FormalPara Key Points

The efficacy of cholinesterase inhibitors and memantine for the treatment of Alzheimer’s disease dementia is modest.

Practical issues on the optimal duration of drug treatment, predictors for good response, and long-term efficacy remain to be addressed.

Evidence supporting cholinesterase inhibitors and memantine in other dementia types is limited except for dementia with Lewy bodies and Parkinson’s disease dementia.

1 Introduction

Cholinesterase inhibitors (ChEIs) and memantine are the only medications approved for the treatment of dementia (Table 1). They are primarily developed for the treatment of dementia due to Alzheimer’s disease (AD); however, they are frequently prescribed for off-label use in other types of dementia such as vascular dementia. It is important to note that they cannot cure the dementia; they can only help to alleviate symptoms and possibly delay disease progression.

Table 1 Summary of the mode of actions, dosing recommendation and indications of anti-dementia drugs
Full size table

Donepezil, rivastigmine and galantamine are the three common ChEIs available on the market. All of these ChEIs enhance cholinergic transmission by inhibiting acetylcholinesterase (AChE) activity to increase the availability of acetylcholine to interact with postsynaptic acetylcholine receptors. Donepezil is a specific and reversible inhibitor of AChE. In contrast, rivastigmine is a pseudo-irreversible inhibitor of both AChE and butyrylcholinesterase (BuChE); AChE selectively hydrolyses acetylcholine and is found mainly in the brain, whereas BuChE is a non-specific cholinesterase that hydrolyses many different choline esters including acetylcholine and is found mainly at the periphery. The level of AChE is significantly decreased, but BuChE level is increased in the brain of AD patients. It has been proposed that rivastigmine dually inhibits AChE and BuChE and could further increase the availability of acetylcholine for neurotransmission. Galantamine is a selective and reversible inhibitor of AChE; it has additional modulating action on nicotinic acetylcholine receptors, which is expected to further facilitate neurotransmission. Although the three ChEIs have slightly different modes of action, their clinical efficacy is similar [1–5] and is related primarily to the degree of AChE inhibition. All three of these ChEIs have been approved for mild-to-moderate AD dementia, but only donepezil and rivastigmine transdermal patches have expanded their indication to include severe AD dementia in the USA. The ChEIs are licensed for the treatment of mild-to-moderate AD dementia only in Europe.

Memantine is a non-competitive, low-to-moderate affinity N-methyl-D-aspartate receptor antagonist. It works by regulating the activity of glutamate to prevent overstimulation of receptor from excessive glutamate but does not affect the normal glutamatergic transmission such that the physiological function of glutamate can be maintained. It has been approved for moderate-to-severe AD dementia in the USA and Europe.

Clinical trials often use a mini-mental state examination (MMSE) score to define the stage of dementia (21–25 for mild, 11–20 for moderate and 0–10 for severe dementia). Although it has been shown that the MMSE score correlates well with the Clinical Dementia Rating for the staging of dementia in AD [6], it should also consider the patient and caregiver’s input for the cognition, functional ability, and behavioral disturbance to determine the severity of dementia and the need for drug treatment.

The treatment efficacy of ChEIs and memantine has been shown in randomized controlled trials (RCTs) [2–5, 7–12], which allows the development of guidelines to suggest the optimal use of ChEIs and memantine in clinical practice. However, it is still challenging for a clinician to implement them into clinical practice. This article integrates the guidelines and evidence from clinical trials to address the specific issues about the use of ChEIs and memantine in daily practice.

2 What is the Efficacy of Cholinesterase Inhibitors and Memantine?

2.1 Cholinesterase Inhibitors

There are numerous RCTs and corresponding meta-analyses to address the efficacy of ChEIs for the treatment of AD dementia. Most studies included patients with mild-to-moderate dementia and were 24–26 weeks in duration. Most studies evaluated cognitive and global function as primary outcomes. Although the overall improvement is more persistent in cognition and global function, the change is generally modest; the mean difference in change from baseline between the treatment and placebo groups was <4 points on the Alzheimer’s Disease Assessment Scale-cognitive subscale (ADAS-cog) and the difference on the Clinician’s Interview-Based Impression of Change plus Caregiver input (CIBIC-plus) scale between the treatment and placebo groups was ≤0.5 points, which may not be translated into a clinically significant benefit [2, 4, 8]. Furthermore, there was wide variation in the clinical response—the proportion of patients who achieved a clinically important improvement in cognition (an improvement of ≥4 points from baseline on an ADAS-cog, which is equivalent to delaying disease process by 6 months [13]) and global function (any improvement on CIBIC-plus) ranged from 15.4 to 60 % in the treatment group versus 7.8–36 % in the placebo group on cognition and 0.4–46 % in the treatment group versus 0–25 % in the placebo group on global function [14]. Overall, there were 10 and 9 % more patients in the treatment group than the placebo group that achieved a significant cognitive and global improvement, respectively [9]. This suggested that not all patients could benefit but only a subset of patients achieved clinically significant improvement. Individual items of cognition that have better response to treatment are rarely reported.

The long-term outcomes such as maintenance of activities of daily living (ADL) and delaying the need for institutionalization are difficult to evaluate because most studies were less than 1 year in duration. Two 1-year RCTs suggested that donepezil continued to have benefits on cognition, global status and ADL, and was associated with a 38 % reduction in the risk of functional decline versus placebo at 1 year [15, 16]. In one large trial (AD2000), the rate of institutionalization and progression of disability in mild-to-moderate AD patients was measured, but it did not show a significant benefit of donepezil over placebo at 3 years [17].

Behavioral and quality-of-life outcomes were less frequently evaluated in clinical trials. Evidence for benefit on behavioral outcome is limited for ChEIs because of mixed results [18].

The clinical efficacy of three available ChEIs is similar. Both head-to-head comparative studies and indirect comparison by sub-analysis of data for different ChEIs did not demonstrate superiority of one ChEI over another [2–5, 9].

2.2 Memantine

Most RCTs for the efficacy of memantine were up to 26–28 weeks. They showed that memantine benefited patients with moderate-to-severe AD [11, 12] but without a clear benefit in mild-to-moderate AD [12, 19]. Similar to ChEIs, the efficacy is modest on cognition, global impression and ADL. Assessment of memantine treatment effect on slowing clinical progression in AD using responder analysis showed fewer memantine-treated than placebo-treated patients had clinical worsening on cognition (24.4 versus 35 %), global status (39.8 versus 48.6 %), and function (38.1 versus 43.4 %) over 6 months [20]. The particular aspects of cognition that were positively affected were language, memory, praxis, and functional communication [21].

Long-term RCT is limited in memantine monotherapy, but long-term follow-up studies of memantine in combination with ChEIs showed that the benefits of memantine were sustained and might delay nursing placement [22, 23].

Memantine demonstrated a consistent benefit on behavioral outcome with delusion, agitation, aggression, and irritability being the most responsive symptoms [3, 11, 12].

Of note, most RCTs tended to include relatively healthy patients. Thus, whether the results or conclusions could be applied to the demented patient with comorbidities—who constitute a significant proportion of patients in clinical practice—remains to be determined.

3 What is the Predictor of Good Response?

The clinical response of patients to ChEIs varies such that only a subset of patients achieves a clinically significant benefit. However, no definitive response predictors have been identified. Various studies have predicted a good response based on the severity of dementia and disabilities [24, 25], rate of pre-treatment disease progression [26], neurological feature (electroencephalography studies) or neurochemical feature (cerebrospinal fluid amyloid and tau) [26–28], genetic features (apolipoprotein E4 genotype) [24, 26], and initial response to ChEIs [27]. Some seem to be reliable predictors but the findings are inconsistent and need further studies.

4 When to Start? Which Anti-Dementia Drugs Should Be Chosen When Starting Treatment?

There is agreement that ChEIs and memantine should be considered once the diagnosis of AD dementia is made [29]. There is also a recommendation on the initiation of ChEIs as early as possible [29, 30] because a delay in the initiation of therapy failed to provide the same cognitive response as those who began earlier [31]. Similarly, starting memantine earlier when patients reach moderate stage of dementia may be more beneficial as treatment effect on slowing clinical progression appears to be more striking in early moderate stage [21].

The choice of ChEI should be based on the patient tolerance, clinician’s experience, ease to use, and cost [32, 33] because no differences in the efficacy among the three ChEIs has been demonstrated in the limited comparative studies [2–5].

5 What are the Adverse Effects and Contraindications to Cholinesterase Inhibitors and Memantine?

5.1 Cholinesterase Inhibitors

The adverse effects of ChEIs are related to the increased cholinergic activity. The most common are gastrointestinal symptoms (nausea and vomiting, diarrhea, and abdominal pain), anorexia and muscle cramp [34–36]. Others include weight loss and urinary incontinence. Furthermore, there is a concern about cholinergic stimulation on the vagus nerve, which may provoke bradycardia, heart block and syncope. This can lead to permanent pacemaker insertion or precipitate fall-related injuries [37]. However, in two large RCTs of donepezil in vascular dementia patients who had a high rate of cardiovascular and cerebrovascular disease and concomitant medication use, there was no increase in the occurrence of bradycardia, transient ischemic attack or stroke in the treatment group compared to the placebo group [38, 39]. Another large community-based trial of donepezil for AD also did not show increased risk of bradycardia in donepezil-treated patients who had concomitant beta-blocker, non-dihydropyridine calcium channel blockers or digoxin use [40]. Nonetheless, ChEIs should be avoided in patients with sick sinus syndrome and cardiac conduction defects. In addition, the increased airway reactivity and gastric acid secretion with cholinergic stimulation can worsen asthma, chronic obstructive airway disease and active peptic ulcer disease; it should be used with caution in these populations.

The incidence and severity of adverse effects are dose related and can be reduced by starting at a low dose and titrating gradually over weeks or months [34–36]. Besides, decreasing the dose temporarily for a few days and administrating it with a meal can also be helpful in patients developing gastrointestinal adverse effects [41]. If patients still cannot tolerate the adverse gastrointestinal effect, then a patch formulary (transdermal patch) may be worth trying because it has been shown to cause less nausea and vomiting than oral form [42]. However, the transdermal patch may be associated with skin reactions that range from the most common form of mild erythema and pruritus to severe contact or allergic dermatitis. The likelihood of the skin irritation can be decreased by rotating the application site daily with no reapplication to the same site within 14 days and with the application of moisturizers [43].

5.2 Memantine

Memantine seems to be better tolerated than ChEIs. It is well tolerated with an adverse effect profile similar to that of placebo; the dropout rate and the proportion of patients with adverse effects are comparable to those of placebo [3, 10–12]. The most common adverse effects are headache, confusion, dizziness and constipation; others include high blood pressure, somnolence and vomiting [44]. It should be used with caution in patients predisposed to conditions that raise urine pH (e.g. intake of sodium bicarbonate and carbonic anhydrase inhibitors, and severe urinary tract infection) because these may reduce memantine clearance and lead to the accumulation of memantine in the body and increase the risk of adverse effects.

6 What Should Be Assessed When Taking Anti-Dementia Drugs?

Patients on medication should be monitored for drug adverse effect and their response to drugs.

In clinical trials, ADAS-cog is often used to measure cognitive response. However, performing ADAS-cog is time consuming; it takes approximately 45 min to complete, and thus is seldom used in daily practice. In contrast, the MMSE is simple and easy to administer. It is used extensively in clinic settings to assess treatment response. However, it is subject to several drawbacks—the MMSE cannot detect the modest benefits seen with ChEIs [45], and it is also insensitive to progression in severe dementia [46]. There is wide individual variability in cognitive decline as measured by MMSE [47]. Besides, a decline in cognitive function does not always correlate with functional impairment. Thus, the MMSE should not be regarded as the only assessment tool [48]. Evaluating functional abilities and behavioral and psychological symptoms of dementia (BPSD) via the Barthel index of ADL and neuropsychiatry inventory should also be considered. The global deterioration scale (GDS) or functional assessment staging (FAST) to measure overall severity are also recommended to monitor disease progression [49]. In addition to the formal assessment, input from caregivers about their general impression of response and any change in cognitive, behavioral and ADL performance as well as the caregiver burden should also be obtained. All these data are important to help clinicians determine if the response is favorable in a given patient though uncertainty about the treatment benefit often remains. The patient should be assessed every 6–12 months [33].

7 What is Regarded as Positive Response?

The natural history of AD is of progressive decline with patient’s cognitive, physical and social functions. The rate of decline in AD is not linear [50]. Cognitive deterioration is slow during the early and very late stages of disease and more rapid during the middle stage. The ADAS-cog is often used to determine the rate of cognitive decline; mild AD patients have an average rate of decline of 5 or fewer ADAS-cog points (≦2 MMSE points) per year, whereas patients with moderate dementia have an average 7–11 ADAS-cog points (2–4 MMSE points) decline over 1 year [50, 51].

There is no medication to reverse or stop disease progression. Thus, positive response is defined as an improvement or stabilization of symptoms or slowing of the rate of decline [51]. For example, studies have shown that the average difference in point changes from baseline between treatment and placebo groups at 6 months is 2.66 in favor of treatment [4]. This is the equivalent of a delay of 7 months and 2–5 months in disease progression in mild dementia and moderate dementia, respectively [51], which is an improvement. If there is no change in assessment score over a period, then it is regarded as stabilization. If the drop in scores is less than the natural course, i.e. below 5 ADAS-cog points or 2 MMSE points in mild dementia, and below 7 ADAS-cog points or 2 MMSE points in moderate dementia over a year, then it is regarded as a slowing of the decline. In addition, functional and behavioral domains as well as patient and caregiver input should be considered in tandem when evaluating the response.

8 When Can We See Effect After Commencing Anti-Dementia Drugs or What is the Minimum Duration of Trial Before Considering the Drug Has No Benefit?

Most studies are 24–26 weeks long. This showed benefits in terms of cognition and global function over placebo. There are shorter studies (<6 months), and they also showed benefit; however, measurement tools such as the ADAS-cog is not sensitive enough to measure cognitive progression within a short period of time (<6 months) [13]. Seeing efficacy in <6 months is questionable. It is reasonable to continue the drugs for at least 6 months with optimal doses before concluding that they are ineffective [52].

9 Can Patients Benefit From Other Cholinesterase Inhibitors if They Do Not Tolerate or Do Not Seem to Benefit From One Cholinesterase Inhibitor?

Because of the differences in the pharmacologic profiles among the three ChEIs, prior ChEI therapy cannot predict future tolerability or response to another ChEIs; thus, patients with poor tolerance to or lack of efficacy in treatment with one ChEI may benefit by switching to other ChEIs [53, 54]. Before considering one ChEI to be ineffective, clinicians are advised to ensure optimal dosage and at least 6 months of initial ChEI usage. Switching can be performed safely without a washout period if switching is solely due to the lack of benefit. However, if the motivation is tolerability, then cessation of the ChEI for 7–14 days should be considered before commencing a new ChEI depending on its half-life (longer for donepezil, shorter for rivastigmine and galantamine) [55]. The transdermal patch may be considered if the patient cannot tolerate the adverse gastrointestinal effects (see adverse effects section).

10 Should We Add Memantine on Top of Cholinesterase Inhibitors When Patients Progress to Severe Stage of Dementia?

Large-scale RCTs and the corresponding meta-analyses comparing the efficacy of memantine and ChEIs combination therapy with ChEI monotherapy showed favorable results in combination therapy over ChEI monotherapy on cognitive, functional and behavioral outcomes and overall impressions—particularly in moderate-to-severe AD patients [56–58]. A post hoc meta-analysis also favored combination therapy in delaying clinical worsening. Here, fewer patients receiving memantine with donepezil than those receiving placebo with donepezil had marked clinical worsening in cognition, function and global status [59].

Longer term naturalistic studies also demonstrated beneficial effect. One study showed that combination therapy slowed cognitive and functional decline in terms of a lower annualized rate of deterioration on the Blessed Dementia Scale and ADL scores versus ChEI monotherapy and no drug treatment [22]. Although the effect size of combination therapy started out as modest, it increased with time on treatment across 4 years of study. Another study with a mean follow-up time of 5 years found that AD patients on ChEIs had significant delays in nursing home admission. The effect was significantly augmented with the addition of memantine [23]. Furthermore, adverse effects and dropout rates of combination therapy were not significantly different from ChEI monotherapy.

Despite the apparent benefit, clinical relevance of the superiority of combination therapy over ChEI monotherapy is unclear. All the studies involved solely the addition of memantine to the existing ChEI monotherapy, but not the simultaneous initiation of memantine and ChEIs. Thus, they cannot exclude the possibility that the effect is provided mainly by memantine. In the DOMINO trial, both donezepil and memantine monotherapy were associated with cognitive and functional benefit in patients with moderate-to-severe AD dementia at 1 year. No additional benefit was seen when adding memantine on top of ChEIs. The efficacy of donepezil and memantine did not differ significantly in the presence or absence of the other [60]. Overall, the current evidence supported a positive effect in adding memantine on top of ChEIs but still has unclear clinical significance versus memantine monotherapy; they could only be considered in moderate-to-severe AD dementia. Nonetheless, combination therapy is widely considered as a treatment practice in many centers and was approved by the USA for moderate-to-severe AD dementia.

11 When to Stop?

The optimal duration of anti-dementia drugs is unknown. There is no doubt that the anti-dementia drugs should be stopped if the patient experiences intolerable adverse effects or it is the preference of a competent patient or caregiver after being appraised of the risks and benefits of continuation and discontinuation. This should also be done if the patient is non-adherent with medications [32, 61]. Significant comorbidities with the burden of polypharmacy that places the patient continuing anti-dementia drugs at increased risk of adverse effects or would be futile should is also a reason to consider drug discontinuation [32].

Apart from that, there is no clear guidance on when to discontinue the drug treatment. It is generally suggested to discontinue the anti-dementia drugs if the potential risks outweigh the benefits—especially when the patient experiences greater than expected decline despite drug treatment. However, the benefits of treatment can be difficult to judge. It is difficult to know whether the drug has already slowed down the disease progression because the rate of natural decline is subject to individual variation and the stage of illness [13, 50]. Furthermore, we should not depend solely on the decline of a single domain such as cognition or test scores to determine the discontinuation. It is more appropriate to take composite measure of various domains such as GDS or FAST because decline in one domain does not necessarily mean the patient is not benefiting in other domains. Supplementing information from a reliable informant to judge treatment response is also important.

When a patient deteriorates to a totally dependent state without meaningful social interactions, it is reasonable to stop the drug [32, 62]. On the other hand, for those patients who are not at the severe end-stage of dementia but considered by clinicians as no longer benefiting from an anti-dementia drug, then drug continuation may still have advantages. The DOMINO trial showed moderate-to-severe AD patients worsened dramatically on cognition and function upon donepezil discontinuation versus those who continued donepezil [60]. Nonetheless, it is important to discuss and inform the patient and caregiver about the potential risk and benefit of continuing and discontinuing anti-dementia drugs so that a consensus on whether to discontinue the treatment can be reached.

Besides, it is important to ensure good drug compliance and exclude other causes of decline such as cerebrovascular events, thyroid disorders, vitamin B12 deficiency and occult infection, as well as medications that impair cognition—especially if the decline is out of expectations.

There is a concern about further cognitive or functional decline or the emergence of behavioral problems upon discontinuation of anti-dementia drugs. Thus, it is recommended to taper the drug rather than abruptly discontinuing it to avoid a withdrawal effect. If there is an obvious decline upon discontinuation, then restarting the anti-dementia drug may need to be considered.

12 Should Patients Living in an Institution Continue or Discontinue Anti-Dementia Drugs?

One of the goals of taking anti-dementia drugs is to delay institutionalization. If the patients deteriorate to requiring institutionalization, then continuing the drug may argue against cost effectiveness. However, patients are admitted to long-term care institutions for many reasons and these are not always related to patient’s cognition or functional status. Thus, institutionalization should not be regarded as a sole factor in discontinuing anti-dementia drugs [32].

Demented patients who live in the institutions are generally at more advanced stages of dementia with higher functional impairment and increased frequency of behavioral problems as well as other comorbidities. Thus, the goal of patient management in institutions is different from those living in the community. In addition to the maintenance of the barely remaining cognition and functional ability that enables patients to communicate their symptoms and needs, more focus is needed on BPSD to minimize self-harm and disturbance to others. This reduces the need for care and helps maintain better quality of life.

Few studies have looked for the effectiveness of anti-dementia drugs in institutionalized patients. Some have supported the continuation of anti-dementia drugs [63, 64]. A review committee used severity of dementia, functional impairment, BPSD and social interactions to ensure the appropriate ChEIs prescription. This model was an effective tool for decision making in terms of continuation or discontinuation of ChEIs in institutionalized patients [65]. Nonetheless, further studies are need before making recommendations. In addition, we need to adjust the management goal and assess potential benefits for an individual institutionalized patient before deciding on discontinuation. It may be justified to continue therapy in those patients who can still manage some basic ADL or have social interactions.

13 Are Cholinesterase Inhibitors and Memantine Effective for Mild Cognitive Impairment or Other Dementia Types?

13.1 Mild Cognitive Impairment

Neither ChEIs nor memantine are recommended in patients with mild cognitive impairment (MCI) because they did not significantly improve cognition or functional status or delay progression to dementia [66, 67]. However, their use is common in clinical practice [68]. Diagnostic uncertainty as well as heterogeneous pathophysiology and prognosis—limit clinical trials in identifying therapeutic options for MCI [69]. Better characterizing MCI people with high chance of progression to AD dementia via biomarkers such as positron emission tomography scans of beta-amyloid deposition may help predict responders to anti-dementia drugs.

13.2 Vascular Dementia

Clinical trials showed that both ChEIs and memantine produced only small cognitive benefits (1–2 points difference in ADAS-cog), but no corresponding effects on global, functional, and behavioral outcomes [70]. Thus, they are generally not approved for treating vascular dementia (VD). The VD patients vary widely in the type, location, and the extent of the cerebrovascular disease as well as in the clinical course. This may affect the individual response to drugs. Further studies are needed to address which subgroup of patients would benefit from anti-dementia treatment. For VD patients with coexisting AD, ChEIs and memantine are likely to be beneficial and can be considered [48].

13.3 Dementia with Lewy Bodies and Parkinson’s Disease Dementia

Only rivastigmine has been approved for mild-to-moderate Parkinson’s disease dementia (PDD) patients in US and European countries. A Cochrane review of ChEIs for dementia with Lewy bodies (DLB) and PDD only supported the use ChEIs in patients with PDD who showed a positive effect on global and cognitive function, behavioral disturbance, and ADL [71]. The effect of ChEIs in DLB was not clear because there was only one RCT on DLB in the review. However, ChEIs are regarded as a mainstay of treatment for DLB in many centers because increasing evidence shows that ChEIs improve cognition and decrease visual hallucinations, apathy, fluctuation in attention, and delusion in DLB patients [72, 73]. National Institute for Health and Care Excellence (UK) allows the prescription of ChEIs to patients with DLB or PDD if the non-cognitive symptoms such as hallucination and agitation cause distress or challenging behavior [48]. In Japan, donepezil has been approved for use in patients with DLB.

There is also increasing evidence to support the use of memantine for both DLB and PDD patients. Memantine has been shown to improve episodic memory, global clinical status, attention, and behavioral disturbance in both mild-to-moderate DLB and PDD patients [74–76].

13.4 Frontotemporal Dementia

Both ChEIs and memantine should not be considered in patients with frontotemporal dementia (FTD) because they did not demonstrate beneficial effects on global function and neuropsychiatric symptoms [77, 78]. Rather, ChEIs may cause more agitation, and increased aspiration risk in a subset of FTD patients with motor neuron disease because of the adverse effects of increased oral secretion. Memantine may cause adverse cognitive effects including confusion, memory loss and language disorders.

14 What are the Up-Coming Therapeutic Agents for Demenia?

New therapeutic agents may modify the disease process. Advances in the understanding of dementia pathophysiology allow potential targets such as beta-amyloid, tau protein, and inflammation to be pharmacological targets [79]. Of these, targeting the build-up of beta-amyloid seems to receive the most attention. The amyloid hypothesis postulates that aggregation of beta-amyloid leads to toxic oligomers that then trigger a series of events leading to neuronal death. Thus, anti-amyloid approaches such as monoclonal antibodies to bind and clear beta-amyloid in the brain seem to be promising. However, supportive evidence from clinical trials in patients with mild-to-moderate AD dementia is lacking [41]. Nonetheless, positive results from ongoing studies involving different or combination of potential target approaches is anticipated.

15 Conclusion

ChEIs and memantine cannot cure or prevent the dementia progression. They should not be regarded as a dominant treatment because their treatment effect is modest and only a subset of patients has significant benefit. Consultation should be given before the drug prescription to avoid false expectations. Issues such as their optimal duration of treatment, predictors for good response, and long-term efficacy (e.g. functional abilities or delay in institutionalization) remain to be addressed. Non-pharmacotherapy including cognitive training and caregiver education or support should be included in the management plan. Maintaining good health or a stable medical condition with optimal management of comorbidities and cardiovascular risk factors is also important. Further studies to guide the optimal use of ChEIs and memantine are needed before the emergence of more promising pharmacotherapy.