In major neurocognitive disorders (i.e., dementia) caused by Alzheimer’s disease, behavioral dysexecutive syndrome (which includes hypoactivity with apathy) affects 86 % of patients [34]. Hypoactivity with apathy is the most frequent behavioral disorder and is observed in between 30 and 85 % of patients [13, 34, 35]. This broad range of values is mainly due to differences in the clinical stage and the diagnostic criteria for Alzheimer’s disease. However, variability is also due to the disease subtype, since apathy is the most frequent behavioral manifestation of the recently characterized behavioral/dysexecutive variant of Alzheimer’s disease [36]. Apathy in patients with Alzheimer’s disease is frequently associated with depression; in Starkstein’s study, 13 % of patients with Alzheimer’s disease presented with apathy and 24 % presented with a combination of apathy and depression [13]. The characteristics and prognostic value of apathy in Alzheimer’s disease are subject to debate. Although apathy may appear in the early stages of dementia [37] and in the pre-dementia stage [38–41], the frequency increases with disease severity [35, 42–44]. The presence of apathy has been linked to faster cognitive and functional decline [45, 46] and greater caregiver distress [47].

In mild neurocognitive disorders, apathy is more frequent in patients who are progressing to dementia due to Alzheimer’s disease [38–41]. In the Alzheimer’s Disease Neuroimaging Initiative, 45 % of the patients with mild cognitive impairment had at least one symptom of apathy, and the presence of apathy (but not depression) was associated with an increased risk of progression to major neurocognitive disorders caused by Alzheimer’s disease [41]. Accordingly, the presence of apathy in mild cognitive impairment has been found to be relatively specific for Alzheimer’s disease [40] as defined by clinical criteria. In familial Alzheimer’s disease, apathy is most frequent neuropsychiatric symptom in 40 % of mildly symptomatic carriers of a mutation [48]. These findings emphasize the high frequency of global hypoactivity–apathy in Alzheimer’s disease—even at the pre-dementia stage.

Apathy is one of the core diagnostic criteria for behavioral variant frontotemporal degeneration [49]; it constitutes the most common initial symptom [50] and the most frequent common behavioral symptom [51–53]. When compared with Alzheimer’s disease, apathy in behavioral variant frontotemporal degeneration is more frequent [51, 54–56] and is associated with more frequent and more severe impairments of socio-emotional processes [27, 28, 57, 58]. Although the pre-dementia stage of frontotemporal degeneration has yet to be characterized, it may correspond to the recently formulated criteria for mild behavior impairment [59], which include apathy.

The anatomical correlates of severe apathy have been identified in several studies of patients with Alzheimer’s disease, with higher lesion loads bilaterally in the anterior cingulate cortex, the posterior cingulate cortex, the frontal cortex and specifically the orbitofrontal cortex, and the inferior temporal cortex [60]. Single-photon emission tomography and positron emission tomography studies have evidenced bilateral hypoperfusion/hypometabolism in the anterior cingulate cortex, the posterior cingulate cortex, and the orbitofrontal cortex [61–64]. MRI studies have reported cortical thickness in the same regions [65–70], as well as atrophy of the putamen and the left caudate nucleus [66]. A neuropathological study [71] has shown a relationship between apathy and the presence of neurofibrillary tangles in the left anterior cingulate cortex. Apathy is also correlated with white matter hyperintensities [72, 73] and alterations in white matter integrity—especially within the genu of the corpus callosum [74]. Lastly, apathy is associated with frontal amyloid ß deposition assessed using amyloid PET [75].

The determinants of apathy in behavioral variant frontotemporal degeneration involve much the same structures as in Alzheimer’s disease and especially the dorsal anterior cingulate cortex, the dorsolateral prefrontal cortex [76, 77], the left frontal operculum–anterior insula, the right temporoparietal junction, and right posterior inferior and middle temporal gyri [57]. Furthermore, apathy was found to be correlated with loss of structural integrity of the left uncinate fasciculus [78]. The frequently suggested relationship with striatal atrophy (according to a literature review [12]) remains subject to debate [59, 79].

Pharmacotherapy for apathy depends primarily upon the underlying etiology and disease background. In terms of treatment strategies for apathy in Alzheimer’s disease, Rea et al.’s [80] systematic review emphasized that four categories of drugs were used: cholinesterase inhibitors, monoaminergic agents (methylphenidate and modafinil), the selective serotonin reuptake inhibitor (SSRI) citalopram, and various other drugs (such as Ginkgo biloba extract Egb 761). Cholinesterase inhibitors have been evaluated in randomized controlled trials in which behavioral disturbances were secondary outcome measures. Some trials reported positive effects on behavior in Alzheimer’s disease [81, 82], Lewy body dementia [83], and Alzheimer’s disease and mixed dementia [84], including a reduction in apathy in few trials [83, 84]. The randomized, controlled trial of methylphenidate for the treatment of apathy (the primary outcome) was positive [85]. Ginkgo biloba extract Egb 761 did not prove to be beneficial in cognitive disorders but reportedly improved apathy in a mixed population with various major neurocognitive disorders [86]. A trial of the SSRI citalopram was negative [87]. In a randomized, controlled study in patients with a variety of major neurocognitive disorders [88], memantine was found reduce apathy (evaluated as a secondary outcome). In terms of behavioral disturbances due to frontotemporal degeneration, the benefits reported with trazodone and with paroxetine in one trial did not include apathy. Rivastigmine [89] and memantine [90] failed to relieve apathy. Interestingly, a recent Phase II study suggests that oxytocin relieves apathy in frontotemporal dementia [91], and Phase III trials are now eagerly awaited. Lastly, the ongoing development of non-pharmacological approaches may improve the management of apathy in major neurocognitive disorders.

Apathy is the most common neuropsychiatric symptom reported in Parkinson’s disease, but its prevalence and clinical correlates are debated. Its frequency varies from 15 to 70 % [3, 15, 92–94] depending on the sample population, the assessment, and the diagnostic criteria. A mean prevalence of 30–40 % was reported in the review of Santangelo [95]. It can precede the onset of the first motor symptoms [96]. It occurs in drug-naïve new-onset parkinsonian patients in 20–36 % of cases [95, 97–99]. Its prevalence seems to decrease after the introduction of dopaminergic treatment. After 5–10 years of disease curse, its frequency increases to 40 % in non-demented patients and to 60 % in demented patients [100–102].

Apathy may occur in Parkinson’s disease as a separate, isolated behavioral symptom (i.e., unrelated to cognitive impairment or depression) [103–105]. Four major subdomains of goal-directed behavior reportedly contribute to apathy [106]: reward deficiency, depression, executive dysfunction [28], and autoactivation failure. Isolated apathy has been reported at early and advanced stages of Parkinson’s disease [104, 107]. A recent meta-analysis reported that apathy affects almost 40 % of patients with Parkinson’s disease [105]. Half of the patients with apathy do not suffer from concomitant depression or cognitive impairment, suggesting that it is indeed a separate feature of Parkinson’s disease.

Apathy is frequently associated with poor prognostic factors, such as older age, a lower mean mini mental state examination score, a higher Unified Parkinson’s Disease Rating Scale motor score, and more severe disability [105]. Apathetic Parkinson’s disease patients are more likely to have severe executive dysfunction and higher risk of developing dementia [108, 109]. As such, apathy is a key symptom of the worsening of the disease and is predictive of poorer functioning in activities of daily living [110], a decreased response to treatment, poor outcomes, diminished quality of life [98, 108, 111], and greater caregiver burden [112].

Apathetic behavior is frequently attributed to abnormalities within the prefrontal cortex-striatal circuits [12, 113]. In Parkinson’s disease, apathetic behavior might be due to dysfunction of dopaminergic transmission in the mesocorticolimbic pathway. PET studies with the dopamine D2 and D3 receptor antagonist [¹¹C] raclopride have shown increased binding in the orbitofrontal cortex, cingulate cortex, dorsolateral prefrontal cortex, amygdala, and striatum in patients with apathy—suggesting either a reactive increase in D2 and D3 receptor expression and/or a reduction in endogenous synaptic dopamine [114]. Increased apathy after deep brain stimulation of the subthalamic nucleus was related to low preoperative metabolism within the right ventral striatum measured three months before surgery [115]. This finding suggests that apathy in Parkinson’s disease results from severe dopamine depletion in the mesocorticolimbic system, which impairs emotional reactivity and decision-making processes [116]. Behavioral and imaging abnormalities in mesocorticolimbic regions have also been recorded following excess dopaminergic stimulation, which results in addictions [117–119]. This supports the hypothesis whereby a behavioral spectrum disorder ranges from a hyperdopaminergic syndrome (including impulse control disorders) to a hypodopaminergic state associated with apathy, anxiety, and depression, as described in dopamine agonist withdrawal syndromes [114, 120, 121].

In addition to the “dopaminergic” emotional-affective syndrome, apathy might also be associated with impaired executive functions. This “non-dopaminergic” cognitive apathy might result from brain lesions affecting either the lateral (dorsolateral and ventrolateral) prefrontal cortex or the caudate nucleus [12]. This hypothesis is supported by the results of several functional imaging studies in non-demented patients [122, 123]. An MRI study of parkinsonian patients with or without cognitive apathy reported an association between apathy and atrophy of the left nucleus accumbens and the dorsolateral head of the left caudate [124]. In the severe form of apathy in which the autoactivation subdomain is predominantly impaired, the combined effect of lesions of the basal ganglia, thalamus, and cortex on the dorsal–medial prefrontal cortex (i.e., the supplementary motor area and anterior cingulate cortex) generally results in dysfunction of both cognitive and emotional neural networks [12]. Lastly, the results of an electrophysiological study suggested that the reduction in amplitude of the P300a wave may be a neurophysiological marker of apathy in Parkinson’s disease [125].

Modulation of the mesocorticolimbic networks by dopaminergic drugs with relatively high affinity for the mesolimbic system [126] is also involved in the appetitive drive to perform pleasurable activities (e.g., creative activities and hobbies) [127, 128], which in turn can lead to behavioral addictions and impulse control disorders [17, 99, 118, 129, 130]. A dose reduction for dopaminergic agonists (e.g., in the context of deep brain stimulation) or a switch to levodopa results in disappearance of the increased drive for artistic creativity [127, 128] and the emergence of severe apathy, which can be reversed (at least partially) with careful re-initiation of agonist treatment [127]. The systematic, prospective assessment of behavior before and after stimulation of the subthalamic nucleus has shown that these observations apply not only to creativity and hobbies but also to the full range of motivated human behaviors [120]. Postoperative apathy is a frequent observation after stimulation of the subthalamic nucleus [107, 131, 132]. It frequently occurs in the first few postoperative months and is often transient, depending on the type of disease management [133, 134]. The only predictive factor for occurrence of apathy during the first year after surgery is the presence of preoperative non-motor fluctuations. Whereas early and potentially reversible apathy occurs in the context of postoperative dose reductions for dopaminergic medications [133], persistent, irreversible apathy appears to be related to cognitive deterioration and disease progression.

The Starkstein Apathy Scale [15] is recommended by the International Movement Disorder Society’s task force for the evaluation of apathy in Parkinson’s disease patients [135]. The Unified Parkinson’s Disease Rating Scale apathy item should be considered for screening purposes. The Apathy Evaluation Scale [8], item 7 of the Neuropsychiatric Inventory [10], and the first three items of the Behavioral Dysexecutive Syndrome Inventory [3] met the criteria for classification but were not recommended. The Lille Apathy Rating Scale [11] has now been validated [136] and is used specifically for research purposes. The diagnostic criteria for apathy in Parkinson’s disease have been validated [9, 137, 138], although some limitations have been reported [98, 102, 139]. To overcome these limitations, Pagonabarraga et al. suggested a set of less restrictive, clinically more operative criteria for the diagnosis of apathy (based on a checklist of symptoms directly related to diminished motivation, irrespective of the latter’s cause) [106].

Several drugs have been evaluated for the treatment of apathy in Parkinson’s disease, using different assessment instruments as endpoints. There is some low-grade evidence of efficacy. The dopamine D2 and D3 receptor agonists ropinirole [140], pramipexole, and rotigotine [119, 141] reportedly reduce apathy as does methylphenidate [142]. In apathetic parkinsonian patients free from dementia and depression, 6 months of rivastigmine treatment was associated with a better Lille Apathy Rating Scale score [143]. Apathy following subthalamic stimulation is slightly improved by taking methylphenidate [144] and piribedil [145]. The use of antidepressants for apathy in Parkinson’s disease is controversial [107, 146]. In non-operated patients with Parkinson’s disease, SSRIs have even been reported as increasing apathy [147], whereas the noradrenaline–dopamine reuptake inhibitor bupropion reportedly increased levels of motivation [148].

The few studies on the behavioral domain of executive function in stroke patients have focused on apathy. A recent meta-analysis [33] of 24 studies reported a pooled mean [95 % confidence interval] prevalence of apathy of 34. 6 % (29.5–40.2 %). The variable prevalence is mainly attributable to inter-study differences in the patient population (time since stroke, the proportion of demented patients, and the type of stroke) and assessment methods.

Apathy may occur in acute stroke patients [149] and is long-lasting in half of these cases [150]. Apathy was found to increase in frequency and severity over time, especially in patients who had cognitive disorders and functional decline [151, 152]. This might be due to the cumulative effects of vascular pathologies. Accordingly, apathy is common in both vascular dementia and “vascular cognitive impairment not dementia” [153]. Furthermore, apathy was found to be more severe in demented patients with subcortical ischemic vascular disease than in those with many large infarcts [152]. The latter finding is consistent with the relatively high frequency of apathy (40 %) reported in patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) [154].

Depression and depressive symptoms are the most frequent comorbidity of apathy in stroke; it is observed in a third of all stroke patients [155–157] and in 40 % of apathetic patient [33]. Apathy and depressive syndromes share a number of symptoms, and so it may be difficult to distinguish between the two conditions [158]. Hama et al. [159] examined apathy and depression in 243 stroke patients: 11. 9 % displayed depression in the absence of apathy, 19. 8 % displayed apathy in the absence of depression, and 20. 6 % displayed both depression and apathy. Very similar results were reported in the review of Van Dalen [33]; apathy in the absence of depression was twice as frequent as depression in the absence of apathy. Lastly, this review has reported that apathetic patients are more frequently and severely depressed and cognitively impaired in comparison to non-apathetic patient.

In stroke patients, apathy has been associated with older age [160, 161], low educational level [149], poor cognitive status [150, 152], and cumulative vascular pathology [151].

The effect of stroke subtype remains controversial. A systematic review and meta-analysis of 19 studies evaluating apathy secondary to stroke [160] has reported no difference between rate and severity of apathy for the type (ischemic and hemorrhagic stroke) or side hemispheric stroke lesion. Apathy has been reported in 42 % of patients with subarachnoid hemorrhage (especially in cases of anterior communicating artery aneurysm) [162] and in 15–20 % of patients after 6 months [163, 164]. In cerebral venous thrombosis, behavioral dysexecutive disorders are less frequent (18 %)—a finding that is partly explained by the absence of brain lesions in some patients [165].

The stroke site has long been regarded as the main determinant of apathy, although this has yet to be comprehensively documented. Damage to the prefrontal–subcortical system (the prefrontal cortex, basal ganglia, thalamus, limbic system structures, and white matter tracts) is expected to be associated with apathy [12]. Accordingly, hypoactivity with apathy has been reported in striatal stroke [158, 166, 167] and frontal stroke—especially the mesial region [23, 168], frontostriatal circuit [169], or the thalamus [170]. However, a study of clinical–anatomic correlations (based on visual analysis of regions of interest) found that apathy was only related to strokes involving the ventral striatum region and the fronto-dorsal region (centered on the middle frontal gyrus) [163]. A study using voxel-based morphometric analysis six months post-stroke revealed a significant correlation between apathy and volume reduction of the posterior cingulate cortex [171].

A range of instruments are currently used to measure apathy in stroke [172]. The most frequently used scales are the Apathy Evaluation Scale [14], the Starkstein Apathy Scale [173], and the Neuropsychiatric Inventory [10]. The Neuropsychiatric Inventory was been selected for the National Institute of Neurological Disorders and Stroke-Canadian Stroke Network’s vascular cognitive impairment harmonization standards [174]. However, the prevalence of apathy reported using the Neuropsychiatric Inventory was found to be lower than in studies using other informant-based scales (23 % vs. 39. 4 %, respectively) [33]. Administration of the Behavioral Dysexecutive Syndrome Inventory has shown that hypoactivity with apathy is the most frequent behavioral change [3, 175]. Furthermore, behavioral disorders were more frequent in cerebral infarct and hemorrhage than in ruptured aneurysm and cerebral venous thrombosis [3, 175].

Several case reports and a few trials on small patient populations have been reported (for review, [33]) with contradictory results. There is no evidence to support the use of a specific pharmacological treatment.