Functional Alterations in Memory Networks in Early Alzheimer’s Disease

Abstract

The hallmark clinical symptom of early Alzheimer's disease (AD) is episodic memory impairment. Recent functional imaging studies suggest that memory function is subserved by a set of distributed networks, which include both the medial temporal lobe (MTL) system and the set of cortical regions collectively referred to as the default network. Specific regions of the default network, in particular, the posteromedial cortices, including the precuneus and posterior cingulate, are selectively vulnerable to early amyloid deposition in AD. These regions are also thought to play a key role in both memory encoding and retrieval, and are strongly functionally connected to the MTL. Multiple functional magnetic resonance imaging (fMRI) studies during memory tasks have revealed alterations in these networks in patients with clinical AD. Similar functional abnormalities have been detected in subjects at-risk for AD, including those with genetic risk and older individuals with mild cognitive impairment. Recently, we and other groups have found evidence of functional alterations in these memory networks even among cognitively intact older individuals with occult amyloid pathology, detected by PET amyloid imaging. Taken together, these findings suggest that the pathophysiological process of AD exerts specific deleterious effects on these distributed memory circuits, even prior to clinical manifestations of significant memory impairment. Interestingly, some of the functional alterations seen in prodromal AD subjects have taken the form of increases in activity relative to baseline, rather than a loss of activity. It remains unclear whether these increases in fMRI activity may be compensatory to maintain memory performance in the setting of early AD pathology or instead, represent evidence of excitotoxicity and impending neuronal failure. Recent studies have also revealed disruption of the intrinsic connectivity of these networks observable even during the resting state in early AD and asymptomatic individuals with high amyloid burden. Research is ongoing to determine if these early network alterations will serve as sensitive predictors of clinical decline, and eventually, as markers of pharmacological response to potential disease-modifying treatments for AD. Sperling et al.

The cognitive neuroscience of ageing

“…Studies assessing whole brain functional connectivity have shown age differences in global DN functional connectivity 58 (see also Figure 3), suggesting weaker network integration overall in older adults. Functional connectivity in the DN (and other networks) is weakened further in older adults with dementia 180,204 . However, recent work has shown that some imaging artifacts that are more common in older adults, such as the influence of motion in the scanner 205 , can weaken functional connectivity, so issues such as this need to be examined further.…”

Item familiarity and controlled associative retrieval in Alzheimer's disease: An fMRI study

“…In fact, it is one of the brain regions most affected by AD, even at the very early clinical manifestations of the disease (Salmon et al, 2008; for reviews, see Buckner, 2004 andSperling et al, 2010). PET studies showed that episodic memory retrieval is correlated with brain metabolism in the PCC in AD patients (Desgranges et al, 1998(Desgranges et al, , 2002, as well as in patients with MCI and questionable AD (Chételat et al, 2003;Salmon et al, 2008).…”

Functional brain network centrality is related to APOE genotype in cognitively normal elderly

“…The accumulation of amyloid‐β (Aβ) plaques in the brain is one of the first events in the pathological cascade leading to Alzheimer's disease (AD) (Bateman et al., 2012; Hardy & Selkoe, 2002; Sperling et al., 2010). Aβ disrupts synaptic functioning, resulting in aberrant brain connectivity at the synaptic level (Selkoe, 2002; Spires‐Jones & Hyman, 2014), as well as on the whole‐brain connectivity level (Delbeuck, der Linden, & Collette, 2003; Hedden et al., 2009).…”