Tau and β-Amyloid Are Associated with Medial Temporal Lobe Structure, Function, and Memory Encoding in Normal Aging

Abstract

Normal aging is associated with a decline in episodic memory and also with aggregation of the β-amyloid (Aβ) and tau proteins and atrophy of medial temporal lobe (MTL) structures crucial to memory formation. Although some evidence suggests that Aβ is associated with aberrant neural activity, the relationships among these two aggregated proteins, neural function, and brain structure are poorly understood. Using in vivo human Aβ and tau imaging, we demonstrate that increased Aβ and tau are both associated with aberrant fMRI activity in the MTL during memory encoding in cognitively normal older adults. This pathological neural activity was in turn associated with worse memory performance and atrophy within the MTL. A mediation analysis revealed that the relationship with regional atrophy was explained by MTL tau. These findings broaden the concept of cognitive aging to include evidence of Alzheimer's disease-related protein aggregation as an underlying mechanism of age-related memory impairment.SIGNIFICANCE STATEMENT Alterations in episodic memory and the accumulation of Alzheimer's pathology are common in cognitively normal older adults. However, evidence of pathological effects on episodic memory has largely been limited to β-amyloid (Aβ). Because Aβ and tau often cooccur in older adults, previous research offers an incomplete understanding of the relationship between pathology and episodic memory. With the recent development of in vivo tau PET radiotracers, we show that Aβ and tau are associated with different aspects of memory encoding, leading to aberrant neural activity that is behaviorally detrimental. In addition, our results provide evidence linking Aβ- and tau-associated neural dysfunction to brain atrophy.

Keywords: PET; amyloid; episodic memory; fMRI; hippocampus; tau.

Figure 1.

Lure discrimination paradigm and behavioral performance. A, Participants were instructed to identify objects as being new (first presentation of object), old (repeated object), or similar (lure object resembling a previous trial). Objects were presented for 2000 ms, followed by a 500 ms intertrial interval. Similar lures acted as the primary trials for assessing memory performance. B, Proportion of response for each trial type. Responses to all trial types differed between YA and OA, with OA generally performing worse. C, LDI, quantifying the likelihood of correctly identifying lure objects, was significantly lower for OA compared with YA. Data presented as means ± SE.

Figure 2.

Patterns of fMRI activation during memory encoding in OA. Shown are one-sample t tests of activation (shown in warm colors) and deactivation (shown in cool colors) in OA during trials of sH (A), sCR (B), and sFA (C) compared with novel stimuli presented only once. Data are presented as t statistics.

Figure 3.

Differences in fMRI activation during memory encoding between OA and YA. Patterns of activation associated with group difference between OA (warm colors) and YA (cool colors) during trials of sH (A), sCR (B), and sFA (C). Data are presented as t statistics.

Figure 4.

PIB and AV-1451 PET imaging. DVR and SUVR images of PIB and AV-1451 binding in representative participants are shown. Areas of significant Aβ burden were seen in frontal and parietal cortices and posterior cingulate. Significant tau burden was largely restricted to the MTL.

Figure 5.

Relationship between fMRI activation and AD pathology. A, Positive relationship between PIB DVR (measure of Aβ) and sH deactivations (r₍₃₆₎ = 0.47, p = 0.05). B, Positive relationship between AV-1451 Braak I/II SUVR (measure of tau) and sFA activations (r₍₂₈₎ = 0.41, p = 0.01). Data are residuals controlling for age, sex, education, and hippocampal volume.

Figure 6.

Relationships between pathological activation, memory, and cortical thickness. A, Negative relationship between pathological activation (as defined by combining sH deactivations and sFA activations) and lure discrimination index (r₍₃₈₎ = 0.35, p = 0.05). B, Negative relationship between pathological activation and average entorhinal cortex thickness (r₍₃₈₎ = 0.44, p = 0.007). Data are residuals controlling for age, sex, and education.

Figure 7.

Mediation analysis of pathological activation, Braak I/II tau, and cortical thickness. Mediation analysis with pathological activation (red), mediated by Braak I/II AV-1451 standard uptake volume ratio (blue), predicting right entorhinal cortical thickness (green) are shown. Pathological activation positively predicted Braak I/II AV-1451, Braak I/II AV-1451 negatively predicted entorhinal cortical thickness, which resulted in a significant mediation. Numerical values are regression coefficients (β) from models controlling for age, sex, and education. See text for more details. *p < 0.05.