currently developing methods to detect Aβ oligomers in CSF, as oligomers are widely believed to be the neurotoxic form of Aβ. Hansson will investigate whether adding CSF oligomer levels to the equation will improve diagnostic accuracy. Monitoring changes in CSF oligomers might also provide a way to assess the effectiveness of anti-amyloid therapies, Hansson told ARF.—Madolyn Bowman Rogers

Comments

  1. The recent paper by Buchhave and colleagues in the Archives of General Psychiatry is, to my knowledge, the first report of relatively long-term (about nine years) clinical follow-up of an MCI cohort with baseline CSF biomarker data. Their initial 2006 paper (Hansson et al., 2006) demonstrating the high prognostic utility of the ratios of CSF tau(s)/Aβ42 in predicting clinical “conversion” from MCI to DAT (over about five years) in these same individuals was very important to the field, and set the stage for longer-term follow-up, which they have now been able to achieve. As expected, a greater percentage of individuals “converted” from MCI to AD over nine years (53.7 percent) compared to over five years (42 percent), and the combination of tau(s) and Aβ42 measures showed a greater positive predictive value over the longer- compared to the shorter-term follow-up (91 percent versus 81 percent, respectively), supporting the notion of AD as a progressive disease with a long developmental time course. Our group (Fagan et al., 2007) and the group at the University of Washington (Li et al., 2007) have shown that these same markers are useful for predicting (within three to five years) future MCI/dementia of the Alzheimer’s type in older individuals while they are still cognitively normal. Together, these data demonstrate that AD pathology begins to develop very early in the disease process, even prior to any cognitive symptoms. Such findings have significant ramifications for the design and evaluation of AD prevention trials of disease-modifying therapies (with the goal of preventing cognitive impairment as opposed to slowing or halting already existing deficits).

    Importantly, whereas CSF Aβ42, tau and phospho-tau (p-tau) in the present study were associated with “conversion to AD” within the first five years of baseline, Aβ42 was the only marker that was associated with conversion in individuals followed for five to 10 years. These data lend further support for the proposed trajectory of such biomarker changes (Perrin et al., 2009; Jack et al, 2010; Jack et al., 2011): CSF Aβ42 dropping very early in the disease process (and plateauing) in concert with its deposition as amyloid plaques, followed by elevations in CSF p-tau and tau (and atrophy), markers of tangles and neurodegeneration, that continue as the disease progresses. The ultimate test of this hypothesis will require not only longitudinal clinical follow-up in individuals while they are still cognitively normal (preclinical/presymptomatic stage), but also assessment of biomarker changes over time within such individuals. Such studies are currently underway in both sporadic AD (e.g., The Adult Children Study [ACS], Biomarkers for Older Controls at Risk for Dementia [BIOCARD], Wisconsin Registry for Alzheimer Prevention [WRAP]), as well as genetic forms of AD (e.g., The Dominantly Inherited Alzheimer Network [DIAN], The Alzheimer’s Prevention Initiative Biomarkers Project [API-BIO]).

    The data presented in the paper by Buchhave et al. are important beyond their face value. Not only do they support the proposed trajectory of specific biomarker changes very early in the course of the disease, but they also provide support for the importance for assigning an underlying etiology to the construct of MCI (Albert et al., 2011). The data demonstrate that individuals classified as being “MCI” and who have biomarkers supportive of AD (i.e., low Aβ42 and elevated tau(s) and the tau(s)/Aβ42 ratios) actually have AD, but that the clinical manifestations of the disease pathology have not yet become severe enough for some to call it “dementia.” Thus, these individuals aren’t “converting” from MCI to AD; they are not merely at risk for AD: they have AD and are progressing in their pathological and clinical course as one would expect. While this may seem like merely splitting semantic hairs, the AD lexicon needs to reflect our understanding of the protracted and progressive nature of the disease pathological processes which eventually culminate in more significant cognitive impairment (dementia). The data from the current paper have contributed nicely to this evolving concept, and I predict that longer clinical follow-up in cognitively normal individuals who exhibit AD biomarker profiles will provide support for the utility of such biomarkers to identify individuals with the disease even earlier, before the onset of any clinical symptoms (Sperling et al., 2011). Stay tuned….

    References:

    Albert MS, DeKosky ST, Dickson D, Dubois B, Feldman HH, Fox NC, Gamst A, Holtzman DM, Jagust WJ, Petersen RC, Snyder PJ, Carrillo MC, Thies B, Phelps CH. The diagnosis of mild cognitive impairment due to Alzheimer's disease: recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease. Alzheimers Dement. 2011 May;7(3):270-9. Epub 2011 Apr 21 PubMed.

    Fagan AM, Roe CM, Xiong C, Mintun MA, Morris JC, Holtzman DM. Cerebrospinal fluid tau/beta-amyloid(42) ratio as a prediction of cognitive decline in nondemented older adults. Arch Neurol. 2007 Mar;64(3):343-9. Epub 2007 Jan 8 PubMed.

    Hansson O, Zetterberg H, Buchhave P, Londos E, Blennow K, Minthon L. Association between CSF biomarkers and incipient Alzheimer's disease in patients with mild cognitive impairment: a follow-up study. Lancet Neurol. 2006 Mar;5(3):228-34. PubMed.

    Jack CR, Knopman DS, Jagust WJ, Shaw LM, Aisen PS, Weiner MW, Petersen RC, Trojanowski JQ. Hypothetical model of dynamic biomarkers of the Alzheimer's pathological cascade. Lancet Neurol. 2010 Jan;9(1):119-28. PubMed.

    Jack CR, Vemuri P, Wiste HJ, Weigand SD, Aisen PS, Trojanowski JQ, Shaw LM, Bernstein MA, Petersen RC, Weiner MW, Knopman DS, . Evidence for ordering of Alzheimer disease biomarkers. Arch Neurol. 2011 Dec;68(12):1526-35. PubMed.

    Li G, Sokal I, Quinn JF, Leverenz JB, Brodey M, Schellenberg GD, Kaye JA, Raskind MA, Zhang J, Peskind ER, Montine TJ. CSF tau/Abeta42 ratio for increased risk of mild cognitive impairment: a follow-up study. Neurology. 2007 Aug 14;69(7):631-9. PubMed.

    Perrin RJ, Fagan AM, Holtzman DM. Multimodal techniques for diagnosis and prognosis of Alzheimer's disease. Nature. 2009 Oct 15;461(7266):916-22. PubMed.

    Sperling RA, Aisen PS, Beckett LA, Bennett DA, Craft S, Fagan AM, Iwatsubo T, Jack CR Jr, Kaye J, Montine TJ, Park DC, Reiman EM, Rowe CC, Siemers E, Stern Y, Yaffe K, Carrillo MC, Thies B, Morrison-Bogorad M, Wagster MV, Phelps CH. Toward defining the preclinical stages of Alzheimer's disease: recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease. Alzheimers Dement. 2011 May;7(3):280-92. Epub 2011 Apr 21 PubMed.

    View all comments by Anne Fagan

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References

Webinar Citations

  1. Together at Last, Top Five Biomarkers Model Stages of AD

News Citations

  1. Research Brief: Evidence Supports Model of AD Biomarker Progression

Paper Citations

  1. Hansson O, Zetterberg H, Buchhave P, Londos E, Blennow K, Minthon L. Association between CSF biomarkers and incipient Alzheimer's disease in patients with mild cognitive impairment: a follow-up study. Lancet Neurol. 2006 Mar;5(3):228-34. PubMed.
  2. Jack CR, Vemuri P, Wiste HJ, Weigand SD, Aisen PS, Trojanowski JQ, Shaw LM, Bernstein MA, Petersen RC, Weiner MW, Knopman DS, . Evidence for ordering of Alzheimer disease biomarkers. Arch Neurol. 2011 Dec;68(12):1526-35. PubMed.

Further Reading

Primary Papers

  1. Buchhave P, Minthon L, Zetterberg H, Wallin AK, Blennow K, Hansson O. Cerebrospinal fluid levels of β-amyloid 1-42, but not of tau, are fully changed already 5 to 10 years before the onset of Alzheimer dementia. Arch Gen Psychiatry. 2012 Jan;69(1):98-106. PubMed.

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