Alzheimer’s pathology targets distinct memory networks in the ageing brain

Abstract

Alzheimer’s disease researchers have been intrigued by the selective regional vulnerability of the brain to amyloid-β plaques and tau neurofibrillary tangles. Post-mortem studies indicate that in ageing and Alzheimer’s disease tau tangles deposit early in the transentorhinal cortex, a region located in the anterior-temporal lobe that is critical for object memory. In contrast, amyloid-β pathology seems to target a posterior-medial network that subserves spatial memory. In the current study, we tested whether anterior-temporal and posterior-medial brain regions are selectively vulnerable to tau and amyloid-β deposition in the progression from ageing to Alzheimer’s disease and whether this is reflected in domain-specific behavioural deficits and neural dysfunction. 11C-PiB PET and 18F-flortaucipir uptake was quantified in a sample of 131 cognitively normal adults (age: 20–93 years; 47 amyloid-β-positive) and 20 amyloid-β-positive patients with mild cognitive impairment or Alzheimer’s disease dementia (65–95 years). Tau burden was relatively higher in anterior-temporal regions in normal ageing and this difference was further pronounced in the presence of amyloid-β and cognitive impairment, indicating exacerbation of ageing-related processes in Alzheimer’s disease. In contrast, amyloid-β deposition dominated in posterior-medial regions. A subsample of 50 cognitively normal older (26 amyloid-β-positive) and 25 young adults performed an object and scene memory task while functional MRI data were acquired. Group comparisons showed that tau-positive (n = 18) compared to tau-negative (n = 32) older adults showed lower mnemonic discrimination of object relative to scene images [t(48) = −3.2, P = 0.002]. In a multiple regression model including regional measures of both pathologies, higher anterior-temporal flortaucipir (tau) was related to relatively worse object performance (P = 0.010, r = −0.376), whereas higher posterior-medial PiB (amyloid-β) was related to worse scene performance (P = 0.037, r = 0.309). The functional MRI data revealed that tau burden (but not amyloid-β) was associated with increased task activation in both systems and a loss of functional specificity, or dedifferentiation, in posterior-medial regions. The loss of functional specificity was related to worse memory. Our study shows a regional dissociation of Alzheimer’s disease pathologies to distinct memory networks. While our data are cross-sectional, they indicate that with ageing, tau deposits mainly in the anterior-temporal system, which results in deficits in mnemonic object discrimination. As Alzheimer’s disease develops, amyloid-β deposits preferentially in posterior-medial regions additionally compromising scene discrimination and anterior-temporal tau deposition worsens further. Finally, our findings propose that the progression of tau pathology is linked to aberrant activation and dedifferentiation of specialized memory networks that is detrimental to memory function.

Functional Brain Network Connectivity Patterns Associated With Normal Cognition at Old-Age, Local β-amyloid, Tau, and APOE4

“…Though the reduction in connectivity is a prominent finding in the literature, our results coincide with a longitudinal PET connectivity study (Jack et al, 2013) and a recent β-amyloid and tau study (Schultz et al, 2017), that suggests that along the AD spectrum there are phases of hyperand hypoconnectivity, with the former preceding the latter. Moreover, our findings are consistent with recent data on functional alterations associated with the presence of AD-pathology in non-demented old-aged adults (Jack et al, 2019;Maass et al, 2019;Ossenkoppele et al, 2019). Considering that the here investigated study population still had a low βamyloid burden (Aβ−) and was cognitively relatively healthy, the observed increase in PCP connectivity may reflect the presence of pathological impairment prior to significant βamyloid aggregation.…”

“…Functional connectivity changes within the ''default mode network'' (DMN) relate to AD-pathology and precede the manifestation of cognitive disorder by years (Sorg et al, 2007;Sperling et al, 2009;Wang et al, 2013;Sorg and Grothe, 2015). Moreover, large clinical studies demonstrate an association between AD-pathology and brain functionality in non-demented old-aged adults, as reflected by functional network integrity (Jack et al, 2019;Maass et al, 2019;Ossenkoppele et al, 2019). This may be consistent with functional network change in other neurodegenerative diseases (Rektorova et al, 2012;Ross et al, 2014;Kronenbuerger et al, 2019).…”

Noradrenergic-dependent functions are associated with age-related locus coeruleus signal intensity differences

“…In addition, NAdependent and NA-independent functions, as represented by their respective observed variables, were separable into two distinct factors in younger but not older adults in our sample. One potential explanation for this could be that older adults show greater "age dedifferentiation", whereby correlations among distinct measures of cognitive function become more intercorrelated with age [40][41][42] , possibly related to neuropathological changes 43 ; however, this is not a consistent finding as other studies have also found no evidence for age-related dedifferentiation among cognitive factors 38,44 . A second possible explanation is that although specific cognitive and behavioral functions relying on the LC-NA system have been described, it is conceivable that putatively NAindependent measures such as fluid intelligence, sentence comprehension, and facial recognition might also be reliant on this system due to the widespread distribution of noradrenergic neurons and the role of NA in attention and arousal that underlies diverse tests of cognitive functions.…”

Age differences in retrieval-related reinstatement reflect age-related dedifferentiation at encoding

“…This phenomenon -age-related neural dedifferentiation -has been conjectured to play a role in age-related cognitive decline [20][21][22] . Notably, lower specificity of neural responses to perceptual events has been reported to predict poorer subsequent memory for the events in both young and older adults [23][24][25] . These findings raise the possibility that the distinctiveness or fidelity with which the perceptual features of an event are neurally represented at the time of encoding (that is, its level of neural differentiation) are a determinant of the fidelity with which the features are reinstated at retrieval.…”