Frailty is a complex and heterogeneous clinical syndrome. It is described by augmented vulnerability resulting from age-related decline across several body organs and physiological systems (1, 2). Frailty leads to a decrease in the ability to remain independent and to maintain a good quality of life (3). Moreover, it increases the risk of disability and mortality (3). The frailty syndrome has principally been explored by focussing on the physical domain, mostly relying on signs and symptoms such as muscle weakness, sedentary behaviour, slow gait speed, and weight loss (1). Frailty has also been involved in general cognitive decline and impaired global cognition (4).

Canevelli and colleagues (5) have recently emphasised some criticalities of these studies: (a) the overwhelming majority of them have assessed frailty using the criteria proposed by Fried and colleagues (1), primarily aimed at describing the physical dimension of frailty; (b) most of these researches adopted only a measure of global cognitive functioning, mostly assessed by the Mini Mental State Examination [MMSE; (6)] to assess cognition, in absence of a comprehensive neuropsychological evaluation; (c) finally, the sample populations were mainly composed of community-dwelling older adults, preventing the applicability of results to other types of patients. The limitations of those studies have also been previously reported (7).

The overall concept of examining the specific cognitive correlates of frailty is interesting and may indeed shed light on a more comprehensive model of frailty that details a specific neuropsychological profile. Interestingly, the most novel evidence comes from a small number of studies aimed at examining the association between specific cognitive functions and physical frailty (5). In particular, Canevelli and colleagues (5) pointed out a significant impairment of attention and executive functions. Importantly, literature has shown that the executive function and attention domains are related to frailty, while gait speed or grip strength are the components of frailty most strongly associated with cognition (8–20). O’Halloran and colleagues (8) recently stated that pre-frail and frail individuals seem less able than robust subjects in the “Sustained Attention to Response Task” (SART). Even if these studies represent a first important attempt to describe the association between cognitive functions and physical frailty, there is still the need to assess frailty with a multidimensional approach (21–23).

Although executive function and attention domains may be related to physical frailty, no previous studies have investigated the role of different neuropsychological domains by carrying out a multidimensional assessment of frailty. In line with this, the multidimensional prognostic index (MPI) currently represents one of the suggested methods for a comprehensive assessment of frailty (24–26).

The aim of this study is to investigate whether pre-frailty, measured through the MPI, might be influenced by cognitive–behavioural measures in individuals with minor and major neurocognitive disorders [DSM-5; (27)], from mild cognitive impairment (MCI) likely due to Alzheimer’s disease (AD), to mild AD patients (28). For this reason, we conducted three multiple linear regression analyses to study: (1) the role of global cognitive functioning and specific cognitive variables (selective attention, episodic memory, language comprehension, and reasoning in the visual modality); (2) the role of metacognitive executive functions, such as response monitoring; and (3) the relationship with mood changes, quality of life, and awareness of independence for daily living instrumental activities.

Over a 24-month period, 72 patients—complaining of different cognitive deficits and presenting for the first time at the out-dep of our clinics—were evaluated with the overall neuropsychological assessment. After a month, based on CSF analysis results, only subjects with an AD-compatible liquor were included in the experimental sample. As a result, 12 patients were excluded, while 60 subjects were enrolled. Based on the exclusion criterion, 12 patients were excluded, while 60 subjects (M/F = 22/38; mean age ± SD = 69.6 ± 6.8 years) were enrolled (see Table 1 for demographic and clinical data). In particular, 24 MCI due to AD patients according to the CSF analysis, were included in the study. For those patients with major neurocognitive disorders, the CSF diagnosis provided in vivo evidence of Alzheimer’s pathology for 36 patients. The neuropsychological assessment reflected the diagnoses made by the CSF (see Table 2 and Table S1 in Supplementary Material), biomarkers and neurological exams. Fifty-six of the 60 patients obtained a CDR score of between 0 and 1 attesting a low level of cognitive impairment.

The aim of this study was to analyse the association among a multidimensional assessment of frailty, executive dysfunction and specific cognitive and behavioural variables using an overall neuropsychological battery. Our findings suggested that pre-frailty was associated with metacognitive executive dysfunction, in terms of action monitoring in MCI-likely due to AD and AD patients. Specifically, we observed a significant association between the MPI index and MR underlying the role of MR, where patients fail to distinguish between correct and incorrect sorts. The results obtained were specific and not influenced by other cognitive functions such as global cognition, memory, language comprehension, and non-verbal reasoning, with the exception of the selective attention task that reached a near significance level. Moreover, taking the MPI scores into account, we observed an involvement of mood changes in terms of depression, apathy, and disinhibition and a reduced awareness of iADL, while the relationship with hypomania was near to the significance value.

Although we considered patients with different degrees of cognitive impairment, our sample was homogeneous in terms of the etiopathogenesis, MPI level of risk, comorbidity with physical illness, somatic complaints, laboratory tests, and the level of mood changes. Moreover, we excluded all patients with neurological diseases other than AD. Most importantly, our attempt to consider these kinds of patients in the same sample was justified by the regression analysis approach we used and by the international guidelines on ageing that consider patients with cognitive impairment to lie on a continuum between MCI and mild AD (28, 63, 64).

Based on the results we obtained, there appear to be no straightforward associations between pre-frailty and specific aspects of neuropsychological functioning such as global cognition, long-term verbal memory, language comprehension, and non-verbal reasoning. As underlined by a review on cognitive impairment and frailty, not all cognitive domains may become impaired simultaneously (7). Although Canevelli et al. (5) have described a possible association between memory and physical frailty, other studies have found that memory does not seem to be clearly associated with frailty [i.e., Ref. (17, 65)]. As far as we are aware, no previous studies have addressed the association between frailty and language comprehension on the one hand, and frailty and non-verbal reasoning on the other (18). Moreover, we found no generalised cognitive impairment as a prerequisite of pre-frailty in our patients. Nevertheless, previously researches have reported a substantial association between frailty and cognitive deterioration (5, 7, 18, 66), although the phenotype model often used in these does not include cognitive function in its definition (1). Despite these evidences—as previously suggested by Robertson and colleagues (7)—statistical analyses of the proposed components of frailty suggest that, while energy, mobility, mood, physical activity, and strength aggregate as one concept, cognitive function does not clearly correlate with this and therefore may not be part of the frailty syndrome (67, 68). Furthermore, a study of AD patients found that 22% had no indications of frailty (69, 70). Indeed, Fougère and colleagues in their review concluded that “it seems most useful, therefore, to treat frailty and cognitive impairment as related but distinct concepts that frequently co-occur” [(71), p. 3].

Notably, the assessment of executive dysfunction should be seen as an important early predictor of cognitive frailty (9), since these problems may appear as the first cognitive changes in MCI patients (72), with concomitant iADL difficulties (73). Indeed, the early identification of executive impairments may be helpful for predicting the long-term functional outcome (74). Interestingly, O’Halloran and colleagues (8) recently stated that pre-frail and frail individuals seem to make more commission errors and omissions than robust subjects on the SART that evaluates the ability to sustain attention for a long time with a response–suppression element (75, 76). This fact suggests that they may be impaired in response monitoring, as we have demonstrated through the association between pre-frailty and action monitoring using the m-WCST. Indeed, the main predictor at this level has been MR, expressed by Koren and colleagues as the correlation between the level of confidence expected from the response and correctness of the sorts in the entire WCST (46–48). In particular, our patients have shown failure to monitor their own performance considering the errors made during task execution, in terms of low metacognitive self-awareness. Moreover, we have found an association between the MPI and monetary gain, which can be interpreted as subjects’ ability to benefit from environmental feedback, anticipate the consequences of their future actions and make decisions accordingly. In addition, we have also found pre-frailty to be associated with an inability to report unsuccessful experiences in iADL through the Awareness Questionnaire in Dementia (AQ-D) (56). In our previous article concerning impaired awareness of deficits in AD and the role of everyday executive dysfunction (56), mood orientation changes, inhibition, self-monitoring, and set shifting appeared to be important skills for awareness of iADL (AQD_iADL) (56). According to this and considering the neural substrate, AD patients with impaired awareness showed reduced activation in the Mid Cingulate Cortex during an event-related fMRI response-inhibition paradigm, compared to subjects aware of their deficits (77).

Through our current results we hypothesise that pre-frailty may arise by a disruption of the comparator mechanisms responsible for monitoring behavioural mood changes and cognitive disturbances (56). If the executive system does not function properly, as frequently described in MCI-likely due to AD and AD patients (78), the comparator mechanism does not detect incongruities between the previous and the actual state of behaviour/performance. This phenomenon has been observed as an inability: (1) to monitor one’s own performance with reference to the impact of errors made during task execution, in terms of a reduction in metacognitive self-awareness; and (2) to relate fruitless experiences in one’s everyday living through the AQ-D.

The few studies investigating the neuropsychiatric factors (79–81) have suggested that “one mechanism underlying the link between frailty and cognition may be due to psychological factors such as mood. Indeed, mood disorders such as depression have been found to be both a risk factor for and a consequence of frailty” [(7), p. 847]. In line with this, we observed a role of HDR-S scores in pre-frailty condition. The HDR-S actually measures mood changes, in terms of apathetic behaviour and depressive mood possibly related to prefrontal dysfunctions (82). This evidence also suggests a possible role of apathy in pre-frailty conditions (83). Interestingly, apathy, disinhibition, and metacognitive executive dysfunction appear to be neurally inscribed in the same network (84–87). The results we obtained proposed the suggestive hypothesis that pre-frailty may be due to a possible dysfunction of the medial prefrontal–ventral striatal network observed throughout action-monitoring disability, mood changes, and reduced awareness of iADL. These findings ask for new neuroimaging investigations and replication in a larger group of patients.

This study represents a first important attempt to extend the frailty issue to neuropsychological correlates taking in consideration a multidimensional approach These findings suggest that the assessment of pre-frailty conditions must be achieved quantitatively by means of a multidimensional approach to clarify the nature and correlates of this multifaceted phenomenon. In particular, the impact of everyday executive dysfunction, early changes in mood and the awareness of iADL disabilities must be considered. Our results benefit from the homogeneity of the experimental sample in terms of etiopathogenetic mechanisms, disease severity (CDR) and functionality in daily life (ADL/iADL). The evaluation of pre-frailty conditions and their neuropsychological correlates is clinically relevant. Indeed, this multifaceted phenomenon has diagnostic, nosological, and prognostic implications that may affect patients’ wellbeing in the continuum from MCI to AD.

The study is based on a concept developed by MA who wrote the paper and took part in the review and critique processes as PI. She also organised the study and participated in the statistical analyses (execution and organisation, review, and critique). SP performed the neuropsychological assessment (execution and organisation), participated in the statistical analyses, participated in writing the paper and created the infographics. RR conducted the statistical analyses (execution), participated in interpretation of results and in writing the paper. ER performed the neurological assessment (execution) and took part in the organisation of the study and in the diagnostic phase (organisation and diagnosis). MZ and MB performed the neuropsychological assessment (execution), participated in writing the paper and in drafting the work. DL and IR supervised the neurological assessment, took part in the organisation of the study and participated in writing the paper (organisation, review, and critique). All the contributors gave their approval of this version of the manuscript to be submitted.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.