Management of apathy in patients with Alzheimer’s disease

People diagnosed with Alzheimer’s disease often experience symptoms of apathy, which can be treated by pharmacological and behavioural interventions.

The purpose of this evidence summary is to present the best available evidence regarding the pharmacological management of apathy in patients with Alzheimer’s disease. For the full review, refer to Pharmacological interventions for apathy in Alzheimer’s disease.1


According to the World Alzheimer report, it is estimated that the number of people with dementia due to Alzheimer’s disease will reach 131 million by 2050.

People diagnosed with Alzheimer’s disease experience changes in cognition, function and behaviour.2

Other symptoms include apathy and depression. These changes are associated with a decrease in quality of life and increased dependence on carers for daily activities.

Apathy and depression are different symptoms and are not related, as shown by several neuroimaging studies.

People with apathy have pathological changes such as increased neuronal loss, neurofibrillary tangles and white matter intensities compared to individuals with no apathy.3,4

The treatment of apathy involves both pharmacological and behavioural interventions. The current pharmacological interventions include CNS stimulants, antidepressants, atypical antipsychotics, apomorphine, amantadine, cholinesterase inhibitors and dopamine agonists.

The results of studies on the effectiveness of these treatments for apathy in patients with Alzheimer’s disease are summarised below.5,6


  • The following databases were searched: Specialized Register of the Cochrane Dementia and Cognitive Improvement Group (ALOIS), MEDLINE, Embase, CINAHL, PsycINFO, LILACS, ClinicalTrials. gov and the World Health Organization (WHO) portal.
  • The primary outcome measures included apathy measured by a validated scale such as Apathy Evaluation Scale (AES), the apathy component of the Clinical Global Impressions of Change scale (CGI-C apathy), and the Neuropsychiatric Inventory (NPI) apathy subscale. The incidence of adverse events was also reported.
  • Secondary outcomes included neuropsychiatric symptoms other than apathy, cognition, functional performance, changes in global disease severity (CGI-C) and dropouts due to adverse events (AEs).
  • The review included 21 studies with a total 6,384 participants. The studies addressed stimulant medicines, sodium valproate, cholinesterase inhibitors and atypical antipsychotics.
  • Four studies included stimulant medicines (three studies included methylphenidate and one study examined modafinil). The authors found that methylphenidate was associated with a decrease in apathy when apathy was measured using the apathy evaluation scale (MD -4.99, 95% CI -9.55 to -0.43, n = 145, 3 studies). However, apathy was not affected by methylphenidate when it was measured using the NPI-apathy subscale (MD -0.08, 95% CI -3.85 to 3.69, n = 85, 2 studies).
  • Methylphenidate was also associated with an improvement in cognition (MD 1.98, 95% CI 1.06 to 2.91, n = 145, 3 studies), and instrumental activities of daily living (MD 2.30, 95% CI 0.74 to 3.86, P = 0.004, n = 60).
  • The risk of adverse events was low in the methylphenidate group (RR 1.28, 95% CI 0.67 to 2.42, n = 145, 3 studies).
  • Modafinil was included in one study with 22 patients. Its efficacy was assessed with the FrSBe-apathy subscale (MD 0.27, 95% CI -3.51 to 4.05). There was no evidence of its efficacy in reducing apathy. There was no evidence of a difference between modafinil and placebo in change in functional status over 8 weeks (MD -0.54, 95% CI -1.40 to 0.32, P = 0.22).
  • The review also included studies investigating the efficacy of donepezil, galantamine or rivastigmine, antipsychotics and antidepressants. Most of these studies were sponsored by drug companies. Moreover, the results were only available upon request. None of these medicines produced any significant improvement in apathy. On the other hand, it was found that antipsychotics may slightly worsen apathy compared to placebo (standardised mean difference) (SMD 0.14, 95% CI -0.00 to 0.28, P = 0.05, n = 1070, 2 studies).
  • A total of three studies investigated the efficacy of valproate for the treatment of apathy and found limited evidence to support its benefit.

Characteristics of studies

Placebo-controlled, parallel and crossover randomised controlled trials investigated medicines for the management of apathy in patients with Alzheimer’s disease. Participants were included if they met the standardised criteria for Alzheimer’s disease.

Quality of the research

Studies included in the report had a low or unclear risk of bias. Overall, the quality of the evidence ranged from high to moderate. The main sources of bias were selective reporting of data.


Methylphenidate may be associated with a small improvement of apathy in individuals with Alzheimer’s disease. All of the other classes of medicines had limited benefit in the management of apathy.

Implications for practice

Future studies should aim at validating the apathy scales to minimise variability of testing for apathy. Moreover, apathy has been associated with functional and cognitive decline; therefore future studies should include cognitive and functional outcome measures.


  1. Ruthirakuhan MT, Herrmann N, Abraham EH, et al. Pharmacological interventions for apathy in Alzheimer’s disease. Cochrane Database of Systematic Reviews 2018, Issue 5. Art. No.: CD012197. DOI: 10.1002/14651858.CD012197. pub2.
  2. Prince M, Wimo A, Guerchet M, et al. World Alzheimer report 2015: the global impact of dementia. 2015.pdf.
  3. Starkstein SE, Mizrahi R, Capizzano AA, et al. Neuroimaging correlates of apathy and depression in Alzheimer’s disease. Journal of Neuropsychiatry and Clinical Neurosciences 2009;21(3):259–65.
  4. Tagariello P, Girardi P, Amore M. Depression and apathy in dementia: same syndrome or different constructs? A critical review. Archives of Gerontology and Geriatrics 2009;49(2):246–9.