To know or to not know: The importance of assessing awareness of cognitive function in the early stages of Alzheimer's disease

Alzheimer's disease (AD) is the most prevalent form of dementia and the leading cause of cognitive decline in old age. A person's awareness that he/she is having cognitive problems helps them to recognize their functional limitations and ensure that they continue to make healthy and safe life decisions. ¹ Self-awareness, or the ability to identify and understand one's own character, feelings, and experiences, is a unique human ability and arguably one of the most fundamental issues in psychology. If an individual loses self-awareness, he/she will likely require increased supervision to stay safe and avoid risky or potentially dangerous behaviors. This is especially true in AD, as anosognosia, that is, the partial or complete unawareness of deficits, has been related to a delayed and worse diagnosis as well as less compliance to treatment or rehabilitation activities. ² The disorder is frequently observed in the AD dementia stage. ³ Although it is unknown at what disease stage deficits of self-awareness first appear, a growing number of studies have found evidence of unawareness already in the predementia (i.e., preclinical and prodromal) stages,^4–7 see also reviews by.^8,9 The prodromal stage is characterized by mild cognitive impairment (MCI) that cannot be classified as dementia, and at this stage, the patient has largely preserved autonomy. In contrast, heightened awareness, defined as self-perceived changes in cognitive function that are not corroborated by an informant or objective cognitive assessment (a.k.a. hypernosognosia) ¹⁰ has mainly been observed in the preclinical stage (i.e., before the prodromal stage) of AD. This latter concept is somewhat close to subjective cognitive decline (SCD) ¹¹ with the important distinction that SCD only considers the participant's self-reports of memory worsening. It has been estimated that the prevalence of SCD is high in the elderly (non-demented) population, ¹² which has sparked a debate in the field as to its sensitivity and specificity to identify people with neurodegenerative processes. ¹³ This latter finding could be due to the fact that SCD also includes the worried well individuals, that is, individuals who are complaining about their memory performance due to other reasons that are not related to AD, e.g., nosophobia (fear of disease), normal age-related changes, anxiety, or depression. Interestingly, recent studies have shown that unawareness can be observed even in the preclinical stage of AD.^4,14,15 Despite its critical importance, significant gaps remain in our understanding of awareness of cognitive function in neurodegenerative diseases, especially in the predementia stages of AD.

In a recent issue of the Journal of Alzheimer's Disease, Furuya et al. ¹⁶ investigates self-awareness of cognitive function using the discrepancy between self-perceived and study partner assessment of recent cognitive changes (as assessed with the Cognitive Function Instrument ¹⁷ ) in two clinical trial cohorts of preclinical individuals: (1) the Anti-Amyloid Treatment in Asymptomatic Alzheimer's Disease (A4) study ¹⁸ and (2) predementia individuals: the Japanese Trial-Ready Cohort onsite study. ¹⁹ Using this approach, a lower score indicates under-estimation of changes in cognitive functioning (these individuals believe they are functioning at a higher level than their study partner would suggest), and a higher score indicates over-estimation of changes in cognitive functioning (these individuals believe they are functioning less well than their study partner would suggest). Using a mixed-effects logistic regression model, the authors found that a lower discrepancy score (i.e., decreased awareness) was associated with an increased likelihood of harboring amyloid pathology (as measured with positron emission tomography). These results are in line with an increasing number of studies that have found that decreased awareness in the preclinical and prodromal stages is associated with increased amyloid pathology.^4,10,14 It is important to note that in the model, the authors also found that older age, female sex, carrying an APOE4 allele(s), and increased cognitive complaints by the participant were also associated with an increased likelihood of harboring amyloid pathology. Interestingly, the latter finding is seemingly contradictory to their unawareness findings. Even though the current study did not pin these measures against each other, a recent study by Cacciamani et al., ¹⁴ found that low awareness but not subjective complaints was a marker of preclinical AD. On the other hand, Bellaali et al., ²⁰ found that spouse-appraised memory functioning was more predictive of memory decline in APOE ε4 carriers (who are at increased risk for AD pathology) as compared to SCD or their awareness measure. At the very least, the findings by Furuya and colleagues highlight the importance of further studies to understand the presence and evolution of altered self-awareness of cognitive function across the preclinical and prodromal stages of AD. Importantly, and in line with previous findings of the variability of awareness in the early stages of AD, this will inevitably have implications for the use of SCD, as loss of awareness has been associated with reduced validity of the subjective experience of cognitive abilities.

Furuya et al. ¹⁶ also investigated how different demographical and clinical factors were related to the awareness measure. They found that not only older age, larger Clinical Dementia Rating (CDR)-sum of boxes, amyloid positivity, and if the study partner was the spouse, but also decreased complaints by the participant and male sex were related to a decreased awareness score. These findings are somewhat in contrast to their first regression model in which increased complaints by the participants and female sex were associated with an increased likelihood of harboring amyloid. These findings suggest complex interactions between self-awareness and demographic variables that warrant a more detailed investigation to disentangle these associations fully. Nonetheless, the results reported by Furuya and colleagues are in support of the notion that there is a different trajectory of cognitive complaints by the participant as compared to the complaints by the study partner across the predementia stages. Future studies are needed to shed more insight into whether an individual's self-judgment of his/her own cognitive abilities changes over the course of the disease as pathology increases.

Beyond this work, we also acknowledge that there might be other factors that can explain the interindividual variability of awareness in the predementia stages. For example, previous studies have demonstrated that anosognosia may increase vulnerability to neuropsychiatric symptoms in the prodromal^21,22 and dementia ²³ stages, although it remains unknown how these factors relate to each other in the preclinical stage. Also, measuring hypernosognosia/anosognosia by explicitly interviewing subjects and their partners about their cognitive changes may not be sufficient to provide an accurate estimate of the individual's level of self-awareness. In fact, increasing evidence suggests that some individuals may retain some form of implicit awareness of their cognitive deficits despite showing anosognosia when explicitly asked about their performance, ²⁴ a finding that seems to be dependent on specific brain mechanisms. ²⁵ Recent studies have also started to shed some light on the mechanism giving rise to anosognosia, suggesting it to be the result of a disconnection between large-scale brain networks.^26,27 By investigating the mechanisms underlying altered self-awareness across the AD spectrum and recognizing their relationship to AD pathophysiology future studies may provide key missing insights that will enable us to predict the onset of anosognosia.

In summary, while the short communication by Furuya et al., has limitations, it significantly advances our understanding of awareness of cognitive function and underscores the importance of also collecting an assessment from the patient's informant in the predementia stages of AD. As research advances in this field, these findings add valuable knowledge that may help in the development of targeted interventions for anosognosia, a major factor contributing to the decline in functional status, development of disability, and loss of independence in patients.