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Amyloid-beta (Aβ) accumulation was evaluated with two PIB PET scans about 2.5 years apart in 146 cognitively normal adults. Seventeen of 21 participants with initially elevated Aβ deposition demonstrated subsequent Aβ plaque growth (approximately 8.0% per year) and none reverted to a state of no Aβ deposits. Ten individuals converted from negative to positive PIB status, based on a threshold of the mean cortical binding potential, representing a conversion rate of 3.1% per year. Individuals with an ε4 allele of apolipoprotein E demonstrated increased incidence of conversion (7.0% per year). Our findings suggest that the major growth in Aβ burden occurs during a preclinical stage of AD, prior to the onset of AD-related symptoms.
The amyloid hypothesis of Alzheimer disease (AD) posits that the accumulation of amyloid-beta (Aβ) peptide, typically aggregated in brain parenchyma as senile plaques is a primary pathogenic feature of AD1. However, candidate “disease-modifying” drugs that target Aβ have yet to demonstrate efficacy in persons with symptomatic AD, even when it appears that the treatment may succeed in reducing cerebral Aβ burden2. It is possible that the failure to date of anti-Aβ therapies to benefit individuals with clinically diagnosed AD is because treatment is initiated too late in the disease process. By the time the earliest symptoms of AD can be detected clinically, 30%–60% of neurons in the entorhinal cortex and hippocampus already are lost3. The optimal window of opportunity for anti-Aβ therapies thus may be very early in the pathologic course of AD, before the presence of substantial synaptic and neuronal damage and prior to the onset of symptoms.
The concept of preclinical AD holds that Aβ deposits accumulate without detectable cognitive dysfunction but ultimately culminate in symptomatic AD should the individual live long enough4. Cognitively normal individuals with presumptive preclinical AD as detected by increased uptake of positron emission tomography (PET) amyloid tracer [11C] Pittsburgh compound (PIB) have a greater risk of progression from cognitive normality to symptomatic AD after 3–4 years of follow-up5, suggesting that preclinical AD is not benign. However, there have been relatively few longitudinal studies using PIB as an indicator of Aβ accumulation 6–9. In particular, the study of Aβ accumulation in preclinical AD has been limited 10, 11. Because information on the rates of appearance and growth of Aβ deposits may be important for the design of potential prevention trials of AD, we used longitudinal PIB imaging to evaluate the natural history of Aβ plaques in a large cohort of cognitively normal adults.
Participants were community dwelling volunteers (age at entry ranged from 45 to 86 years) enrolled in the longitudinal studies of the Washington University Knight Alzheimer Disease Research Center. The clinical assessment protocol has been described12, 13. Only cognitively normal individuals with Clinical Dementia Rating (CDR) of 0 were included in the study, and all participants remained CDR 0 at the assessment closest to their follow-up PIB scan (Table 1).
All assessment and imaging procedures were approved by Washington University’s Human Research Protection Office. Written consent was obtained from each participant and their informant.
TaqMan assays (Applied Biosystems, Foster City, USA) for both rs429358 (ABI#C_3084793_20) and rs7412 (ABI#C_904973_10) were used for genotyping. Allele calling was performed using the allelic discrimination analysis module of ABI Sequence Detection Software. Positive controls for each of six possible APOE genotypes were included on the genotyping plate.
Magnetic resonance imaging (MRI) was obtained for anatomic reference and consisted of MPRAGE T1-weighted images (1mm × 1mm × 1.25mm) on a Siemens (Erlangen, Germany) MR scanner. The PIB PET imaging has been described in detail13 and was conducted with a Siemens 961 HR+ ECAT PET scanner (Siemens/CTI, Knoxville KY) or a Siemens Biograph 40 scanner.
Three dimensional regions-of-interest (ROIs) were drawn on the initial MRI for each participant and applied to co-registered initial and follow-up PIB PET scans. The ROIs included prefrontal cortex, lateral temporal cortex, precuneus, anterior cingulate, occipital lobe, head of the caudate, gyrus rectus, and cerebellum13. As an indicator of global Aβ deposition we used the Mean Cortical Binding Potential (MCBP) which averages the gyrus rectus, prefrontal, precuneus, and lateral temporal cortex binding potential (BP) values, as these regions have high PIB uptake in individuals with symptomatic AD13. Test-retest of global Aβ estimates with this approach are excellent with very high correlation (r2 = 0.975) between successive scans obtained in 20 persons from 0 to 97 days apart, with a mean change of −0.003 of MCBP and a standard deviation of 0.043 (Table 1 and Figure 1, Supplementary materials). MCBP values greater than 0.18 were considered abnormal (i.e. “PIB positive”)13. Because BP was measured at two time points for every individual, the rate of Aβ accumulation was calculated as the change in BP per year.
The rate of Aβ accumulation was analyzed as a function of baseline Aβ accumulation (PIB positive vs. PIB negative), family history of AD (positive vs. negative), and presence of one or more APOE ε4 alleles by the Analysis of Variance (ANOVA) and further as a function of baseline age by the Analysis of Covariance (ANCOVA) 14. Significance level was set at p<0.05.
One hundred forty six participants (Table 1) underwent two PIB PET scans within 1 to 5 years (mean interval 2.6 ± 1.1 years) (Figure 1). A family history of AD, was present in 89 of 146 (61.0%) participants but was not associated (independent of APOE4) with the rate of Aβ accumulation in MCBP or with the BP of any individual ROIs (F(1, 142)= 1.38, p= 0.2412).
In 21 (High-PIB, 13 females, mean age 69.0 ± 6.7 years) of the 146 participants, both PIB scans were positive (MCBP>0.18). From first to second PIB scans, 17 of the 21 (81%) High-PIB individuals showed subsequent increase in Aβ accumulation and 4 individuals (3 were 80 years or older) had decreases in MCBP and regional BP. The mean MCBP at first scan in the High-PIB group was 0.44 ± 0.20, with a mean change of 0.091 ± 0.106. This translated to a MCBP annual increase of 0.035 ± 0.040, or approximately 8% per year. The High-PIB group did not differ significantly in age from the Low-PIB group (MCBP < 0.18, n=125, 86 females, mean age 65.5 ± 10.7 years) at initial scan (F(1, 144)= 2.10, p= 0.1498), but demonstrated higher age-adjusted rate of Aβ accumulation for all ROIs except for anterior cingulate, occipital cortex and caudate. Age at initial scan was not associated with the rate of change in MCBP in the Low-PIB group (t(142)=0.58, p= 0.5635). In the High-PIB group, the rate of Aβ accumulation decreased slightly (but significantly) as a function of age at the first PIB scan (t(142)= −4.07, p <.0001), primarily driven by the 3 oldest individuals (>80 y) whose rate of change in MCBP was negative (Figure 2).
Ten (7 females, mean age 65.5 ± 8.3 years) of the 125 (8.0%) Low-PIB individuals became positive on the second PIB scan, yielding an incidence of conversion from normal to abnormal Aβ burden of 3.1% per year. Including the second scan, 31 of the 146 (21%) cognitively normal individuals had elevated PIB retention. The youngest participant to convert was 56 yrs at the second PIB scan. Seven of the 10 converters were APOE4 positive.
Fifty participants (Table 1) had at least one APOE ε4 allele. Thirteen (61.9%) individuals in the High-PIB group were APOE4 carriers versus 37 (29.6%) in the Low-PIB group. The incidence of conversion from negative to positive PIB scan in APOE4 individuals was 7.0% per year, more than double that of the entire group (3.1%/yr). With age as a covariate, APOE4 was unassociated with rate of change in MCBP and in the BP of any individual ROI. When the 3 oldest individuals (> 80 y)with decreases in MCBP and regional BP were removed from the analysis, however, the rate of Aβ accumulation in the precuneus was associated with APOE4 (0.010 ± 0.037 BP/yr for APOE4−; 0.026 ± 0.040 BP/yr for APOE4+; F(1,139)= 8.86,p= 0.0034). A similar association was observed in the precuneus when the analyses (adjusting for age) were limited to individuals (absent the 3 oldest) in the High-PIB group (0.016 ± 0.020 BP/yr for APOE4−; 0.065 ± 0.032 BP/yr for APOE4+; t(139)= −2.83, p= 0.0053).
To our knowledge, this is the first documentation of the development of preclinical AD in cognitively normal persons. The rate of “conversion” from no preclinical AD (PIB negative) to preclinical AD (PIB positive) in this sample was 3.1% per year beginning at age 56 years. Recognizing that “conversion” is arbitrarily determined by the MCBP threshold used to dichotomize PIB “positive” and “negative” in what may be a continuous process of amyloid growth, nonetheless this rate now can be evaluated in other, larger samples to better characterize the incidence of preclinical AD.
Our results suggest that the presence of Aβ deposits in cognitively normal individuals is not a static phenomenon but a dynamic process of substantial growth. Once appreciable Aβ deposits are established, they remain high; none of the 21 participants with a positive baseline PIB scan was PIB negative at the second scan. Most individuals with Aβ deposits continued to accumulate Aβ on the order of 8.0% per year; however, we found a negative correlation between Aβ accumulation and age in High-PIB individuals, likely due to decreased Aβ burden in the 3 oldest (80 yr or older) individuals at time of the second PIB scan. More longitudinal data are required to determine whether an age effect truly is present.
The increase in Aβ accumulation, expressed as percent change, observed here is higher than that reported in previous longitudinal PIB studies where only small, if any, percent increases in Aβ over time were demonstrated 6–11. However, those reports expressed percent increase compared to total uptake in the brain using SUVR or distribution volume ratio (DVR). Numerically, BP is equal to DVR – 1. If we express our data in DVR, the mean MCBP at first scan in High-PIB group will be 1.44, and per cent annual increase becomes 2.4% per year, which is comparable to DVR data in other studies. However, DVR and SUVR , are ratios to nonspecific uptake, and thus numerically lower the percent change resulting in underestimation of changes in Aβ accumulation. We used BP to calculate percent change as it is BP that is proportional to the specific binding to amyloid plaques 13, not DVR (or SUVR); hence more directly reflecting percent change in plaque burden.
Our findings are consistent with other reports showing substantial growth in Aβ burden during the preclinical phase of AD, prior to the onset of symptoms 10, 11. This growth appears to attenuate once the symptomatic stage of AD is reached 6–8. In preclinical AD, APOE4 is associated with increased prevalence of Aβ deposits 15, 16. Our findings support an association of APOE4 not only with a higher risk of initiating Aβ deposition but also with a higher rate of subsequent Aβ plaque growth in the precuneus, at least for individuals below age 80 yr. However, larger sample sizes are required to fully appreciate the effect of APOE4.
There are several limitations to our study. Determining the trajectory of longitudinal change requires more than two data points. Longitudinal measurements may be susceptible to technical problems such as misregistration between PET and MRI and partial volume effects caused by cerebral atrophy. The biological relevance of a MCBP threshold of 0.18 is unclear without clinicopathologic correlation. Nonfibrillar Aβ deposits may not be detected by PIB 17, 18.
The Clinical and Genetic Cores of Washington University’s Knight Alzheimer Disease Research Center provided the participant assessments and APOE genotyping. We thank the following Washington University colleagues: Abraham Snyder for image processing advice; Jon Christensen for help with data analysis; Patricia Stevenson, Lori Groh, Mary Coats, and Virginia Buckles for coordinating the participant assessments; and Jennifer Frye, Helen Kaemmerer, Linda Becker, and Lenis Lich for skilled technical assistance.
This work was supported by NIH: P50 AG05133, P50 AG05681, P30 NS048056, P01 AG026276, P01 AG03991, the Dana Foundation, and the Charles F. and Joanne Knight Alzheimer’s Disease Initiative.