INTRODUCTION — Alzheimer disease (AD) is a neurodegenerative disorder of uncertain cause and pathogenesis 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 exceptions. While treatments are available that can ameliorate some symptoms of the illness, there is no cure currently available, and the disease inevitably progresses in all patients.
This topic discusses the treatment of AD. Other aspects of AD are discussed separately:
●(See "Genetics of Alzheimer disease".)
PATIENT 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 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 when there is a strong family history.
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 dementia – MMSE 19 to 26; MoCA 12 to 16; CDR 1
●Moderate dementia – MMSE 10 to 18; MoCA 4 to 11; CDR 2
●Severe dementia – MMSE <10; MoCA <4; CDR 3
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 10 to 26; MoCA 4 to 16; CDR 1 or 2) is a small improvement in cognition, neuropsychiatric symptoms, and activities of daily living (ADLs) [1-8].
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) . 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 ; 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 .
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 [1,10-14]. 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 .
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 [15,16], while a smaller proportion (up to 20 percent) may show a greater than average response (≥7 point ADAS-Cog improvement) [17,18]. These findings reinforce the importance of making individualized decisions for each patient based on clinical response and side effects.
Advanced disease — The relative effects of cholinesterase inhibitors appear to be similar for patients with more severe dementia (eg, MMSE <10; MoCA <4; CDR 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.
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 [19-23].
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 . (See "Cholinesterase inhibitors in the treatment of dementia", section on 'Follow-up and monitoring'.)
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 . One of the receptors activated by glutamate is the NMDA receptor, which is involved in learning and memory . 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) . In addition, the physiologic function of the remaining neurons could be restored, resulting in symptomatic improvement .
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; improvement in quality of life and other domains are suggested but not proven . As a result, treatment decisions should be individualized and include considerations of drug tolerability and cost .
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 in two different strengths is available.
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 . 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 .
●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 . 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 .
The combination of memantine and a cholinesterase inhibitor leads to modest improvements in cognition and global outcomes in patients with advanced disease . 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 . 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) . 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 . 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 AD – 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 . 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 20 to 23) from three trials and found no substantial benefit with memantine . No benefit was seen in patients assigned to memantine in the Department of Veterans Affairs (VA) Cooperative Studies Program discussed below . (See 'Vitamin E' 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 in age with Down syndrome found no benefit to memantine therapy after 52 weeks on treatment . A low baseline prevalence of dementia (35 percent) at onset of treatment may have contributed to the negative results.
Dosing — Memantine is initiated 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 also appears to have fewer side effects than the cholinergic agents . 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) .
ADUCANUMAB — Aducanumab is a recombinant monoclonal antibody directed against amyloid beta. The US Food and Drug Administration (FDA) has approved aducanumab for the treatment of mild AD using the accelerated approval pathway, based on the positive clinical results of one of the two pivotal phase III trials (the results in the other were negative) and aducanumab's effect on a surrogate endpoint of reducing amyloid beta plaques in the brain .
The approval of this medication has led to significant controversy given that the FDA scientific advisory panel had previously recommended against approval of aducanumab, and since the surrogate endpoint of reducing amyloid beta plaques is not yet established as predicting clinical benefit [40-47]. Postapproval trials are required to verify the clinical benefit. As the first new therapy for AD since 2003, there is a great deal of excitement in the community, but this must be tempered by the lack of clarity in the clinical trials, the risk of adverse effects, and the monitoring requirements.
Patient selection — To date, aducanumab has been administered primarily in research settings. Its approval by the FDA was controversial, and it is likely that clinical practice will vary initially and evolve over time.
At present, there is uncertainty about whether patients with AD benefit clinically from aducanumab. Thus, we suggest against the routine use of aducanumab for patients with AD. However, some patients with mild AD and their physicians may reasonably choose treatment with aducanumab despite the unknown benefit and known risks of treatment . In accordance with proposed appropriate use criteria (table 3) , aducanumab should only be considered for selected patients with mild cognitive impairment (MCI) due to AD or mild AD itself. Patient selection is based upon neurologic and physical examination and dementia staging, which should be completed by an experienced clinician who performs cognitive testing along with appropriate laboratory testing and magnetic resonance imaging (MRI) of the brain.
●Mild cognitive impairment or mild dementia – Cognitive decline should be mild, and testing cutoffs such as Mini-Mental State Examination (MMSE) ≥21, Montreal Cognitive Assessment (MoCA) ≥17, or clinical dementia rating (CDR) 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 aducanumab to those patients proven to be amyloid positive (by amyloid positron emission tomography [PET] scan or lumbar puncture), as was required in the clinical trials that evaluated the drug. (See "Clinical features and diagnosis of Alzheimer disease", section on 'Neuroimaging' and "Clinical features and diagnosis of Alzheimer disease", section on 'Role of biomarkers'.)
●No contraindications – Patients with cognitive decline attributed to non-AD pathologies (eg, Lewy body disease, vascular dementia [VaD]) should not be offered aducanumab. At present, experts suggest against treating patients with AD in the setting of Down syndrome until more information is available .
Patients should not be offered aducanumab if they have a high risk of hemorrhagic side effects. Risk factors include hemorrhagic findings on brain MRI including >4 microhemorrhages, any areas of superficial siderosis, prior macrohemorrhage, and underlying brain lesion or vascular malformation. Other risk factors contraindicating treatment are anticoagulant or antiplatelet use (other than aspirin 81 mg daily), bleeding disorders, or any other condition leading to increased risk of central nervous system (CNS) hemorrhage.
Aducanumab should also not be offered to patients with unstable medical conditions, patients with unstable psychiatric conditions, or patients who are pregnant or breastfeeding.
As patients with an apolipoprotein E epsilon 4 (APOE ε4) allele have a greater risk of side effects, clinicians should also discuss with patients whether to check APOE allele status prior to initiating treatment (see 'Amyloid-related imaging abnormalities (ARIA)' below). For patients undergoing APOE genotyping, genetic counseling should be offered to patients and families prior to testing.
In addition, it remains uncertain as to whether public and private payers will cover this treatment. It is also uncertain as to whether studies to confirm the presence of amyloid by PET scan or lumbar puncture will be paid for as well.
Ultimately, the choice to initiate treatment with aducanumab will be an individual one, based on discussion with patients and caregivers that includes both what is known and what is uncertain in regard to benefits, risks, burdens, and costs of therapy.
Dosing and administration — Aducanumab is administered by intravenous (IV) infusion every four weeks, typically in an infusion center.
A recent (within one year) brain MRI study is required prior to initiating treatment; additional MRIs are required during dose escalation. (See 'Monitoring' below.)
●Doses 1 and 2 (weeks 0 and 4) – 1 mg/kg IV over one hour
●Doses 3 and 4 (weeks 8 and 16) – 3 mg/kg IV over one hour
A brain MRI is required prior to initiating a fifth dose. (See 'Monitoring' below.)
●Doses 5 and 6 (weeks 24 and 32) – 6 mg/kg IV over one hour
A brain MRI is required prior to initiating a seventh dose. (See 'Monitoring' below.)
●Dose 7 and beyond (week 36 and on) – 10 mg/kg IV over one hour
A brain MRI is required prior to initiating the twelfth dose (week 44). (See 'Monitoring' below.)
If a patient misses three or more doses and the patient and clinical team decide to reinitiate treatment, titration should be restarted at a dose one step lower than the previous dose administered.
There is no clear guidance regarding duration of treatment with aducanumab. We would not continue after the patient has progressed to moderate dementia. Future guidance may suggest that treatment be stopped once amyloid PET scan is read as negative.
Amyloid-related imaging abnormalities (ARIA)
Clinical and neuroimaging features — ARIA was reported in approximately 40 percent of patients treated with the highest dose of aducanumab in clinical trials . The risk of ARIA is greater in patients with an APOE ε4 allele. ARIA can occur at any time during treatment but is most common within the first eight doses and/or when dose escalation is occurring.
ARIA can take the form of edema (ARIA-E) and/or microhemorrhage (ARIA-H).
●ARIA-E is characterized by focal vasogenic edema with fluid-attenuated inversion recovery (FLAIR) hyperintensity; it is thought to have a similar pathophysiology to reversible posterior leukoencephalopathy syndrome (RPLS) . Most patients (70 percent) with ARIA-E are asymptomatic, but others have fatigue, headache, confusion, dizziness, falls, vision change, or nausea. ARIA-E is graded as mild, moderate, or severe (table 4).
In most patients (88 percent), ARIA-E resolves over time without long-term side effects; however, some patients experience a recurrence.
●ARIA-H usually manifests as microhemorrhage and/or superficial siderosis . Macrohemorrhage (hemorrhagic stroke) occurred very infrequently in the clinical trials. ARIA-H often, but not always, occurs concurrently with ARIA-E in the affected brain region. Microhemorrhage will continue to show up on follow-up MRI even after stability.
Monitoring — Treatment-related adverse effects (cerebral edema and/or hemorrhage) mandate ongoing monitoring (see 'Risks' below). The monitoring recommendations made here align with proposed appropriate use criteria that mimic the procedures used in the clinical trials; these are somewhat different from the FDA label prescribing instructions [49,50].
●Clinical assessments – During the titration phase, patients should be monitored for clinical symptoms suggestive of a treatment-related adverse effect (eg, headache, confusion, focal neurologic signs including vision disturbance). Serial monitoring with cognitive tests should be administered by the clinical team with each dose administration.
In addition, because the presenting symptoms of ARIA may be subtle, and because patients may not be able to report their own symptoms, we recommend that patients are monitored for clinical change by a designated family member or friend for the duration of aducanumab therapy. If this is not possible, remote cognitive assessments administered by the treatment team could alternatively be used to monitor cognitive status.
●MRI monitoring – A brain MRI is required prior to initiating therapy as well as prior to the fifth, seventh, and twelfth doses to assess for possible adverse effects, especially ARIA. This guidance is somewhat different from the FDA labeling but is recommended by experts and mirrors procedures used in the clinical trials .
In addition, a brain MRI should be performed for any symptoms suggestive of ARIA (eg, headache, confusion, focal neurologic signs).
Brain MRI sequences should include FLAIR, T2*, gradient echo (GRE) or susceptibility-weighted images (SWI), and diffusion-weighted images (DWI). All follow-up brain scans should occur on the same scanner with the same sequences to allow for comparability between the scans.
MRIs must be read by an experienced clinician familiar with the detection and reporting of ARIA. ARIA is assessed as mild, moderate, or severe (table 4).
Management — If a brain MRI shows ARIA, the patient should be evaluated clinically.
●Asymptomatic patients with mild MRI findings – Patients who are asymptomatic and who have mild MRI changes (table 4) may be able to continue aducanumab with close clinical monitoring and monthly MRI scans . However, the aducanumab dose should not be increased until ARIA-E resolves even if the patient is asymptomatic.
Efficacy — The efficacy of aducanumab has been evaluated in clinical trials . While a robust effect has been consistently demonstrated in regard to reduction in brain amyloid levels, observed benefits on clinical endpoints have been small and inconsistent and therefore uncertain .
In a dose-escalation phase 1b trial of aducanumab in 165 patients with prodromal or mild AD, substantial reduction of amyloid plaques was demonstrated on amyloid PET imaging in a dose- and time-dependent manner . After 12 months, almost half of patients no longer had positive amyloid PET imaging. However, only small and inconsistent clinical effects were observed on clinical rating scales.
Two subsequent placebo-controlled trials (EMERGE and ENGAGE) studied patients with MCI due to AD or very mild dementia due to AD (MMSE >24, CDR score of 0.5, and positive amyloid PET scan) . Both trials were stopped early after a planned futility analysis, which examined clinical outcomes. Following this decision, analyses were performed that included additional trial data collected subsequent to the termination decision. Both clinical trials observed a substantial reduction in brain amyloid levels as assessed by amyloid PET imaging; however, the FDA data analysis showed no association between reduction in brain amyloid levels and clinical outcomes .
In one of these trials (EMERGE; 1638 patients), patients treated with high-dose aducanumab had a smaller clinical decline from baseline compared with those treated with placebo, specifically a 22 percent relative reduction in the CDR Sum of Boxes score at week 78. The absolute difference of 0.39 is of uncertain clinical significance . Small but statistically significant benefits were also noted on three other prespecified secondary outcomes.
In the other trial (ENGAGE; 1647 patients), the CDR Sum of Boxes scores were not different between patient groups, and benefits were not seen on most secondary outcomes .
The full results of these studies have not been published in peer-reviewed form.
Risks — Adverse effects observed with aducanumab include ARIA, which were reported in approximately 40 percent of patients treated with the highest dose of aducanumab in clinical trials, and especially in APOE ε4 carriers . (See 'Amyloid-related imaging abnormalities (ARIA)' above.)
Hypersensitivity, including angioedema and urticaria, was reported in one patient in the clinical trials .
Headache, falls, diarrhea, and confusion were also modestly more frequent in aducanumab- versus placebo-treated patients . Except for diarrhea, these may reflect symptoms of ARIA.
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 . 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.
Vitamin E — 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 both studies and the general lack of very effective therapies for patients with AD. The benefits of vitamin E are likely to be modest.
●The Alzheimer Disease Cooperative Study (ADCS) trial compared vitamin E, selegiline, the combination, and placebo . The primary outcome in the study was the time to a combined endpoint of death, institutionalization, loss of the ability to perform activities of daily living (ADLs), or progression to severe dementia on a clinical dementia rating (CDR) scale.
There was a delayed progression to outcome 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 . Performance on cognitive tests (including the MMSE and the Alzheimer Disease Assessment Scale-Cognitive Subscale [ADAS-Cog]) was similar between the groups.
●The Department of Veterans Affairs (VA) Cooperative Studies Program compared vitamin E (2000 international units per day), memantine (20 mg per day), the combination, and placebo in 613 (mostly male) patients with mild to moderate AD .
After mean follow-up of two years, patients treated with vitamin E experienced 3.15 units smaller decline in the ADCS-ADL Inventory compared with those taking placebo (95% CI 0.92-5.39). There was no evidence of a difference between groups on the ADAS-Cog or MMSE.
●In a smaller clinical trial of antioxidant therapy in 78 patients with AD, 16 weeks of treatment with 800 international units per day of vitamin E (along with vitamin C and alpha-lipoic acid) was not associated with changes in cerebrospinal fluid biomarkers related to amyloid or tau pathology, but was associated with an accelerated deterioration in MMSE scores relative to either placebo or coenzyme Q-treated patients .
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 . 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 . (See "Vitamin intake and disease prevention", section on 'Mortality'.)
In summary, although both of the larger studies have issues limiting confidence in the conclusion that vitamin E is an effective therapy for AD, this is balanced by the excellent safety and tolerability profile of supplementation in both studies and the general lack of effective therapies for patients with AD. We therefore feel that vitamin E (2000 international units daily) is a reasonable intervention in patients with mild to moderate AD. The benefits of vitamin E are likely to be modest, however, and could be offset by combination therapy with memantine.
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'.)
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 . 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 MMSE scores at baseline. Performance on cognitive tests (including the MMSE and the 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 8 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 . 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 ADLs, or severe dementia) [59,63,64]. However, the magnitude of the benefits in the meta-analysis was small and largely dependent on the ADCS study . Thus, the clinical importance for the population at large is unclear.
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 . An observational study compared the progression of Mini-Mental State Examination (MMSE) scores in 301 patients with AD (without cerebrovascular disease history) . 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 . As an example, one study in 172 patients with dementia or mild cognitive impairment (MCI) 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) . 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 .
While a pilot clinical trial demonstrated trends toward benefit for atorvastatin in a 63-patient trial of mild to moderate AD , 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 . 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 .
BEHAVIORAL DISTURBANCE — 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".)
NONPHARMACOLOGIC THERAPY AND SUPPORTIVE CARE — The role of nutrition, cognitive rehabilitation, exercise programs, and occupational therapy in the management of patients with dementia is discussed separately. (See "Management of the patient with dementia".)
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".)
THERAPIES WITH UNPROVEN BENEFIT — A variety of additional therapies have been explored in patients with dementia with largely negative results.
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 . 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 [74-76]. (See "Estrogen and cognitive function", section on 'Estrogen and dementia'.)
Until recently, the majority of studies of estrogen therapy for the treatment of AD have been uncontrolled, unblinded, and of short duration . 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 [78-80]. 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 .
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 . 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 .
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. Pathophysiologic studies have demonstrated an amyloid-induced inflammatory reaction with microglial activation and cytokine release [84,85]. In addition, some epidemiologic studies have suggested that use of nonsteroidal antiinflammatory drugs (NSAIDs; and other antiinflammatory medications) are associated with a reduced odds ratio for developing AD [86,87]. (See "Prevention of dementia", section on 'NSAID therapy'.)
However, clinical trials do not support this treatment: Except for one small clinical trial of indomethacin , 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 [89-94]. 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 . 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 . 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", section on 'Ginkgo biloba'.)
●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 .
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 [98,99].
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 5th to 6th 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 10th to 12th 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] 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 <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 ≤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 <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.)
●Aducanumab – Aducanumab is approved by the US Food and Drug Administration (FDA) for the treatment of mild AD. While aducanumab appears highly effective in reducing brain amyloid levels, it is uncertain that patients benefit clinically from treatment. In addition, aducanumab has known risks that require close monitoring with clinical and imaging assessments. (See 'Efficacy' above and 'Risks' above.)
At present, we suggest against the routine use of aducanumab for patients with AD (Grade 2C). However, some patients with mild AD and their physicians may reasonably choose this treatment because of the potential (but uncertain) benefit and despite the known risks of treatment. Shared decision-making must include discussions regarding both what is known and what is uncertain in regard to benefits, risks, burdens, and costs of therapy. (See 'Patient selection' above.)
In addition, safety guidelines for administration and monitoring should be followed, and use of aducanumab should not extend beyond the population of patients that were studied in clinical trials. (See 'Dosing and administration' above and 'Monitoring' above and 'Patient selection' above.)
●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 'Vitamin E' 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 an earlier version of this topic review.
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