Biomarker Changes Precede Symptoms by 20 Years

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Amyloid accumulation. Cross-sectional analysis using florbetapir PET shows that brain amyloid deposits ramp up steeply in AD mutation carriers between the ages of 28 and 38, several years before clinical symptoms appear. Movie courtesy of Adam Fleisher and Lancet Neurology

Evidence keeps building that the first signs of Alzheimer’s disease appear decades before symptoms. In two companion papers in the November 6 Lancet Neurology, theAlzheimer’s Prevention Initiative (API) formally published cross-sectional biomarker data from young adults who carry a presenilin 1 mutation and are destined to develop AD. Researchers led by Eric Reiman at Banner Alzheimer’s Institute, Phoenix, Arizona, and Francisco Lopera, University of Antioquia, Medellin, Colombia, report that mutation carriers show structural and functional brain abnormalities characteristic of AD more than two decades before they are expected to develop cognitive symptoms of the disease. Notably, the changes occur in the presence of high levels of Aβ42, but before there is evidence of amyloid accumulation in the brain. Although it is not yet proven that these results will generalize to late-onset AD, researchers noted the changes are consistent with brain imaging findings in young adults at increased risk for sporadic AD, suggesting the two forms of the disease progress similarly. The researchers saw the first evidence of amyloid deposits about 16 years before the expected symptom onset, in agreement with findings from the Dominantly Inherited Alzheimer Network (DIAN) cohort. Much of these data were previously presented at conferences.

The API studies a single large Colombian kindred who carry the presenilin 1 E280A mutation thought to lead to Aβ overproduction (seeARF API series 2010 and API series 2011 for background). Carriers typically develop mild cognitive impairment (MCI) around the age of 44, and dementia at about 49. In the first paper, co-first authors Reiman and Yakeel Quiroz of Boston University, Massachusetts, report that among 18- to 26-year-olds, the 20 mutation carriers had less gray matter in several parietal regions, and showed greater hippocampal activation and less precuneus and posterior cingulate deactivation during a memory task than the 24 non-carriers. In a subset of this young group, 10 carriers had higher levels of Aβ42 in cerebrospinal fluid (CSF) and plasma than 10 non-carriers, consistent with the idea that the mutation leads to Aβ overproduction.

In the second paper, first author Adam Fleisher at Banner compared positron emission tomography (PET) scans with the amyloid-binding agent florbetapir of 30 carriers and 20 non-carriers between 18 and 60 years old. In carriers, fibrillar Aβ began to accumulate at the age of 28. Levels rose steeply until about age 38, six years before expected MCI onset, when they plateaued (see movie below). These results closely match findings from DIAN, which reported that Aβ accumulation in people with familial AD begins about 15 years before expected symptomatic onset (see ARF related news story). The DIAN study included a heterogeneous mix of mutations from families around the world, and used a different agent (PIB instead of florbetapir) to assess brain amyloid.

“The data are very complementary to and supportive of what DIAN found,” said DIAN leader John Morris at Washington University, St. Louis, Missouri.

Researchers also pointed out that the early biomarker changes echo results from studies of sporadic AD. Reiman and others have previously shown that young adult carriers of ApoE4, the primary genetic risk factor for late-onset AD, activate their brains differently during tasks and in the resting state than do non-carriers (see ARF related news story;Reiman et al., 2004; Valla et al., 2010). Reisa Sperling at Brigham and Women’s Hospital, Boston, who is a DIAN site leader and a coauthor on the first Lancet paper, noted that the pattern of functional changes seen in the young PS1 mutation carriers is identical to that seen in older people with brain amyloid or MCI who go on to develop late-onset AD. “That [the data] are so congruent across autosomal-dominant early-onset AD and sporadic AD is reassuring me that we are on the right track toward understanding the pathophysiologic process,” she told Alzforum.

The API data largely support current models of how biomarkers change as AD progresses (see ARF Webinar). However, the authors report reductions in gray matter in young carriers compared to controls, whereas current biomarker models suggest that gray matter atrophy is a late symptom, occurring after amyloid and tau deposits have formed. Reiman noted that the thinner gray matter seen in PS1 mutation carriers could be a developmental effect rather than a sign of early neurodegeneration. Morris speculated that the early gray matter losses could be a feature specific to the PS1 mutation, since DIAN studies did not see reductions prior to amyloid deposition. Conversely, current models might need tweaking to better reflect the exact ordering of biomarker changes, Sperling suggested. All researchers agreed that ongoing longitudinal studies in the DIAN and API cohorts and in late-onset AD will help clarify this issue.

Researchers were intrigued by the fact that AD biomarkers show up before any evidence of amyloid deposits. In a commentary accompanying the second Lancet paper, William Jagust at the University of California, Berkeley, wrote, “Structural and functional neural alterations before Aβ deposition have important consequences for our understanding of the amyloid hypothesis and our use of biomarkers to investigate it, since present models suggest that these changes are a result of brain Aβ deposition.” Since the young PS1 carriers have high levels of soluble Aβ42, the data support the idea that soluble oligomeric forms of Aβ are the most toxic species, Sperling told Alzforum.

The API is gearing up to conduct a clinical prevention trial of the anti-amyloid antibody crenezumab in participants 30 and older (see ARF related news story and ARF news story). Because amyloid deposits climb steeply throughout the thirties in carriers, this looks like a good age to begin anti-amyloid therapy, Reiman noted, although he added that some treatments may need to be started at even younger ages. In a commentary on the first Lancet paper, Nick Fox at University College London, U.K., pointed out, “These findings add to accumulating evidence that Alzheimer’s disease is characterized by a long presymptomatic period of slowly progressive changes that can be identified and tracked using imaging and fluid biomarkers, thereby opening up a therapeutic window for early intervention.”—Madolyn Bowman Rogers.

References:
Reiman EM, Quiroz YT, Fleisher AS, Chen K, Velez-Pardo C, Jimenez-Del-Rio M, Fagan AM, Shah AR, Alvarez S, Arbelaez A, Giraldo M, Acosta-Baena N, Sperling RA, Dickerson B, Stern CE, Tirado V, Munoz C, Reiman RA, Huentelman MJ, Alexander GE, Langbaum JB, Kosik KS, Tariot PN, Lopera F. Brain imaging and fluid biomarker analysis in young adults at genetic risk for autosomal dominant Alzheimer’s disease in the presenilin 1 E280A kindred: a case-control study. Lancet Neurol. 2012 Nov 6.

Fox N. When, where, and how does Alzheimer’s disease start? Lancet Neurol. 2012 Nov 6.

Fleisher AS, Chen K, Quiroz YT, Jakimovich LJ, Gutierrez Gomez M, Langois CM, Langbaum JB, Ayutyanont N, Roontiva A, Thiyyagura P, Lee W, Mo H, Lopez L, Moreno S, Acosta-Baena N, Giraldo M, Garcia G, Reiman RA, Huentelman MJ, Kosik KS, Tariot PN, Lopera F, Reiman EM. Florbetapir PET analysis of amyloid-β deposition in the presenilin 1 E280A autosomal dominant Alzheimer’s disease kindred: a cross-sectional study. Lancet Neurol. 2012 Nov 6.

Jagust W. Tracking brain amyloid-β in presymptomatic Alzheimer’s disease. Lancet Neurol. 2012 Nov 6.