Treatment of Alzheimer disease

INTRODUCTION — 

Alzheimer disease (AD) is a neurodegenerative disorder that primarily affects older adults and is the most common cause of dementia. The most essential and often earliest clinical manifestation of AD is selective memory impairment, although there are less common presentations of deficits in other cognitive domains: executive, language, and visuospatial. While treatments are available that can ameliorate some symptoms of the illness and slow the disease to some extent, there is no cure currently available, and the disease inevitably progresses in all patients [1].

This topic discusses the treatment of AD. Other aspects of AD are discussed separately:

●(See "Clinical features and diagnosis of Alzheimer disease".)

●(See "Epidemiology, pathology, and pathogenesis of Alzheimer disease".)

●(See "Genetics of Alzheimer disease".)

Aspects of management in patients with dementia that are not specific to AD are also discussed separately:

●(See "Management of the patient with dementia".)

●(See "Care of patients with advanced dementia".)

SPECIALTY REFERRAL — 

Timing of referral to a specialist depends upon the comfort and knowledge base of the primary care provider in managing dementia and on the availability of specialty clinics where additional resources are available, such as social workers and neuropsychologists.

Factors that are important in considering patient referral are when there is uncertainty about the diagnosis of an early dementia (eg, when difficulty arises in distinguishing dementia from normal aging, depression, or encephalopathy), when a non-Alzheimer dementia is likely (early and severe behavioral changes, language problems, hallucinations, or parkinsonism), when there is a young onset (<65 years old), and/or when there is a strong family history.

Patients who may be candidates for amyloid-targeted therapies, namely, patients with likely AD pathology who have mild cognitive impairment or mild dementia (eg, Mini-Mental State Examination [MMSE] score ≥22), should also be referred to a specialist in dementia. (See 'Amyloid-targeted therapies' below.)

CHOLINESTERASE INHIBITORS — 

Patients with AD have reduced cerebral content of choline acetyltransferase, which leads to a decrease in acetylcholine synthesis and impaired cortical cholinergic function. Cholinesterase inhibitors (donepezil, rivastigmine, and galantamine) increase cholinergic transmission by inhibiting cholinesterase at the synaptic cleft and provide modest symptomatic benefit in patients with AD.

The majority of patients with newly diagnosed AD should be offered a trial of a cholinesterase inhibitor for symptomatic treatment of cognition and global functioning. As discussed below, the degree of expected benefit is modest, and therapy should not be continued indefinitely in patients who do not appear to be benefiting or who have significant side effects. There is no convincing evidence that cholinesterase inhibitors are neuroprotective or have the ability to alter the underlying disease trajectory. (See "Cholinesterase inhibitors in the treatment of dementia", section on 'Duration of therapy'.)

Cholinesterase inhibitors have been studied in patients with varying severities of dementia. Although eligibility criteria are not uniform across all trials and cutoffs are variably defined, dementia severity can generally be categorized by Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA), or Clinical Dementia Rating (CDR) scores (table 1) as follows:

●Mild cognitive impairment – MMSE >23; CDR 0.5; objective or caregiver-reported evidence of cognitive decline but no loss of instrumental activities of daily living (ADLs)

●Mild dementia – MMSE 19 to 26; MoCA 12 to 16; CDR 1; impairment in one or more instrumental ADLs only

●Moderate dementia – MMSE 10 to 18; MoCA 4 to 11; CDR 2; impairment in one or more ADLs

●Severe dementia – MMSE <10; MoCA <4; CDR 3; impairment in most ADLs

Mild cognitive impairment — There is no evidence for the use of cholinesterase inhibitors in patients with mild cognitive impairment. However, some clinicians may offer these after a risk-benefit discussion with patients. (See "Mild cognitive impairment: Prognosis and treatment", section on 'Acetylcholinesterase inhibitors'.)

Mild to moderate dementia — For patients with newly diagnosed mild to moderate AD dementia, we suggest a trial of a cholinesterase inhibitor. The choice of agent, dosing, administration, and side effects are described separately (table 2). (See "Cholinesterase inhibitors in the treatment of dementia".)

The average benefit of cholinesterase inhibitors in patients with mild to moderate dementia (eg, MMSE score 10 to 26; MoCA score 4 to 16; CDR score 1 or 2) is a small improvement in cognition, neuropsychiatric symptoms, and ADLs [2-9].

The degree of benefit is summarized by a meta-analysis of 13 randomized trials of donepezil, galantamine, or rivastigmine versus placebo in more than 3000 patients with AD (mostly mild to moderate disease severity) [7]. When assessed at 6 to 12 months, cholinesterase inhibitors led to modest improvements on the 70-point Alzheimer Disease Assessment Scale-Cognitive Subscale (ADAS-Cog; mean difference 2.7 points, 95% CI 2.3-3.0) and MMSE (mean difference 1.37 points, 95% CI 1.13-1.61) as well as global impression by caregivers and ADLs. One analysis estimated that these effects would be similar to preventing a two-months-per-year decline in a typical patient with AD [2]; another concluded that for every 12 patients treated, one would benefit by achieving minimal improvement or better and one would develop a treatment-related adverse effect [10].

Whether these drugs significantly improve long-term outcomes, such as the need for nursing home admission or maintaining critical ADLs, remains in doubt, and the evidence is conflicting [2,11-15]. The AD2000 study, one of few nonindustry-sponsored trials of a cholinesterase inhibitor versus placebo with long-term follow-up, found no significant benefit of donepezil compared with placebo for the two primary endpoints: entry to institutional care and progression of disability [11].

Additional evidence suggests that the response to cholinesterase inhibitors may be quite variable, with as much as 30 to 50 percent of patients showing no observable benefit [16,17], while a smaller proportion (up to 20 percent) may show a greater-than-average response (≥7 point ADAS-Cog improvement) [18,19]. These findings reinforce the importance of making individualized decisions for each patient based on clinical response and side effects. (See "Cholinesterase inhibitors in the treatment of dementia", section on 'Approach to common side effects'.)

Advanced disease — The relative effects of cholinesterase inhibitors appear to be similar for patients with more severe dementia (eg, MMSE score <10; MoCA score <4; CDR score 3) at the time of diagnosis, but fewer studies have been performed and the absolute effects may be less clinically important than those seen in patients with mild to moderate dementia. The choice of agent, dosing, administration, and side effects are described separately (table 2). (See "Cholinesterase inhibitors in the treatment of dementia".)

As in earlier-stage disease, small benefits on some but not all cognitive and functional outcomes have been noted in short-term trials of either donepezil or galantamine in previously untreated community-dwelling adults and nursing home residents with moderate to advanced dementia [20-24].

Decisions on long-term use depend on the patient's functional response to treatment and long-term goals of care and should be made in consultation with caregivers and family [25]. (See "Cholinesterase inhibitors in the treatment of dementia", section on 'Follow-up and monitoring'.)

Mixed dementia — Cholinesterase inhibitors have been less well studied in mixed dementia. However, because of demonstrated efficacy in patients with vascular dementia (VaD) and dementia with Lewy bodies (DLB), it is reasonable to use these agents in patients with AD plus VaD and in patients with AD plus DLB. (See "Treatment of vascular cognitive impairment and dementia", section on 'Cholinesterase inhibitors' and "Prognosis and treatment of dementia with Lewy bodies", section on 'Cholinesterase inhibitors'.)

MEMANTINE — 

Memantine is an N-methyl-D-aspartate (NMDA) receptor antagonist. The mechanism of action of memantine is distinct from those of the cholinergic agents; it is proposed to be neuroprotective. Glutamate is the principal excitatory amino acid neurotransmitter in cortical and hippocampal neurons [26]. One of the receptors activated by glutamate is the NMDA receptor, which is involved in learning and memory [27]. Excessive NMDA stimulation can be induced by ischemia and lead to excitotoxicity, suggesting that agents that block pathologic stimulation of NMDA receptors may protect against further damage in patients with vascular dementia (VaD) [28]. In addition, the physiologic function of the remaining neurons could be restored, resulting in symptomatic improvement [29].

Memantine does not appear to have significant side effects. A 2008 systemic review concluded that memantine has been shown to improve cognition and global assessment of dementia, but with small effects that are not of clear clinical significance; improvements in quality of life and other domains are suggested but not proven [3]. As a result, treatment decisions should be individualized and include consideration of drug tolerability and cost [25].

Moderate to severe Alzheimer disease — We suggest the use of memantine in combination with a cholinesterase inhibitor in patients with advanced AD. A combination capsule of donepezil-memantine is available in different strengths.

Memantine appears to have modest benefits in patients with moderate to severe AD:

●A 28-week randomized trial in 252 patients with AD with Mini-Mental State Examination (MMSE) scores of 3 to 14 (mean approximately 8) at study entry found that memantine significantly reduced deterioration on multiple scales of clinical efficacy [30]. Adverse event rates with memantine were similar to placebo, and more patients taking placebo than memantine discontinued the study medication. An open-label extension to this study demonstrated benefits for patients previously taking placebo in all efficacy measures relative to their previous rate of decline and also confirmed the favorable adverse event profile seen in the double-blind study [31].

●A clinical trial of 295 patients with moderate to severe AD who were already taking donepezil compared the efficacy of four treatment strategies: no therapy (donepezil discontinued), donepezil continued alone, donepezil continued with memantine added, and memantine therapy alone [14]. After one year, patients assigned to receive memantine therapy had a higher score on the standardized MMSE and a lower score on the Bristol Activities of Daily Living Scale (both implying benefit) compared with those not receiving memantine; however, the average differences in scores (1.2 and 1.5 points, respectively) did not meet the prespecified threshold considered to be clinically important. The trial was stopped early due to slow recruitment. With long-term follow-up, memantine had no effect on the rate of nursing home placement over a four-year period after randomization [15].

The combination of memantine and a cholinesterase inhibitor leads to modest improvements in cognition and global outcomes in patients with advanced disease [32]. The largest trials demonstrating the efficacy of combination therapy include the following:

●A 24-week trial studied the effects of either memantine or placebo in addition to donepezil in 322 patients with moderate to severe AD [33]. MMSE scores ranged from 5 to 14 (mean approximately 10) at study entry. Treatment with memantine plus donepezil resulted in significantly better outcomes than placebo plus donepezil on measures of cognition, activities of daily living (ADLs), global outcome, and behavior. Significantly more patients taking placebo than memantine discontinued the trial, and the rate of discontinuation due to adverse events was lower in the memantine-treated group than in the placebo group.

●A second 24-week randomized trial compared memantine with placebo in 433 patients with mild to moderate AD who were on stable doses of a cholinesterase inhibitor (either donepezil, rivastigmine, or galantamine) [34]. There was no difference in outcome measures between the treatment groups.

●A clinical trial of 295 patients with moderate to severe AD who were already taking donepezil compared the efficacy at one year of four treatment strategies: no therapy (donepezil discontinued), donepezil continued alone, donepezil continued with memantine added, and memantine therapy alone, as discussed above [14]. No significant benefits of the combination of donepezil-memantine over donepezil alone were noted; however, this study was stopped early due to slow recruitment.

Other patient groups

●Mild Alzheimer disease – There is little, if any, evidence that patients with milder AD benefit from memantine. A systematic review reported the results of pooled data from three unpublished studies of memantine in mild to moderate AD [35]. Intention-to-treat analysis indicated a very small but statistically significant beneficial effect for memantine at six months on cognition (<1 point on the 70-point Alzheimer Disease Assessment Scale-Cognitive Subscale [ADAS-Cog]) but no effect on behavior or ADLs. Another study analyzed data on 431 patients with mild AD (MMSE score 20 to 23) from three trials and found no substantial benefit with memantine [36]. No benefit was seen in patients assigned to memantine in the Department of Veterans Affairs (VA) Cooperative Studies Program discussed below [37]. (See 'Antioxidants' below.)

●Vascular or mixed dementia – Memantine has shown some evidence of efficacy in patients with VaD. (See "Treatment of vascular cognitive impairment and dementia".)

●Down syndrome – The prevalence of AD in older patients (>40 years) with Down syndrome is very high, suggesting that treatments effective in the general population with AD might be of benefit in these patients as well. (See "Down syndrome: Clinical features and diagnosis", section on 'Dementia/Alzheimer disease'.)

However, we do not advise use of memantine in patients with Down syndrome. A randomized trial of memantine in 173 patients >40 years of age with Down syndrome found no benefit to memantine therapy after 52 weeks on treatment [38]. A low baseline prevalence of dementia (35 percent) at onset of treatment may have contributed to the negative results.

Dosing — Memantine is initiated at 5 mg once daily; the dose can be increased by 5 mg weekly to a maximum tolerated dose of 20 mg per day, usually in two divided doses. An extended-release form for once-daily administration is available.

When medication is discontinued, a tapering schedule with a similar timeline should be followed.

Adverse effects — Memantine appears to have fewer side effects than the cholinergic agents [35]:

●Dizziness is the most common side effect associated with memantine.

●Confusion and hallucinations are reported to occur at a low frequency, but we have noticed that memantine use seems to increase agitation and delusional behaviors in some patients with AD. Others have reported that worsening of delusions and hallucinations is particularly problematic in patients who have dementia with Lewy bodies (DLB) [39].

AMYLOID-TARGETED THERAPIES — 

Amyloid-targeted therapies refer to recombinant monoclonal antibodies directed against amyloid beta. These agents are highly effective in reducing amyloid plaque burden on positron emission tomography (PET) imaging and are therefore believed to be disease modifying; this contrasts them with cholinesterase inhibitors and memantine, which are symptomatic treatments. However, the efficacy in regard to clinical outcomes is modest, and there are risks for adverse effects.

Two amyloid-targeted therapies have been approved and are available in the United States: lecanemab and donanemab [40,41].

Individuals with early AD are eligible for amyloid-targeted therapy. Such patients are those who have:

●Mild cognitive impairment or mild dementia – Cognitive decline should be mild, and testing cutoffs such as Mini-Mental State Examination (MMSE) score ≥22, Montreal Cognitive Assessment (MoCA) score ≥17, or Clinical Dementia Rating (CDR) score 0.5 to 1 can be used. Formal neuropsychological testing can be considered for quantification of deficits and changes over time.

●Documented amyloid pathology – Clinicians should limit use of lecanemab and donanemab to those patients proven to be amyloid positive (by amyloid PET scan or the presence of AD biomarkers in the cerebrospinal fluid [CSF]), as was required in the clinical trials that evaluated these drugs. (See "Clinical features and diagnosis of Alzheimer disease", section on 'Neuroimaging' and "Clinical features and diagnosis of Alzheimer disease", section on 'Role of biomarkers'.)

We offer amyloid-targeted treatment to eligible patients without contraindications to therapy (table 3). The choice to initiate treatment with lecanemab or donanemab will be an individual one, based on discussions with patients and caregivers that include both what is known and what is uncertain in regard to benefits, risks, burdens, and costs of therapy.

The use of these therapies is discussed in detail separately. (See "Amyloid-targeted therapies for the treatment of Alzheimer disease".)

ANTIOXIDANTS — 

Vitamin E (alpha-tocopherol) and selegiline (a monoamine oxidase inhibitor) have been studied in AD because of their antioxidant properties, and results from randomized trials have been mixed [42]. Overall, the available data suggest that vitamin E at a dose of 2000 international units per day confers a modest benefit in delaying functional progression in patients with mild to moderate AD, with no measurable effect on cognitive performance. We see no advantage for the use of selegiline, which has more side effects and is more costly. (See 'Selegiline' below.)

We feel that vitamin E (1000 international units twice daily) is a reasonable intervention in patients with mild to moderate AD. Although the available data allow only limited confidence that vitamin E is an effective therapy for AD, this is balanced by the excellent safety and tolerability profile of supplementation in randomized studies and the general lack of very effective therapies for patients with AD. The benefits of vitamin E are likely to be modest.

A few randomized trials have examined the effects of vitamin E in patients with AD [42]:

●In the Alzheimer Disease Cooperative Study (ADCS) trial, there was a delayed progression to a composite outcome of death, institutionalization, or progression to severe dementia for patients treated with vitamin E compared with placebo (440 versus 670 days) after statistical adjustment because the placebo group had higher Mini-Mental State Examination (MMSE) scores at baseline [43].

●The Department of Veterans Affairs (VA) Cooperative Studies Program studied 613 (mostly male) patients with mild to moderate AD [37]. After a mean follow-up of two years, patients treated with vitamin E experienced 3.15 units smaller decline in the ADCS/Activities of Daily Living (ADCS-ADL) Inventory compared with those taking placebo (95% CI 0.92-5.39).

However, high-dose vitamin E supplementation has been inconsistently associated with an increase in all-cause mortality and also with heart failure in patients with cardiovascular disease [44]. Such concerns have not been validated in the AD population, however; in the VA study described above, patients assigned to 2000 international units of vitamin E daily had a trend towards lower annual mortality compared with patients assigned to memantine, the combination, or placebo [37]. (See "Vitamin intake and disease prevention", section on 'All-cause mortality'.)

We do not recommend vitamin E for the routine prevention of AD or for the treatment or prevention of other types of dementia. (See "Prevention of dementia", section on 'Antioxidant vitamins'.)

VASCULAR RISK FACTOR MANAGEMENT — 

Identification and treatment of risk factors for stroke, cardiovascular disease, and dementia may represent an important strategy for slowing the progression of cognitive decline [45]. An observational study compared the progression of Mini-Mental State Examination (MMSE) scores in 301 patients with AD (without cerebrovascular disease history) [46]. Patients whose vascular risk factors were treated had a slower decline in MMSE scores compared with those whose vascular risk factors were not treated. Patients with some but not all of their vascular risk factors treated had an intermediate rate of decline.

However, data are not entirely consistent, and there are potential harms to overly aggressive risk factor management [47]. As an example, one study in 172 patients with dementia or mild cognitive impairment found that MMSE scores declined fastest in patients being treated with antihypertensive drugs who had the lowest tertile of daytime systolic blood pressures (≤128 mmHg) [48]. Orthostatic hypotension associated with overly aggressive blood pressure management is also of concern.

In addition, strong support from randomized controlled clinical trials of vascular risk factor treatment in patients with dementia is lacking. A randomized study of patients with AD found that after two years, progression of white matter lesions on magnetic resonance imaging (MRI) was less in those who were assigned to aggressive risk factor reduction, but clinical progression was not assessed [49].

While a pilot clinical trial demonstrated trends toward benefit for atorvastatin in a 63-patient trial of mild to moderate AD [50], a randomized controlled trial of simvastatin (40 mg per day for 18 months) in 406 patients with mild to moderate AD found no evidence of benefit of therapy on the progression of AD symptoms [51]. Similarly, a randomized clinical trial of 640 patients with mild to moderate AD found that 80 mg of atorvastatin per day did not influence cognitive endpoints after 72 weeks of treatment [52].

These topics as they relate to the incidence and prevention of dementia are discussed separately. (See "Risk factors for cognitive decline and dementia" and "Prevention of dementia".)

NEUROPSYCHIATRIC SYMPTOMS — 

Behavioral disturbances can profoundly affect patients with dementia as well as their families and caregivers. Recognition and treatment of delusions, hallucinations, depression, agitation, aggression, and sleep disturbances are important aspects of the care of patients with dementia. This topic is discussed separately. (See "Management of neuropsychiatric symptoms of dementia" and "Sleep-wake disturbances and sleep disorders in patients with dementia".)

EXACERBATING FACTORS — 

Medication lists and other aspects of the patient's history should be periodically reviewed for substances that can exacerbate dementia. In general, problematic substances should be eliminated where possible or lowered in dose. Such substances can include:

●Prescribed medications – Adverse effects of prescribed medications can contribute to cognitive impairment and exacerbate dementia. Drugs of particular concern in adults with dementia include anticholinergic drugs (table 4), benzodiazepines, opioids, and antipsychotic drugs. (See "Management of the patient with dementia", section on 'Avoiding adverse drug effects'.)

●Alcohol – Alcohol can exacerbate cognitive dysfunction and behavioral disturbance in patients with dementia. (See "Management of the patient with dementia", section on 'Alcohol use'.)

Sleep deprivation and social isolation are also believed to exacerbate cognitive disturbance in patients with dementia.

NONPHARMACOLOGIC THERAPY AND SUPPORTIVE CARE — 

The roles of nutrition, cognitive rehabilitation, exercise programs, and occupational therapy in the management of patients with dementia are discussed separately. (See "Management of the patient with dementia".)

THERAPIES WITH UNPROVEN BENEFIT — 

A variety of additional therapies have been explored in patients with dementia, with largely negative results.

Selegiline — We do not use selegiline in patients with AD, as the evidence of efficacy is quite limited.

The ADCS trial compared vitamin E, selegiline, the combination, and placebo and is discussed above [43]. There was a delayed progression to outcome for patients treated with selegiline compared with placebo (655 versus 670 days) after statistical adjustment because the placebo group had higher Mini-Mental State Examination (MMSE) scores at baseline. Performance on cognitive tests (including the MMSE and the Alzheimer Disease Assessment Scale-Cognitive Subscale [ADAS-Cog]) was similar between the groups.

In addition to the ADCS trial, a number of smaller studies have also investigated the use of selegiline, with varying results. A meta-analysis of 12 trials found that eight of the studies suggested some beneficial effect of selegiline in the treatment of cognitive benefits and, in three trials, in the treatment of behavior and mood [53]. Analysis of three studies with a longer-than-one-year follow-up reported significant delays in time to the primary outcome (death, institutionalization, loss of ability to perform activities of daily living [ADLs], or severe dementia) [43,54,55]. However, the magnitude of the benefits in the meta-analysis was small and largely dependent on the ADCS study [43]. Thus, the clinical importance for the population at large is unclear.

Estrogen replacement — There is no evidence that initiating estrogen replacement is beneficial in the treatment or prevention of dementia.

Studies of estrogen and AD in postmenopausal females have focused on two areas: the role of estrogen in preventing the development of dementia and the potential efficacy of estrogen in the treatment of dementia. These investigations are based upon a large body of preclinical evidence that estrogen enhances cerebral blood flow, prevents atrophy of cholinergic neurons, reduces oxidative stress, and modulates the effects of nerve growth factors [56,57]. However, large randomized trials have now shown that the use of hormone replacement therapy (HRT) with estrogen plus progestin or estrogen alone in females aged 65 and older who are free from dementia may increase the risk of developing dementia [58-60]. (See "Estrogen and cognitive function", section on 'Estrogen and dementia'.)

The majority of studies of estrogen therapy for the treatment of AD have been uncontrolled, unblinded, and of short duration [61]. Three randomized controlled trials of estrogen therapy for treatment of AD involving 42, 50, and 120 females had similar results: Treatment with estrogen at varying doses and for a varying duration of time did not improve cognitive or functional outcomes compared with placebo [62-64]. A fourth trial reported different results: In 20 postmenopausal females with AD who were treated with a relatively high dose of 17-beta estradiol by skin patch (0.1 mg/day) or placebo, active treatment was associated with significant improvement in verbal memory, visual memory, and attention [65].

A meta-analysis found that females who had menopause symptoms had improvements in verbal memory, vigilance, reasoning, and motor speed with estrogen replacement, but no enhancement of other cognitive functions [66]. No benefits were observed in asymptomatic females. (See "Estrogen and cognitive function".)

Estrogen does not appear to enhance the effects of cholinesterase inhibitors in patients with AD. A study of 117 females that looked at adding HRT (transdermal estradiol and oral progesterone) to treatment with rivastigmine found no additional benefit in the females randomized to receive HRT [67].

In summary, we see no current evidence for initiating HRT in patients with established dementia, and, given the data on HRT for primary prevention of dementia, HRT may actually be harmful. (See "Estrogen and cognitive function".)

Antiinflammatory drugs — A role for the use of antiinflammatory drugs in the treatment and prevention of AD continues to be investigated, based on extensive evidence of inflammation in the brain as well as the periphery. Pathophysiologic studies have demonstrated an amyloid-induced inflammatory reaction with microglial activation and cytokine release [68,69]. In addition, some epidemiologic studies have suggested that use of nonsteroidal antiinflammatory drugs (NSAIDs; and other antiinflammatory medications) is associated with a reduced odds ratio for developing AD [70,71]. (See "Prevention of dementia", section on 'NSAID therapy'.)

However, clinical trials do not support this treatment: Except for one small clinical trial of indomethacin [72], randomized trials of antiinflammatory medications including naproxen, hydroxychloroquine, diclofenac, rofecoxib, and aspirin have not found a benefit for these agents in slowing cognitive decline in patients with AD [73-78]. In addition, adverse events have been more common in treated patients compared with controls.

In particular, long-term use of the cyclooxygenase 2 (COX-2) inhibitor rofecoxib has been associated with an increased risk of cardiovascular events, and this problem may be a drug class effect of COX-2 inhibitors. In addition, a placebo-controlled AD prevention trial comparing celecoxib with naproxen was suspended in December 2004; the suspension was due to the finding of an increased rate of cardiovascular events in patients receiving celecoxib in an unrelated colonic polyp prevention trial; however, it was announced that subjects receiving naproxen sodium had an increased rate of cardiovascular events. These issues are discussed in detail elsewhere. (See "NSAIDs: Adverse cardiovascular effects".)

Ginkgo biloba — A systematic review of ginkgo for cognitive impairment and dementia concluded that ginkgo biloba, while safe, has inconsistent and unconvincing evidence of benefit [79]. There have not been subsequent studies that alter this conclusion. We do not advocate use of ginkgo because of questionable efficacy and lack of regulation, including variability in the dosing and contents of herbal extracts [80]. The studies evaluating ginkgo biloba for the prevention and treatment of dementia are discussed separately. (See "Clinical use of ginkgo biloba", section on 'Treatment' and "Prevention of dementia".)

Dietary supplements

●Vitamin B – Supplementation with B vitamins, in particular those that are involved in homocysteine metabolism, have been studied in patients with AD in hopes that they may demonstrate efficacy in preventing or slowing the progression of AD. An 18-month randomized trial of high-dose vitamin B-complex supplementation (folate, B6, B12) in 340 patients with mild to moderate AD found no beneficial effect on cognitive measures [81].

A discussion of the rationale and clinical utility of vitamin B-complex supplementation in the prevention of AD is discussed separately. (See "Prevention of dementia", section on 'Vitamins B6, B12, and folate'.)

●Omega-3 fatty acids – Observational studies have suggested a possible association between dietary intake of fish and omega-3 fatty acids and a lower risk of dementia. (See "Prevention of dementia".)

However, clinical trials have not supported a therapeutic role for omega-3 fatty acid supplementation in the treatment of AD [82,83].

SAFETY AND SOCIETAL ISSUES — 

Safety issues in patients with dementia, including driving, financial capacity, wandering, and living alone, are discussed separately. (See "Management of the patient with dementia".)

ADVANCED DEMENTIA — 

In the terminal stages of dementia, patients and their caregivers are faced with a range of physical and psychosocial needs, and effective palliative care can improve patients' symptoms, lessen caregiver burden, and help ensure that treatment decisions are well informed and weighed in the context of patient and family goals and needs. Aspects of palliative care that are specific to patients with advanced dementia are discussed separately. (See "Care of patients with advanced dementia".)

SOCIETY GUIDELINE LINKS — 

Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Cognitive impairment and dementia".)

INFORMATION FOR PATIENTS — 

UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topics (see "Patient education: Dementia (including Alzheimer disease) (The Basics)")

●Beyond the Basics topics (see "Patient education: Dementia (including Alzheimer disease) (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

●Cholinesterase inhibitors – For patients with newly diagnosed Alzheimer disease (AD) dementia, we suggest a trial of a cholinesterase inhibitor (Grade 2A).

Patients with dementia of mild to moderate severity (eg, Mini-Mental State Examination [MMSE] score 10 to 26) may be the most likely to derive clinical benefit, which is typically modest and must be balanced with the risk of adverse effects. Decisions should be individualized in patients with very advanced dementia (eg, MMSE score <5) at the time of diagnosis.

The choice among donepezil, galantamine, and rivastigmine can be based upon ease of use, individual patient tolerance, cost, and clinician and patient preference, as efficacy appears to be similar. Formulations and dosing are provided in the table (table 2). (See 'Cholinesterase inhibitors' above.)

●Memantine – In patients with moderate to advanced dementia (eg, MMSE score ≤18), we suggest adding memantine (10 mg twice daily) to a cholinesterase inhibitor or using memantine alone in patients who do not tolerate or benefit from a cholinesterase inhibitor (Grade 2B). (See 'Memantine' above.)

In patients with severe dementia (MMSE score <10), we suggest continuing memantine, given the possibility that memantine may be disease modifying (Grade 2C). However, in some patients with advanced dementia, it may make sense to discontinue administration of medications to maximize quality of life and patient comfort. (See 'Memantine' above.)

●Amyloid-targeted therapies – We offer treatment with amyloid-targeted therapies to patients with AD who have mild dementia or mild cognitive impairment and who meet selection criteria and have no contraindications (table 3).

A decision to initiate an amyloid-targeted medication is based on an individual patient's values and preferences and requires shared decision-making, with a discussion of potential benefits and harms as well as the requirements for drug administration and safety monitoring. (See "Amyloid-targeted therapies for the treatment of Alzheimer disease".)

●Vitamin E – It is reasonable to offer treatment with vitamin E (1000 international units twice daily) to patients with mild to moderate AD after discussing risks and benefits. Experts do not consistently use vitamin E in patients with AD. Vitamin E may provide a benefit in regard to slowing progression of disease; however, the benefit is likely to be small, and some studies suggest that there are risks in patients with cardiovascular disease. (See 'Antioxidants' above.)

●Behavioral disturbances – Behavioral disturbances are common in individuals with dementia and may respond to symptomatic treatment. (See "Management of neuropsychiatric symptoms of dementia".)

ACKNOWLEDGMENT — 

The UpToDate editorial staff acknowledges Michael Alexander, MD, who contributed to earlier versions of this topic review.