Genomewide association studies have turned up genetic risk factors for Alzheimer’s disease, but scientists do not yet know how most of them contribute to disease. For clusterin (CLU), currently number 3 in AlzGene Top Results, the picture has now become a little clearer. Three recent structural or functional magnetic resonance imaging (fMRI) studies of healthy young adults suggest that the AD risk variant of clusterin weakens communication among brain regions involved in memory. What these findings mean for AD risk is still debatable, but one possibility is that people with the risk factor are less able to compensate for the effects of AD pathology later in life.

The hippocampus and prefrontal cortex synchronize poorly during a memory task in people who carry the CLU risk allele, report researchers led by Henrik Walter at Charité-Universitätsmedizin Berlin, Germany, in the December 7 Journal of Neuroscience. The finding, implying a weakened connection between these regions, agrees with work from scientists led by Paul Thompson at the University of California, Los Angeles. In the May 4 Journal of Neuroscience, Thompson and colleagues reported that people with the risk variant have poorer white matter integrity in tracts throughout the brain than do non-carriers. Similarly, a group led by David Linden at Cardiff University, U.K., found that, compared to non-carriers, risk allele carriers activate the hippocampus and prefrontal cortex more strongly during difficult memory tasks. This could be a form of compensation for less efficient neural processing, Linden suggested, writing in the December European Neuropsychopharmacology. The paper was first published online March 11.

“These are important, convergent findings that use cutting-edge neuroimaging techniques,” noted Brad Dickerson at Massachusetts General Hospital. He was not involved in any of the studies.

Clusterin, also known as apolipoprotein J, shares some similarities with apolipoprotein E (ApoE). Intriguingly, previous imaging studies have shown that people with the ApoE4 allele—the most important genetic risk factor for sporadic AD—have poor brain connectivity and hyperactivation compared to those without the allele (see Bookheimer and Burggren, 2009; Honea et al., 2009; and ARF related news story on Sheline et al., 2010).

To see if this was true for clusterin as well, Walter and joint first authors Susanne Erk and Andreas Meyer-Lindenberg recruited more than 100 healthy German volunteers with an average age of 33. Participants performed an episodic memory task that required them to memorize face and profession pairs, then later had to recall the profession associated with each face while blood oxygenation level-dependent (BOLD) fMRI measured blood flow to brain regions. The researchers saw no differences between CLU risk allele carriers and non-carriers in performance, or in the overall levels of activity in hippocampus and prefrontal cortex. However, when the authors compared activity between the right hippocampus and right dorsolateral prefrontal cortex, they found less synchronization in risk allele carriers compared to controls. This suggested a weaker functional connection between these regions. The effect was strongest in people who had two risk alleles. The researchers saw no interaction with ApoE genotype.

A robust interplay between the hippocampus and prefrontal cortex is important for memory formation, Walter told ARF, because the hippocampus itself does not store memories. “The hippocampus must talk to other cortical regions,” he pointed out. Other work shows that the hippocampal-cortical connection is weaker in people with AD or mild cognitive impairment (MCI) than in healthy controls (see Grady et al., 2001; Allen et al., 2007; and Dickerson and Sperling, 2008). This suggests that communication between these regions plays a role in AD risk, Walter said.

Linden and colleagues focused on brain activity rather than connectivity. Joint first authors Thomas Lancaster at Bangor University and Alison Baird at Swansea University, both in the U.K., tested working memory in 43 healthy Caucasians with a median age of 29. Participants were shown between one and four faces, then after a delay were presented with another face and had to decide if it was one they had seen before. Risk allele carriers and non-carriers performed the task equally well. However, carriers had heightened activity in the right hippocampus and entorhinal cortex, right dorsolateral prefrontal cortex, and dorsal posterior cingulate compared to non-carriers, particularly when they had to remember three or four faces (see Lancaster et al., 2011). As Walter and colleagues found, two risk alleles had a stronger effect than one. Linden suggested that CLU risk allele carriers hyperactivate these brain regions to compensate for less efficient neural processing. If true, the data would jibe with Walter’s findings of lessened connectivity. Future studies should measure both activity and connectivity, Linden said.

These studies lack a cellular mechanism to explain the risk allele’s effects, Linden noted. A possible clue comes from the work by Thompson and colleagues. Joint first authors Meredith Braskie, Neda Jahanshad, and Jason Stein scanned almost 400 young adults, average age 24, with a form of structural MRI known as diffusion tensor imaging. This technique measures water diffusion along white matter tracts; if a large amount of water moves perpendicular to the tracts, it suggests that the myelin coating is thin or damaged. By this measure, carriers of the risk allele had less intact myelin than non-carriers, with the strongest effect seen in those with two copies of the allele (see Braskie et al., 2011). Not only does this finding imply a cellular underpinning for decreased functional connectivity, but since clusterin interacts with lipids, it suggests a mechanism by which variations in clusterin might affect the lipid-rich myelin sheath, the authors propose. It also may explain why interconnectivity among different brain regions is not working at its best.

One important caveat about the CLU risk allele is that scientists do not yet know what the disease-promoting mutation is, although they have ruled out a simple coding change in the clusterin protein sequence (see, e.g., ARF related news story). Although AD risk is linked to a single nucleotide polymorphism (SNP) in the vicinity of the CLU gene, this SNP is only a marker for the pertinent mutation. The risk allele, a cytosine (C), is common in Caucasians, with almost 90 percent of this population carrying at least one copy, and more than a third having two copies. Researchers stressed to ARF, however, that the AD risk conferred by this variation is quite small, and should not be a cause for concern. People with two copies of the protective thymine (T) allele have 16 percent less risk of getting the disease (see Bertram and Tanzi, 2010).

Scientists do not know whether differences in brain function in people with the risk allele are the result of early neurodegeneration, or whether their brains are just wired differently from the start. Although several researchers with whom ARF spoke favor a developmental model, Linden pointed out that neurofibrillary tangles have been found in people younger than 30, suggesting neurodegeneration can start even at these early ages (see Braak and Del Tredici, 2011). To start to look at the relationship between early effects and later cognitive problems, Walter plans to do a larger study comparing connectivity in healthy controls, people with subjective memory complaints, those with MCI, and people with AD. Importantly, Dickerson noted that clusterin’s apparent role in brain connectivity does not preclude the protein also having a direct effect on amyloid, as ApoE does. “Probably a lot of these genes are working in multiple ways,” he said.—Madolyn Bowman Rogers


  1. The three studies all contribute to the field of early diagnosis of Alzheimer's disease by investigating how genetic susceptibility genes (in this case, CLU) affect neuronal activation (Erk et al. and Lancaster et al.) and white matter integrity (Braskie et al.). As new treatments for the disease are underway, early identification of individuals at risk of developing Alzheimer's disease is becoming increasingly critical. Thus, the development of neurogenetic markers of AD-related pathology is important for early intervention and prevention of the disease.

    I found the paper by Erk et al. especially interesting, as they are using a novel approach to identify alterations in brain function by analyzing task data (episodic retrieval) using a functional connectivity approach. The results from both fMRI studies (Erk et al. and Lancaster et al.) are in accordance and converge well with previous findings (including the ones from our lab) demonstrating functional alterations in a specific subset of brain regions, including hippocampus, posteromedial cortex, and prefrontal cortex, in cognitively healthy individuals with high risk of developing AD. Interestingly, as the study by Braskie et al. demonstrated, the same areas where we see functional changes are also affected by early pathological changes, i.e., decreased white matter integrity. Recently, our lab and other groups have shown that the same network of regions demonstrates increased amyloid deposition in cognitively normal individuals, suggesting that functional and pathological brain changes may begin far in advance of symptomatic AD.

    I believe that the development of new techniques, especially in neuroimaging, has advanced our detection capabilities and current understanding of Alzheimer’s disease. As more groups are conducting multimodal imaging studies to look at several sensitive markers at the same time, we have started to develop and optimize cognitive, imaging, and genetic biomarkers to track progression through the early changes in the trajectory of AD, even before any clinical signs.

    In order for us to fully appreciate these findings (Erk et al. and Lancaster et al.) I believe there is a need for longitudinal follow-up of these individuals. To confirm if the pattern that is observed in the "high-risk" group really is a marker of early AD, it would be informative to know how many people convert to AD in the future. A faster approach would be to conduct similar studies but include people with mild cognitive impairment (MCI) and AD to investigate if the pattern observed in the high-risk group resembles the pattern in AD and MCI patients.

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News Citations

  1. A Foreshadowing? ApoE4 Disrupts Brain Connectivity in Absence of Aβ
  2. Barcelona: What Lies Beyond Genomewide Association Studies?

Paper Citations

  1. . APOE-4 genotype and neurophysiological vulnerability to Alzheimer's and cognitive aging. Annu Rev Clin Psychol. 2009;5:343-62. PubMed.
  2. . Impact of APOE on the healthy aging brain: a voxel-based MRI and DTI study. J Alzheimers Dis. 2009;18(3):553-64. PubMed.
  3. . APOE4 allele disrupts resting state fMRI connectivity in the absence of amyloid plaques or decreased CSF Aβ42. J Neurosci. 2010 Dec 15;30(50):17035-40. PubMed.
  4. . Altered brain functional connectivity and impaired short-term memory in Alzheimer's disease. Brain. 2001 Apr;124(Pt 4):739-56. PubMed.
  5. . Reduced hippocampal functional connectivity in Alzheimer disease. Arch Neurol. 2007 Oct;64(10):1482-7. PubMed.
  6. . Functional abnormalities of the medial temporal lobe memory system in mild cognitive impairment and Alzheimer's disease: insights from functional MRI studies. Neuropsychologia. 2008;46(6):1624-35. PubMed.
  7. . Neural hyperactivation in carriers of the Alzheimer's risk variant on the clusterin gene. Eur Neuropsychopharmacol. 2011 Dec;21(12):880-4. PubMed.
  8. . Common Alzheimer's disease risk variant within the CLU gene affects white matter microstructure in young adults. J Neurosci. 2011 May 4;31(18):6764-70. PubMed.
  9. . Alzheimer disease: New light on an old CLU. Nat Rev Neurol. 2010 Jan;6(1):11-3. PubMed.
  10. . The pathological process underlying Alzheimer's disease in individuals under thirty. Acta Neuropathol. 2011 Feb;121(2):171-81. PubMed.

External Citations

  1. clusterin
  2. AlzGene Top Results

Further Reading

Primary Papers

  1. . Hippocampal function in healthy carriers of the CLU Alzheimer's disease risk variant. J Neurosci. 2011 Dec 7;31(49):18180-4. PubMed.
  2. . Neural hyperactivation in carriers of the Alzheimer's risk variant on the clusterin gene. Eur Neuropsychopharmacol. 2011 Dec;21(12):880-4. PubMed.
  3. . Common Alzheimer's disease risk variant within the CLU gene affects white matter microstructure in young adults. J Neurosci. 2011 May 4;31(18):6764-70. PubMed.