The goal was to determine whether the same brain changes seen in AD patients could be detected in healthy, late-middle-aged people with varying levels of AD risk. “If so, are these changes progressive, and could we come up with a rapid and cost-effective strategy to evaluate promising prevention strategies?” Reiman said in an interview with ARF.

About 15 years ago, he and colleagues launched a longitudinal study to address these questions using brain volume and glucose metabolism measurements, clinical ratings, and neuropsychological tests to assess cognitively normal people whose AD risk varied according to their ApoE4 gene dose. (ApoE is the top AD genetic risk factor. Having one copy of the ApoE4 allele boosts AD risk about threefold, and ApoE4 homozygotes face a 10-fold or greater risk than do non-carriers.) One and a half years ago, the Arizona scientists offered the volunteers in this ongoing observational study the additional assessment of live brain imaging using the positron emission tomography (PET) tracer Pittsburgh Compound B (PIB).

For this new investigation, Reiman and colleagues analyzed 28 cognitively normal people (mean age 64 years). All participants had a family history of AD, along with either two (n = 8), one (n = 8) or no (n = 12) copies of the ApoE4 allele. In these individuals, fibrillar amyloid burden correlated closely with ApoE4 gene dose in a host of AD-affected brain areas (cortical, frontal, temporal, posterior cingulate-precuneus, parietal, and basal ganglia regions of interest). The amyloid load was highest in an ApoE4 homozygote woman who had recently developed mild cognitive impairment (MCI); her Aβ levels were comparable to those of a group of people from a previous study who were diagnosed with probable AD.

The findings suggest that “fibrillar amyloid deposition in cognitively normal older people may be related to risk of AD,” Reiman said. What remains to be determined, he noted, is whether this correlation is specific to the APOE4 gene or if it is also relevant to APOE4 non-carriers. As for whether amyloid imaging can determine a healthy person’s AD risk, “we do not recommend it clinically at this time,” Reiman said. “We need more precise information about its predictive value so it doesn't risk false alarm or false reassurance.” (For more on what amyloid load could mean for healthy seniors, see (see ARF HAI Chicago story and ARF SfN DC story.)

In the meantime, Reiman hopes the new data can guide the design of clinical trials that could dramatically cut the time and cost of identifying AD prevention therapies. Years earlier, the field was mulling over hormone replacement therapy and other potential treatments (e.g., cholesterol-lowering and blood pressure medications), thinking they could be most effective if begun in midlife. “We estimated that if you were to start a 20-year prevention trial with people at age 50, it would take about 50,000 participants,” Reiman said. “Nobody will ever do that study.”

However, he and colleagues have proposed, based on previous FDG-PET findings, that a presymptomatic treatment could be effectively evaluated in a two-year proof-of-concept prevention trial using just 200 late-middle-aged ApoE4 carriers (see Reiman et al., 2001, see Reiman comment). The new findings using PIB-PET strengthen the case for prevention studies that use biomarkers to evaluate promising amyloid-modifying treatments in at-risk, cognitively normal adults who are approaching their estimated age of clinical onset. Boosting efforts for prevention research represents one of the three core recommendations of the Alzheimer’s Study Group, which issued its final report on 25 March. (The ASG’s Strategic Plan is freely available for download from the ASG website. Scroll down to the hyperlinked word “electronically.”) “What I'm most excited about is capitalizing on this information to help launch the era of Alzheimer's prevention research by doing cost-effective prevention studies using biomarker endpoints,” Reiman told ARF.—Esther Landhuis.

Reference:
Reiman EM, Chen K, Liu X, Bandy D, Yu M, Lee W, Ayutyanont N, Keppler J, Reeder SA, Langbaum JB, Alexander GE, Klunk WE, Mathis CA, Price JC, Aizenstein HJ, DeKosky ST,m Caselli RJ. Fibrillar amyloid-beta burden in cognitively normal people at 3 levels of genetic risk for Alzheimer’s disease. PNAS Early Edition. 2009 April. Abstract