Mapping the effects of ApoE4, age and cognitive status on 18F-florbetapir PET measured regional cortical patterns of beta-amyloid density and growth

Abstract

Background: Although it is well known that many clinical and genetic factors have been associated with beta-amyloid deposition, few studies have examined the interactions of such factors across different stages of Alzheimer's pathogenesis.

Methods: We used 18F-florbetapir F18 PET imaging to quantify neuritic beta-amyloid plaque density across four cortical regions in 602 elderly (55-94 years) subjects from the national ADNI biomarker study. The group comprised of 194 normal elderly, 212 early mild cognitive impairment [EMCI], 132 late mild cognitive impairment [LMCI], and 64 mild Alzheimer's (AD).

Findings: In a model incorporating multiple predictive factors, the effect of apolipoprotein E ε4 and diagnosis was significant on all four cortical regions. The highest signals were seen in cingulate followed by frontal and parietal with lowest signals in temporal lobe (p<0.0001). The effect of apolipoprotein E ε4 (Cohen's D 0.96) on beta-amyloid plaque density was approximately twice as large as the effect of a diagnosis of AD (Cohen's D 0.51) and thrice as large as the effect of a diagnosis of LMCI (Cohen's D 0.34) (p<0.0001). Surprisingly, ApoE ε4+ normal controls had greater mean plaque density across all cortical regions than ε4- EMCI and ε4- LMCI (p<0.0001, p=0.0009) and showed higher, though non-significant, mean value than ε4- AD patients (p<0.27). ApoE ε4+ EMCI and LMCI subjects had significantly greater mean plaque density across all cortical regions than ε4- AD patients (p<0.027, p<0.0001).

Interpretation: Neuritic amyloid plaque load across progressive clinical stages of AD varies strongly by ApoE4 genotype. These findings support the need for better pathology-based and supported diagnosis in routine practice. Our data also provides additional evidence for a temporal offset between amyloid deposition and clinically relevant symptoms.

Figure I. PET Scans Depicting Florbetapir Uptake for Each Diagnosis

Axial brain slices of four florbetapir-PET subjects inferior to superior reflecting approximate median representations of amyloid deposition for each diagnosis. Images depicted in native space with white matter uptake seen to a degree in each subject. SUVR color images are depicted for illustration purposes only. (Note that the remnants of signal outside the EMCI slices are due to image reconstruction and should not be considered.)

Figure II

Box plot figures of beta-amyloid PET SUVR by diagnosis and E4 status in 4 cortical regions. As can be seen the effect of E4 status is far more striking than the effect of clinical diagnosis. For example, E4+ controls had higher mean SUVRs than E4− EMCI, E4− LMCI and E4− AD. E4+ MCI subjects had higher mean SUVRs than E4− AD. See methods and results for details of fitted models. The cingulate has the highest signal of the four regions across all groups.