Distinguishing Apathy from Depression in Dementia: Implications for Diagnosis and Treatment

1. Introduction

Affecting over 47 million people globally, dementia is a group of neurocognitive disorders that have significant impacts on the individual and society [1]. Alongside symptoms of cognitive decline, neuropsychiatric symptoms commonly occur in dementia, impacting patients’ quality of life, independence in daily living, relationship with caregiver, and need for institutionalization [2]. Among neuropsychiatric symptoms of dementia, apathy and depression are two common syndromes, with the prevalence of apathy ranging from 43-59%, and depression ranging from 37-41% across dementia [3]. Although with overlapping features, the two phenomena are conceptually and biologically distinct, with important consequences for prognosis, caregiver burden, and treatment selection [4]. Apathy is best conceptualized as a disorder of motivation, leading to diminished interest, initiative or affective expression [5]. Depression, on the other hand, is characterized by guilt, sadness, hopelessness, suicidality, along with a definable symptom constellation, as summarized in the Diagnostic Statistical Manual (DSM) [6].

Distinguishing apathy from depression in dementia involves differences in clinical presentation, underlying neurobiology, neurodiagnostic findings, and response to treatment. However, this distinction is often challenging, as both syndromes share features such as diminished interest, anhedonia, and reduced energy, and may frequently co-occur. Accurate differentiation carries important clinical implications: misattributing apathy to depression, or vice versa, may lead to suboptimal prognostication and treatment selection.

Both apathy and depression have been found to increase the risk of future development of dementia [4]. Viewed as a potential prodromal symptom to dementia, apathy has been associated with a 2-fold increased risk of cognitive impairment in cognitively normal individuals, including an odds ratio of 2.12 for dementia and 3.38 for mild cognitive impairment (MCI) from a meta-analysis that included over 22000 individuals [7]. Similarly, depression has been associated with an elevated risk of dementia, with one meta-analysis of 20 studies demonstrating an odds ratio of approximately 2 for incident dementia [8]. In another meta-analysis of 10,861 individuals with MCI, depressive symptoms were associated with a 28% higher relative risk of progression to dementia [9]. Beyond its prognostic significance, apathy is associated with functional impairment, worsened cognition, increased caregiver burden, and in some studies shows stronger associations with functional outcomes than depression [10].

In this narrative review, we review the literature on apathy and depression in dementia. Literature was identified using PubMed and search terms related to the subject of interest (i.e., “apathy”, “depression”, “dementia”), coupled with specific topics (i.e., “neuroanatomy”, “neurocircuitry”, “treatment”, “measurement”, “criteria”, “neuroimaging”). We also include additional references based on our knowledge of the literature and articles identified during reference review of our initially identified papers, highlighting important articles related to the topic. This review will describe the diagnostic criteria, clinical presentation, measurement, neurobiological and neurocircuitry differences, and treatment of apathy and depression. Of note, we focus specifically on depression as it presents in the context of cognitive impairment and dementia. While primary depressive disorders and depression as a risk factor for future cognitive decline are important and related constructs, given that they may be conceptually and mechanistically distinct from depression occurring within neurodegenerative disease, we have chosen to not focus on this topic in this narrative review.

2. Definitions and Diagnostic Criteria

Apathy was first described by Marin as a “disorder of diminished motivation not attributable to diminished levels of consciousness, cognitive impairment, or emotional distress” [11]. Over time, the definition has evolved, shifting from the description of motivation to that of goal-directed activity, as well as establishing symptom dimensions such as that of behavior, cognition, emotion, and social interaction [12]. Specific to neurocognitive disorders, a consensus criteria published in 2021 described apathy with 4 elements: 1. Persistent or frequently recurrent symptoms of 4 weeks or greater; 2. A change in usual behavior, as demonstrated by at least two of the following dimensions: diminished initiative, diminished interest, diminished emotional expression/responsiveness; 3. Symptoms causing significant functional impairment; 4. Symptoms are not explained by other etiologies. In the criteria, patients must have a syndrome of cognitive impairment or dementia [5].

Depression is defined by standard psychiatric nomenclatures using DSM-based criteria [6]. A major depressive episode requires ≥5 symptoms during a 2-week period, including either depressed mood or loss of interest/pleasure, plus clinically significant distress/impairment and standard exclusions, as well as a deviation from former baseline. The International Classification of Diseases (ICD) emphasizes that depressive disorder diagnoses remain applicable in people with dementia, though communication deficits may imply a greater reliance on clinician observation and collateral informants in diagnosis [13]. Similar to the DSM-based criteria, the ICD-11 clinical descriptions and diagnostic requirements also frame a depressive-episode by persistent low mood or loss of pleasure, and associated symptoms such as appetite change, worthlessness, and recurrent thoughts of death in its differential diagnosis descriptions. With regards to more dementia specific diagnostic clarification, a provisional criterion has been proposed using the case of depression in Alzheimer’s Disease (AD), as an effort to distinguish it from a primary major depression. Such criteria describes that only 3 or more symptoms of SIGICAPS are required over a 2-week course, as well as including additional features such as social withdrawal and irritability, while continuing to require the remaining criteria as per the DSM-5 [14].

3. Clinical Differentiation and Psychometric Measurement

Apathy and depression share overlapping clinical features—including reduced activity, diminished interest, and low energy—raising the risk of diagnostic overshadowing in dementia. However, several clinical distinctions can help differentiate the two.

One of these includes the degree of affective experience and distress. Depression is more likely to include negative affective changes and suffering, including sadness, hopelessness, guilt and tearfulness, as well as the presence of suicidal ideation [14]. On the other hand, diminished emotional expression and emotional blunting is explicitly included in the apathy symptom dimension, and can present without sadness or subjective distress [5]. To add, apathy is emphasized as a motivation/goal-directed activity syndrome, manifesting as failure to initiate even potentially enjoyable or valued activities [5,15]. In contrast, depression is more closely associated with diminished enjoyment and negative appraisal of experiences, such that even when activities are undertaken, they may not be experienced as rewarding. However, of note, the concept of anhedonia may blur this boundary.

Another distinction relates to the degree of insight. In apathy, reduced awareness and low self-criticism are common, increasing reliance on caregiver descriptions. In contrast, patients with depression more often verbalize distress and endorse subjective complaints, while insight is preserved, although this signal may be attenuated in the context of dementia [4].

Timing and course of progression may also help differentiate these syndromes. Apathy is often persistent and associated with cognitive and/or functional decline across dementia [4]. In some cohorts, it has been shown to predict dementia risk and is increasingly conceptualized as a marker of underlying neurodegenerative disease [4,16]. By contrast, depression is more typically episodic and sometimes recurrent, though it too may represent a prodromal feature of dementia-related change [14].

A rigorous apathy–depression differential in dementia requires a comprehensive assessment. This extends beyond patient self-report, and nearly always incorporates informant-based information, as a patient’s insight and recall may be impaired, and caregiver input helps contextualize change from baseline [17,18]. However, clinicians may need to be careful in that caregivers may not know how to best describe apathy using the most precise language, and clinicians could actively probe for apathy even when “depression” is reported, as well as follow up by asking more specific symptom-screening questions to differentiate the two.

Best practices in assessment include applying syndrome-consistent diagnostic criteria for apathy and depression in dementia, utilizing validated scales and assessment tools to evaluate both conditions, and determining whether one syndrome predominates or whether comorbidity is present. It is also important to account for neurocognitive status, motor impairment, and potential medical or delirium-related mimics [5,15].

From a psychometric perspective, several instruments have been developed to capture these distinctions (Table 1). Apathy-specific scales emphasize domains of motivation, initiation, and emotional blunting. In contrast, depression scales primarily assess affective, physical, and cognitive symptoms of depression. Select instruments, such as the neuropsychiatry inventory, assesses multiple symptom domains, including both apathy and depression within a single framework [17]. Nonetheless, overlap in item content (e.g., reduced interest or activity, physical symptoms such as fatigue) can complicate measurement, underscoring the importance of careful clinical interpretation alongside scale-based assessments.

Importantly, these instruments vary in their validation and applicability across dementia populations. Some are better suited for use in dementia, and at times, in specific stages or types of dementia, while others are validated in non-cognitively impaired individuals. Some rely more on patient self-report and may be limited by impaired insight, whereas others include caregivers or close informants’ perspectives. Certain scales incorporate guidance to help distinguish apathy from depression (i.e., cautioning against attributing diminished initiative to depressive symptoms) [19]. Additionally, instruments differ in administration time and question format, all of which should be considered when selecting appropriate tools for assessment.

4. Neurocircuitry and Neuroanatomical Distinctions

Neurocircuit models of apathy in dementia converge on the principle that apathy reflects strongly on frontal and striatal systems functioning [30,31]. In particular, brain regions that contribute to functions such as reward value, effort cost, action initiation, and reinforcement learning are implicated [30].

Earlier work focused on pre-frontal-basal ganglia loop theories, grouped into three subtypes of apathy-- “emotional-affective”, “cognitive”, and “auto-activation” [31]. Lesions of the orbital-medial prefrontal cortex and associated limbic territories of the basal ganglia (ventral striatum, ventral pallidum) are linked to the disruptions in behavioral response to emotional-affective signals [31]. Lesions in the dorsolateral prefrontal cortex and the dorsal caudate nucleus of the basal ganglia have been implicated in disruption of cognitive processing of behavior [31]. Finally, lesions that affect bilateral limbic territories of the globus pallidus contribute to the inability of self-initiation of behavior, otherwise known as “auto-activation deficit” (or psychic akinesia”) [31]. However, it is important to note that such a domain-based approach to apathy may imply that its components are subserved by distinct, potentially dissociable neurobiological systems. It is possible that these dimensions are more likely to arise from partially overlapping and interacting neural circuits.

More recent models conceptualize apathy as a disruption of integrated motivation-related networks. Further work has focused on conceptualizing neurocircuitry implicated in apathy as that which contributes to reduced motivation for goal-directed behavior, including the ability to sustain such behavior, and learning whether the behavior is worth doing [30]. It is postulated that impairment in any of these components may give rise to the apathy phenotype [30]. Key structures implicated include the dorsal anterior cingulate cortex (dACC), which mediates decision making, weighing cost-benefit tradeoffs, effort allocation, persistence; Ventral striatum (VS)/nucleus accumbens (NAc), which supports reward valuation, reinforcement learning, and energization of behavior; Medial prefrontal and orbitofrontal cortex (mPFC/OFC), which integrate value, outcome evaluation, and emotional and social context to guide goal selection.

From a circuit-level perspective, apathy can be conceptualized as a disorder of frontostriatal networks, particularly involving anterior cingulate–ventral striatal pathways, which govern effort-based decision-making and goal-directed behavior. These circuits are modulated by dopaminergic input from the ventral tegmental area (VTA) via mesolimbic and mesocortical projections [30]. Additional contributions from nigrostriatal pathways, particularly in disorders such as Parkinson’s disease and Lewy body dementia, have also been reported in apathy [32]. Dopaminergic signaling within these networks supports reward valuation and initiation of action, while noradrenergic input from the locus coeruleus modulates arousal.

On the other hand, depression in dementia is often conceptualized via dysregulated connectivity in large-scale network models, including the default mode network (DMN) and salience network. The DMN includes the ventral medial prefrontal cortex (vmPFC), dorsal medial prefrontal cortex (dmPFC), and posterior cingulate cortex (PCC) [33]. In Alzheimer-spectrum cohorts, DMN connectivity differences, including reduced functional connectivity between the PCC and medial superior frontal gyrus, has been thought to be linked to depressive symptoms [34]. Increased connectivity in the anterior DMN has been found in amyloid positive patients with MCI with depression compared to without depression [35]. In Lewy Body Disease, degeneration of dopaminergic circuitry via higher a-synuclein burden is thought to contribute to depressive symptoms [36]. In individuals with MCI with PD, affective symptoms have been associated with greater limbic orbitofrontal cortex and default mode network connectivity, and weaker salience network and medial prefrontal cortex connectivity [37]. Decreased prefrontal-limbic network connectivity has been found in depressed patients with PD [38]. In cerebrovascular disease, including vascular dementia, frontal and subcortical dysfunction is thought to be more likely associated with depression [39].

5. Neurodiagnostic Distinctions

A rich number of neuroimaging studies have revealed structural or functional basis of apathy and depression. Across dementia diagnoses, apathy has been associated with hypometabolism on FDG-PET or hypoperfusion on SPECT studies in the ACC and OFC, and, in some, ventral striatum and thalamic nodes—consistent with fronto-striatal circuit compromise [30].

Volumetric magnetic resonance imaging (MRI) studies of patients with AD have found that apathy is associated with cortical atrophy or thinning in the bilateral anterior cingulate and left medial frontal cortex, with regional brain thinning that can predict worsening apathy trajectories in Alzheimer-spectrum cohorts. Compared to controls, a greater volume of white matter hyperintensities was found in the frontal lobe for those with apathy, and in the right parietal lobe for individuals with depression [40].

In FTD, volumetric analysis has found that patients with depression have greater thickness of the right ventromedial and inferior frontal cortex compared to non-depressed patients [41]. Apathy has been found to be associated with cortical thinning of parts of the right frontal lobe (middle and inferior frontal gyrus), temporal lobe (superior and transverse temporal gyrus), parietal lobe (superior parietal, posterior cingulate and supramarginal gyrus) and the insula [41]. The degree of thinning correlates with apathy severity. FTD patients who have more prominent temporal lobe volume loss, specifically in the right amygdala and right anterior temporal cortex, had significantly more depression than those who had more prominent frontal lobe volume loss, which had more frequent instances of apathy [42].

In cerebrovascular disease, apathy appears to arise primarily from vascular disruption of frontal-subcortical networks, rather than from any single vascular lesion type, with the strongest mechanistic evidence coming from cerebral small vessel disease (SVD) and post-stroke studies [43,44]. Similarly, depression in cerebrovascular disease is thought to arise primarily from cerebrovascular disruption of frontal-subcortical networks, including frontostriatal and frontolimbic mood-regulation networks [44,45]. In SVD specifially, apathy and depression have been differentiated in one study, which showed diminished white matter integrity on diffusion tensor imaging for those with apathy in the temporoparietal regions, but not in depression [46]. Apathy is also associated with reduced white matter connectivity in premotor and cingulate regions, a finding absent in depression in SVD [47].

In PD, apathy is associated with reduced dopamine transporter uptake in the striatum, in particular the right caudate when controlling depression severity, suggestive of dopaminergic involvement of apathy in PD [48]. A distinction has been made between prodromal stage and late-stage PD, where in prodromal stages, apathy is viewed as a disorder of motivation, whereas in later stages, apathy is viewed as a cognitive syndrome that is associated with cognitive decline and PD dementia [49]. In contrast, depending on the stage of PD, depression is characterized by a range of serotonergic, noradrenergic and dopaminergic dysfunction [50]. Depression in PD is also characterized by dysfunction in limbic circuits, including the ACC, OFC, amygdala, thalamus, and ventral striatum [50]. Prefrontal lobe and temporal lobe thinning has been reported in depression in Lewy Body Dementia (LBD), as well as decreased dopaminergic neuron density in the substantia nigra compacta, and a smaller number of neurons in the locus coeruleus [51].

With regards to biomarker studies, apathy and depression show partially separable associations with AD pathobiology. Apathy has been associated with increased amyloid burden in MCI cohorts [52]. NPI-A scores have also been shown to track regional tau burden in the supramarginal gyrus and entorhinal cortex in cognitively impaired older adults with MCI or AD [53]. Meta-analytic evidence has found that depressive symptoms do not correlate with any plasma biomarkers of neurodegenerative disease in multiple population-based cohorts (Aβ42/40, p-tau181, and GFAP), however, Neurofilament light chain was associated with depressive symptoms only in APOE ε4 carriers [54]. These biomarker patterns support a model in which depression may sometimes reflect neurodegenerative vulnerability but is not a simple surrogate of amyloid or tau burden, while apathy shows potential associations with both amyloid burden and regional tau accumulation.

There is more limited evidence with regards to electrophysiologic findings. In PD, apathy severity has been related to resting and task-related alpha/theta oscillatory dynamics during incentivized movement [55], as well as low-beta desynchronization during reward-cuing [56], proposing potential neural markers of apathy linked to motivational motor control. EEG biomarkers that robustly differentiate apathy from depression within dementia cohorts remain underdeveloped relative to imaging markers, representing a potential translational gap.

6. Treatment Distinctions

Selection of appropriate treatment to target apathy or depression (or a mix of both) is important, and also depends on dementia etiology and stage [4,57].

Apathy and depression are both strongly shaped by environment, care structure, and caregiver interaction. Thus, structured nonpharmacologic strategies are emphasized as first-line and foundational components of management [58]. Interventions for apathy include individualized meaningful activities and programs, including physical exercise interventions, music, animals, special care programming, and therapeutic activities [59]. External stimulation and behavioral activation have been more advantageous than intrinsic motivation in severe cognitive impairment [60]. Methodologically, such interventions are heterogeneous with variable outcomes and effect sizes [59,61]. Cognitive behavioral therapy and music therapy have shown benefit for depressive symptoms in some dementia studies [62]; caregiver burden interventions (including behavioral activation strategies for caregivers) can also improve caregiver mood [63]. Counseling of caregivers would be important, as family members may misinterpret apathy as purposeful behavior, leading to implications of potential feelings of loss of connection to the patient [4].

Pharmacologic interventions for apathy have primarily targeted dopaminergic systems, with some agents also having a secondary effect on modulating norepinephrine systems [64]. Methylphenidate, through dopaminergic and norepinephrinergic modulation of prefrontal-striatal-thalamocortical circuits– has the strongest evidence among pharmacologic options for apathy in AD [64,65]. In ADMET 2 (n=200), methylphenidate produced a greater reduction in NPI-apathy scores than placebo over 6 months [64]. A small randomized trial did not have sufficient evidence for finding modafinil in improving apathy [65]. Low quality of evidence was found for use of cholinesterase inhibitors, discontinuation of cholinesterase inhibitors, antipsychotics, discontinuation of antipsychotics, antidepressants, valproate, and experimental drugs including mibampator and semagacestat [65]. One randomized control study looking at bupropion found that it was not superior to placebo for treating apathy in AD, excluding for depression [66]. In LBD, dopaminergic strategies such as levodopa may be considered, given shared fronto-striatal and dopaminergic deficits; however, their use is limited by heightened susceptibility to neuropsychiatric adverse effects, including psychosis and impulse control symptoms [67]. Treatment of apathy in dementia remains challenging, perhaps in part because there is more to apathy than solely a dopaminergic syndrome, but rather a heterogeneous disorder involving multiple neurobiological processes [68].

Pharmacologic treatments for depression in dementia have focused on evaluating the effect of antidepressants [69]. A systematic review found little or no difference between antidepressants and placebo on depression symptom rating scales after 6-13 weeks, with increased dropout rates and adverse events [69]. Another meta-analysis did not find selective serotonin reuptake inhibitors, selective norepinephrine reuptake inhibitors, atypical antidepressants, nor tricyclic antidepressants to have an effective size on depression in dementia, nor when sub-grouped based on depression severity or dementia level [70]. It is unclear if the lack of efficacy in such trials are due to trial design limitations or a distinct depression-in-dementia phenotype, and perhaps the mechanism of antidepressant is affected by dementia disease process [71]. The adverse effects of antidepressants in dementia also warrant consideration, as cognitive and/or medical impacts of such medications would need careful risk-benefit assessment on an individual basis especially in such a vulnerable patient population [70,71].

A rapidly evolving area of treatment involves the use of noninvasive brain stimulation to modulate neurocircuits implicated in apathy and/or depression. For example, repetitive transcranial magnetic stimulation (rTMS) has been reported in a pilot, double-blind, sham-controlled study to improve apathy in AD by targeting the left dorsolateral prefrontal cortex [72], though systematic review suggests heterogeneity and limited high-quality trials for potential efficacy of rTMS for apathy in dementia in general [73]. An additional area of research has been in the use of home-based transcranial direct current stimulation in apathy and depression in dementia, though findings are preliminary only [74,75].

7. Conclusions

Apathy and depression in dementia are overlapping yet distinct neuropsychiatric syndromes with important differences in phenomenology, neurobiology, and treatment response. Distinguishing between them is not merely a diagnostic exercise, but has significant clinical implications. Careful, multidimensional assessment remains essential for accurate differentiation. Advancing diagnostic precision will be critical for guiding targeted interventions, improving functional outcomes, and informing the development of more effective, circuit-based therapies in dementia care.