The integrative memory model presented by Bastin et al. could be augmented to apply more directly to specific memory deficits. Alzheimer's disease (AD) etiology, which is used to describe the application of their model, often involves significant anxiety and comorbid depression (Zhao et al. Reference Zhao, Tan, Wang, Jiang, Tan, Tan, Xu, Li, Wang, Lai and Yu2016). The authors note the involvement of affective and subjective factors, and suggest that memory deficit-related anxiety may be due to not meeting cognitive and memory goals, but do not go into great detail. Failure to meet goal-associated stress could interfere with the salience and strength of cues critical to effective recollection and/or familiarity processes. In both symptomology and assessment, anxiety can significantly affect memory task context, adversely interfering at the familiarity stage and with recollection circuit signaling. Anxiety is also likely to disrupt memory through interactions with metacognition.

While the literature related to the impact of anxiety on specific AD-associated memory nuclei discussed by Bastin et al. is not substantial, there is growing evidence of associations between anxiety and AD (Donovan et al. Reference Donovan, Locascio, Marshall, Gatchel, Hanseeuw, Rentz, Johnson and Sperling2018). Anxiety is a predictor for early onset AD (Kaiser et al. Reference Kaiser, Liang, Melrose, Wilkins, Sultzer and Mendez2014) and the conversion of mild cognitive impairment (MCI) to AD (Gallagher et al. Reference Gallagher, Coen, Kilroy, Belinski, Bruce, Coakley, Walsh, Cunningham and lawlor2011). The importance of familiarity in early etiology and the accumulating observations of anxiety during this period suggests that an increased integrative focus on neural mechanisms of anxiety and familiarity, where nuclei involved in both processes are evaluated simultaneously, may provide valuable insight on the specific nature of the role of anxiety in susceptibility to MCI and AD, progression to AD, and the progression of AD symptomology. Bastin et al. note that recollection is critically dependent on the posterior cingulate, which has also been implicated in anxiety as a component of the default mode network (DMN) (Maddock & Buonocore Reference Maddock and Buonocore1997; Zhao et al. Reference Zhao, Wang, Li, Hu, Xi, Wu and Tang2007). This region could have anxiety-associated effects on recollection due to its strong connections with hippocampal and entorhinal areas, where adverse effects of anxiety exacerbate neurodegenerative changes in the posterior cingulate, disrupting recollection processes there and in related regions. As AD progresses, and as recollection circuits are impaired, the role of anxiety becomes more difficult to assess due to decreased awareness of cognitive and memory deficits. Although the degree to which metacognition is intact in AD is debated (Moulin et al. Reference Moulin, James, Perfect and Jones2003), it is possible that anxiety has more substantial adverse effects in individuals/populations and/or early stages where metacognition is relatively intact. Focusing research on these individuals and/or stages would more effectively target the role of anxiety in AD-related memory deficits.

One could argue that while an anxiety domain could enhance the application of the integrative memory model, it may not be initially necessary. However, it is also possible that the inclusion of the effects of anxiety on memory processes is critical to an accurate and comprehensive understanding of AD, given the acute impact on memory processes, high comorbidity, and growing evidence of anxiety- and stress-related depression as AD risk factors. Anxiety and associated stress may modify interactions between familiarity and recollection, affecting memory acutely through neuroendocrine mechanisms and chronically through neurodegenerative mechanisms (amyloidopathy, tauopathy, neuroinflammation, and microglial dysfunction). Amyloid β has been specifically associated with symptoms of anxiety and depression in cognitively normal older adults (Donovan et al. Reference Donovan, Locascio, Marshall, Gatchel, Hanseeuw, Rentz, Johnson and Sperling2018), and neuroticism may mediate this association (Snitz et al. Reference Snitz, Weissfeld, Cohen, Lopez, Nebes, Aizenstein, McDade, Price, Mathis and Klunk2015). Neuroticism-related anxiety may increase susceptibility for emotional distress and negative affect, and subsequent age-related cognitive decline, MCI, and AD. Anxiety may be more strongly associated with amyloid β and tau levels than depression (Ramakers et al. Reference Ramakers, Verhey, Scheltens, Hampel, Soininen, Aalten, Rikkert, Verbeek, Spiru, Blennow, Trojanowski, Shaw and Visser2012), and increased consideration of anxiety may lead to greater consistency in mechanistic studies of predisposing factors. Psychosocial stress has been linked to neuroinflammation and microglial dysfunction in AD (Piirainen et al. Reference Piirainen, Youssef, Song, Kalueff, Landreth, Malm and Tian2017), and it is postulated that this could involve anxiety-mediated mechanisms. The inclusion of the anxiety domain could be used to identify a key subpopulation of AD patients who would benefit from a targeted intervention, whether it be psychotherapy, pharmacotherapy, or a complimentary intervention, such as mindfulness. Identifying how and when anxiety contributes to memory deficits could also identify key early interventional periods.

The inclusion of anxiety, and potentially other mood factors, in the integrative memory model is not limited to AD, and parallels can be made with the customization of mindfulness-based stress reduction techniques for pathologies ranging from depression and anxiety to hypertension, including dementia (Russell-Williams et al. Reference Russell-Williams, Jaroudi, Perich, Hoscheidt, El Haj and Moustafa Ahmed2018). Given the heterogeneity of AD etiology, this type of precision medicine approach could substantially improve disease progression and/or quality of life outcomes (Reitz Reference Reitz2016). It is suggested that the integrative memory model can be used as a strong foundation for additional population and pathology-specific models of memory deficits.