Episodic memory loss is related to hippocampal-mediated beta-amyloid deposition in elderly subjects

Abstract

Although beta-amyloid (Abeta) plaques are a primary diagnostic criterion for Alzheimer's disease, this pathology is commonly observed in the brains of non-demented older individuals. To explore the importance of this pathology in the absence of dementia, we compared levels of amyloid deposition (via 'Pittsburgh Compound-B' (PIB) positron emission tomography (PET) imaging) to hippocampus volume (HV) and episodic memory (EM) in three groups: (i) normal controls (NC) from the Berkeley Aging Cohort (BAC NC, n = 20); (ii) normal controls (NC) from the Alzheimer's disease neuroimaging initiative (ADNI NC, n = 17); and (iii) PIB+ mild cognitive impairment subjects from the ADNI (ADNI PIB+ MCI, n = 39). Age, gender and education were controlled for in each statistical model, and HV was adjusted for intracranial volume (aHV). In BAC NC, elevated PIB uptake was significantly associated with smaller aHV (P = 0.0016) and worse EM (P = 0.0086). Within ADNI NC, elevated PIB uptake was significantly associated with smaller aHV (P = 0.047) but not EM (P = 0.60); within ADNI PIB+ MCI, elevated PIB uptake was significantly associated with both smaller aHV (P = 0.00070) and worse EM (P = 0.046). To further understand these relationships, a recursive regression procedure was conducted within all ADNI NC and PIB+ MCI subjects (n = 56) to test the hypothesis that HV mediates the relationship between Abeta and EM. Significant correlations were found between PIB index and EM (P = 0.0044), PIB index and aHV (P < 0.0001), as well as between aHV and EM (P < 0.0001). When both aHV and PIB were included in the same model to predict EM, aHV remained significant (P = 0.0015) whereas PIB index was no longer significantly associated with EM (P = 0.50). These results are consistent with a model in which Abeta deposition, hippocampal atrophy, and EM occur sequentially in elderly subjects, with Abeta deposition as the primary event in this cascade. This pattern suggests that declining EM in older individuals may be caused by Abeta-induced hippocampus atrophy.

Figure 1

Qualitative examination of PIB-DVR data. Partial volume corrected PIB-DVR images were overlaid on native space reconstructed surfaces derived from the subject's T1-weighted structural scan for 3 UCSF Alzheimer's disease subjects (A–C) and 3 BAC NC subjects (D–F). Each box shows lateral and medial views of PIB distribution for a single subject (left hemisphere is above right hemisphere in each box). All images reflect the same color scale, with yellow indicating high PIB uptake, red indicating medium PIB uptake, and grey indicating low PIB uptake.

Figure 2

Box and whiskers plot showing the distribution of DVR PIB index values in BAC NC and UCSF Alzheimer's disease subjects.

Figure 3

Box and whiskers plot showing the distribution of SUVR PIB index values in ADNI groups. ADNI SUVR PIB index values are not directly comparable to BAC NC and UCSF Alzheimer's disease DVR PIB index values in Fig. 2 due to differences in image processing (see text).

Figure 4

Partial regression plots showing the relationships between PIB index and aHV (A) and EM (B) within the BAC NC group. Residuals are plotted for each variable to adjust for the effects of age; gender and education. Both regression models are significant (A: ΔR² = 0.45; P = 0.0016; B: ΔR² = 0.35; P = 0.0086).

Figure 5

Partial regression plots showing the relationships between PIB index and aHV (A) and EM (B) after removing the two subjects with the highest PIB uptake from the BAC NC group. Residuals are plotted for each variable to adjust for the effects of age, gender and education. PIB index versus aHV remains significant (ΔR² = 0.28, P = 0.026), whereas PIB index versus EM is no longer significant (ΔR² = 0.03, P = 0.47).

Figure 6

Partial regression plots showing the relationships between PIB index and aHV (A) and EM (B) within the ADNI NC group. Residuals are plotted for each variable to adjust for the effects of age, gender and education. Only PIB index versus aHV shows a significant association (A: ΔR² = 0.22, P = 0.047; B: ΔR² = 0.02, P = 0.60).

Figure 7

Partial regression plots showing the relationships between PIB index and aHV (A) and EM (B) within the ADNI PIB+ MCI group. Residuals are plotted for each variable to adjust for the effects of age, gender and education. PIB index is significantly associated with both aHV and EM (A: ΔR² = 0.27, P = 0.00070; B: ΔR² = 0.11, P = 0.046).

Figure 8

Partial regression plots showing results from a recursive regression procedure suggesting a sequential relationship between the three variables, with aHV mediating the relationship between PIB index and EM. Residuals are plotted for each variable to adjust for the effects of age, gender and education. (A) The relationship between PIB index and EM before (solid line, P = 0.0044) and after controlling for aHV (dashed line; ΔR² = 0.00, P = 0.50). (B) The relationship between aHV and EM before (solid line, P = 0.000023) and after controlling for PIB index (dashed line; ΔR² = 0.15, P = 0.0015).