Neuropsychiatric symptoms (NPS) are suggested to be highly prevalent even in prodromal stages of dementia, such as mild cognitive impairment (MCI) (Monastero et al., Reference Monastero, Mangialasche, Camarda, Ercolani and Camarda2009), a transisitional stage between normal aging and dementia. Not all people with MCI develop dementia (Petersen, Reference Petersen2004); thus, there is need to identify risk factors associated with progression of MCI to dementia. Presence of NPS in MCI patients has been associated with greater cognitive and functional impairments compared to MCI patients without NPS (Martin and Velayudhan, Reference Martin and Velayudhan2020), and hence, important targets for both prognostic and preventative purposes. Apathy and depression are the most prevalent NPS in patients with MCI and can co-occur. Apathy has been defined as loss of motivation, characterized by diminished goal-oriented behavior and cognition and reduced emotional expression (Mortby et al., Reference Mortby2022), and depression is characterized by feelings of sadness and negative cognitions such as hopelessness or inappropriate guilt (Richard et al., Reference Richard2012; Ruthirakuhan et al., Reference Ruthirakuhan, Herrmann, Vieira, Gallagher and Lanctôt2019). Apathy present in approximately between 39.5% of MCI individuals in clinic-based samples and 14.7% in population-based studies (Martin and Velayudhan, Reference Martin and Velayudhan2020), has been associated with a greater than twofold increased risk of progression to cognitive impairment in the cognitively normal population (Fan et al., Reference Fan2021) and associated with high prevalence and worse clinical outcomes in people with dementia (Mortby et al., Reference Mortby2022). Depression is most frequently reported symptom in MCI patients with a prevalence rate that ranges between 20% in population-based samples and 83% in clinic-based samples and has been associated with cognitive impairment as well as a doubled risk of progression, although evidence is largely conflicting (Martin and Velayudhan, Reference Martin and Velayudhan2020).

Studies have focused on apathy and depression as risk factors for conversion to dementia in MCI patients. Apathy was reported as a risk factor for conversion, and depression without apathy was associated with reduced risk of conversion to Alzheimer’s disease (AD) in 124 MCI outpatients followed up for 2 years (Vicini Chilovi et al., Reference Vicini Chilovi, Conti, Zanetti, Mazzù, Rozzini and Padovani2009). MCI patients (N = 1713) with apathy alone or both apathy and depression were found to have a greater risk of developing AD compared to those with no NPS, and depression in the absence of clinically significant apathy in MCI was not associated with a greater risk of AD conversion with a median follow-up of 23 months (Ruthirakuhan et al., Reference Ruthirakuhan, Herrmann, Vieira, Gallagher and Lanctôt2019). In 131 consecutive memory-clinic outpatients who were followed up up to 4 years, patients with both amnestic-MCI and an apathy diagnosis had an almost sevenfold risk of AD progression compared to amnestic-MCI patients without apathy after adjustment for age, gender, education, baseline global cognitive, and functional status, and there was no increased risk of developing AD in amnestic-MCI patients with either a diagnosis or symptoms of depression (Palmer et al., Reference Palmer2010). Of the 397 patients with MCI followed up for average 2.7 years (SD 1.0) who showed symptoms of apathy, but not symptoms of depressive affect, increased the risk of progression from MCI to AD (Richard et al., Reference Richard2012). However, these studies used baseline cross-sectional measures to predict subsequent dementia conversion and few studies controlled for depression. Connors et al. (Reference Connors, Teixeira-Pinto, Ames, Woodward and Brodaty2023) in a recent paper in International Psychogeriatrics addressed these aspects, and the results presented are significant as the authors assessed both the longitudinal trajectories of apathy and depression and their associations with clinical correlates such as cognition, function, other NPS, and caregiver burden, controlling for other variables. Specifically, Connors et al. (Reference Connors, Teixeira-Pinto, Ames, Woodward and Brodaty2023) carried out assessments at baseline, 3 months, 6 months, and annually for 3 years and suggested prevalence of apathy which were present in 36% of the cohort at the baseline, gradually increased over the study period, whilst depression (present in 37% at the baseline) remained constant over the period. Their major findings is that apathy was associated with incident dementia and worse cognition, function, NPS, and caregiver burden independent of depression, incident dementia, and dementia severity over the time. Interestingly, depression was associated with worse function, albeit to lesser degree than apathy, and NPS, but not worse cognition, caregiver burden, or dementia severity after adjusting for other variables. Connors et al. (Reference Connors, Teixeira-Pinto, Ames, Woodward and Brodaty2023) found male sex, depression, antipsychotic use, and incident dementia were associated with greater apathy. On the other hand, younger age, female sex, apathy, and antidepressant use were associated with greater depression. Connors et al. (Reference Connors, Teixeira-Pinto, Ames, Woodward and Brodaty2023) point out that the sex differences seen, that is, greater apathy in men and depression in women, was in keeping with the generally known biological and psychosocial mechanisms and trends across the spectrum of cognitive disorders.

Connors et al. (Reference Connors, Teixeira-Pinto, Ames, Woodward and Brodaty2023) repeated the analysis to examine the longitudinal clinical correlates using baseline apathy and depression scores too and interestingly found that baseline apathy was not significantly related to cognition but did predict function, caregiver burden, dementia severity, and other NPS over the period and the baseline depression predicted only other NPS. Connors et al. (Reference Connors, Teixeira-Pinto, Ames, Woodward and Brodaty2023) in addition found that the patients who developed dementia during the period (28.7%) had different longitudinal trajectories on outcome measures (such as cognitive, function, and NPS), but the differences were not apparent at the time of their MCI diagnosis.

While the Connors et al. (Reference Connors, Teixeira-Pinto, Ames, Woodward and Brodaty2023) study expands on apathy and depression for not only as risk factors for dementia progression but also on their longitudinal course and associations with other clinical outcomes, we must consider the strengths and limitations of the study. Connors et al. (Reference Connors, Teixeira-Pinto, Ames, Woodward and Brodaty2023) used patient primarily recruited from memory clinics across Australia. Although the findings may not be generalizable to other settings, it adds to the growing literature indicating apathy as a risk factor for cognitive decline and dementia. Connors et al. (Reference Connors, Teixeira-Pinto, Ames, Woodward and Brodaty2023) assessed cognition using the Mini-Mental State Examination (MMSE) (Folstein et al., Reference Folstein, Folstein and McHugh1975) which is a crude cognitive measure and limited in examining different domains. Apathy has been associated with executive function deterioration (Fan et al., Reference Fan2021; Martin and Velayudhan, Reference Martin and Velayudhan2020) and depression shown to affect memory, visuospatial, and executive domains (Lee et al., Reference Lee, Kim and Moon2019). Future studies incorporating comprehensive neuropsychological testing would help to examine specific cognitive domains affected longitudinally by apathy and depression and may be specific markers of change for therapeutic and preventive intervention trials.

Connors et al. (Reference Connors, Teixeira-Pinto, Ames, Woodward and Brodaty2023) used antidepressant use, antipsychotic use, and total number of medications as a proxy for physical health. Medical comorbidities such as cardiovascular risk factors and cerebrovascular disease are known to be associated with cognitive impairment, apathy, and depression (Kim et al., Reference Kim2016; Richard et al., Reference Richard2012). In a recent study that compared older adults with MCI, major depressive disorder and healthy controls for baseline distribution of hypertension, smoking, and diabetes found higher prevalence of hypertension in people with MCI and also demonstrated that people with hypertension had lower performance in composite executive functions and composite neuropsychological test score (Karameh et al., Reference Karameh2022). Need for studies that incorporate not only biological markers, but also psychosocial factors to elucidate processes that link cardiovascular factors like hypertension and depression to the risk of cognitive decline has been emphasized (Kraynak and Andreescu, Reference Kraynak and Andreescu2022).

The apathy and depression items on the NPI as used by Connors et al. (Reference Connors, Teixeira-Pinto, Ames, Woodward and Brodaty2023) are the most frequently used tool in such studies; however, they are do not measure different subdomains. Ideally, apathy and depression rating scales should be able to measure different dimensions and be able to measure them independently, since they may be associated with different neurobiological substrates as two distinct syndromes (Mortby et al., Reference Mortby2022; Starkstein et al., Reference Starkstein, Mizrahi, Capizzano, Acion, Brockman and Power2009; Zacková et al., Reference Zacková, Jáni, Brázdil, Nikolova and Marečková2021). As a next step, it is important to use scales that are able to measure different dimensions of apathy and depression in the diagnostic criteria and which are also sensitive to changes (Mortby et al., Reference Mortby2022; Wong et al., Reference Wong, Ismail and Goodarzi2022). Depression and apathy often co-occur in neurodegenerative disorders; however, neuroimaging studies have shown evidence suggesting distinct neurobiological roles. In MCI, there is evidence for apathy’s association with deficits in posterior cingulate and with cortical thinning in inferior temporal and anterior cingulate cortices (Mortby et al., Reference Mortby2022), and depression has been associated with the thickness of the banks of the left superior temporal sulcus, superior frontal gyrus, and posterior cingulate gyrus (Fang et al., Reference Fang, Gao, Schulz, Selvaraj and Zhang2021; Siafarikas et al., Reference Siafarikas2021). There is need for better understanding of these mechanisms, other biomarkers such as blood and cerebrospinal fluid markers, and their interaction with cognitive progression.

In summary, Connors et al. (Reference Connors, Teixeira-Pinto, Ames, Woodward and Brodaty2023) extends previous research by not only demonstrating that apathy consistently increases over time, from when MCI is first diagnosed and continuing after dementia is diagnosed, but also shows that apathy’s associations with adverse outcomes in MCI exist longitudinally and are independent of both dementia and depression. Connors et al. (Reference Connors, Teixeira-Pinto, Ames, Woodward and Brodaty2023) also establishes worsening of caregiver burden with progression of apathy during the period, an outcome largely overlooked in MCI. This makes apathy an important treatment target for pharmacological and non-pharmacological interventions in people with MCI. Future studies may identify the time points when neurobiological factors may impact the apathy subdomains in the longitudinal course of MCI, which are critical for cognitive and functional decline and risk for dementia conversion. It is important to identify the subpopualtions who are at risk and who may benefit from appropriate and tailored interventions to delay or prevent dementia conversion.