Management Guidelines for Alzheimer’s Disease and Related Dementia

Table of Contents

1. Clinical Management Guidelines Alzheimer’s Disease, Lewy Body Dementia,   Vascular/Mixed Dementia, and Frontotemporal Dementia

a. Healthy Lifestyle

b. Risk Factor Management

c. Medication Strategies

             i.  Acetylcholinesterase Inhibitors (ACHEIs) Initiation and Management             ii.  Memantine Initiation and Management

II.  Targeted Management of Common Symptoms of Dementia

a. Depression and Anxiety

b. Neuropsychiatric/Behavioral Symptoms

c. Sleep Disturbances

III. Disease Specific Symptoms

a. Lewy Body Dementia

i.                 Motor Symptoms/Parkinsonism  

ii.  Autonomic Dysfunction  

 iii.  REM Behavior Disorder

iv. Neuropsychiatric Features (delusions, hallucinations, paranoia, agitation)

v. Medication Sensitivity & Acute Metabolic/Infectious Events

b. Frontotemporal Dementia

i.                 Behavioral changes (disinhibition, impulsivity, food behaviors, withdrawal/apathy)  

ii.  Neuropsychiatric Features (delusions, hallucinations, paranoia)  

 iii.  Language Deficits

       iv.  Motor symptoms (specifically in Corticobasal Degeneration (CBD) and

             Progressive Supranuclear Palsy (PSP)

IV.   Tables and Figures

V. References

Clinical Management Guidelines

Alzheimer’s Disease, Lewy Body Dementia,

Vascular/Mixed Dementia, and Frontotemporal Dementia

Healthy Lifestyle

• Regular physical exercise
  
• Cognitive leisure activities
  
• Socialization
  
• Mediterranean diet: https://www.mayoclinic.org/diseases-conditions/alzheimers-disease/expert         answers/alzheimers-disease/faq-20058062
  
• MIND Diet: https://www.mayoclinic.org/healthy-lifestyle/nutrition-and-healthy-eating/in                     depth/improve-brain-health-with-the-mind-diet/art-20454746
  
• Encourage smoking cessation
  
• ETOH limitation
  
• Adequate sleep
  
• Stress and anxiety reduction

Risk Factor Management

• BP lowering for hypertensive individuals.
  
• Avoid aggressive blood pressure lowering (can compromise cerebral perfusion).
  
• Management of hyperlipidemia (follow established norms).
  
• Diabetes management
  
• Follow established recommendations for glucose control to prevent complications, including             cognitive decline associated with diabetes.
  
• Use caution as hypoglycemia can also pose risk in the elderly.
  
• Follow established norms for primary stroke prevention or secondary stroke prevention (in those with history of stroke). 

Medication Strategies

• Eliminate any medications with potential negative cognitive impact and avoid polypharmacy   0   Avoid the following drugs in dementia or cognitive impairment due to adverse CNS effects             (as per Beers criteria).
  
• Anticholinergics
  
• Benzodiazepines
  
• Z drugs (for insomnia)
  
• Antipsychotics (associated with increased mortality risk in elderly dementia patients,                         mostly due to cardiovascular or infections events); avoid unless nonpharmacologic                              options have failed or there is concern for patient/caregiver safety.
  
• Avoid using antimuscarinic medications (atropine, scopolamine, glycopyrrolate,                        ipratropium bromide) in patients taking acetylcholinesterase inhibitors (ACHEIs).
  
• Start acetylcholinesterase inhibitor (***except in Frontotemporal Dementia, see below) (if no       contraindications, e.g. significant bradycardia, sick sinus syndrome/cardiac conduction defects,       gastrointestinal bleeding or ulcer, bladder obstruction, caution if seizure disorder, asthma or Chronic Obstructive Pulmonary Disease (COPD).
  **see algorithm for ACHEI initiation and management
  
• Memantine can be added for progression or prominent Alzheimer’s Disease symptoms (clinically indicated in middle to late stage disease, except in Frontotemporal Dementia, see below).          **see algorithm for Memantine initiation and management
  
  • Has also been shown to decrease neuropsychiatric features such as agitation and              disinhibition.
    ***Treatment of Frontotemporal Dementia should begin by defining relevant signs and symptoms that are impairing quality of life in order to develop an individualized therapeutic strategy with maximal chances for success.
    
  • Consider SSRIs as a first line therapy, especially in behavioral variant Frontotemporal Dementia.
    
  • If delusional consider treatment with an antipsychotic.
    
  • The use of acetylcholinesterase inhibitors and memantine are not supported by the data            and therefore should not be used in the treatment of Frontotemporal Dementia. The                     exception is where there is uncertainty about whether the patient has Frontotemporal                  Dementia or Alzeheimer’s Disease; in such cases, a therapeutic trial of a cholinesterase             inhibitor is reasonable.

                    **see algorithm for ACHEI & memantine initiation and management

Acetylcholinesterase Inhibitors (ACHEIs) Initiation and Management

Indications for Use

• Three acetylcholinesterase inhibitors (ACHEIs) (Donepezil (Aricept), Galantamine (Razadyne), and   Rivastigmine (Exelon) are FDA approved medications for the treatment of Alzheimer’s Disease .
  
• ACHEIs have also shown benefit in Vascular Dementia (because of the evidence of cholinergic           dysfunction in Vascular Dementia and high prevalence of comorbid Alzheimer’s Disease).
  
• ACHEIs have also shown benefit in Lewy Body Dementia (because of the marked decrease in            cholinergic functioning in Lewy Body Dementia patients). Rivastigmine also has a Parkinson’s Dementia FDA label.
  
  • ACHEIs may also have greater potential for improvement in Lewy Body Dementia than            Alzheimer’s Disease and treatments with ACHEIs may improve various neuropsychiatric                symptoms, especially in Lewy Body Dementia. 

Efficacy & Tolerability

• Efficacy: All three ACHEIs have demonstrated clinical benefits on cognitive function, global clinical   status, and performance of activities of daily living. There are no proven clinically meaningful              differences between the agents in terms of efficacy. Tolerability and efficacy are dose dependent.
  
• Tolerability: All three agents have similar tolerability profiles.
  
• Contraindications: Significant bradycardia, sick sinus syndrome/cardiac conduction defects,           gastrointestinal bleeding or ulcer, bladder obstruction; caution if seizure disorder, asthma or           Chronic Obstructive Pulmonary Disease (COPD).
  
• Most Common Side Effects: Nausea, vomiting and diarrhea, urinary incontinence, weight loss,         skin irritation (with Rivastigmine patch).
  
• Other Common Side Effects: Vivid dreams (particularly with Donepezil) and leg cramps. Anecdotally, Rivastigmine capsules appear to have the most problematic side effects.

Initiation and Management

• Diagnosis of Alzheimer’s Disease, Lewy Body Dementia, or Vascular Dementia: Start ACHEI (if no contraindications, e.g. significant bradycardia, sick sinus syndrome/cardiac conduction defects, gastrointestinal bleeding or ulcer, bladder obstruction, caution if seizure disorder, asthma or Chronic Obstructive Pulmonary Disease).
  
  • Begin with Donepezil (oral), Galantamine (oral), or Rivastigmine (oral or transdermal, *note         that oral Rivastigmine historically has the most severe gastrointestinal side effects).
    
• Choice dependent upon caregiver preference of modality (oral vs transdermal), ease   of use, tolerability based on past history, cost (dependent on insurance coverage—all generic but price varies greatly by plan).
  
• Typically Donepezil is preferred tier 1 on most plans.
  
  • Start with the lowest dose and titrate up to highest tolerated dose. (see attached table 1 for dosing titration instructions)
    
  • A 23 mg noncrushable tablet of Donepezil is available, but evidence does not support a             clinically important advantage to the higher dose, and it is associated with increased side        effects (particularly gastrointestinal side effects).
    
• Tolerability Issues
  
  • If gastrointestinal side effects, switch to Rivastigmine patch or alternate oral agent if cost is an issue with the patch.
    
  • With Donepezil, consider morning dosing in patients that have vivid dreams or new nighttime    behaviors/activation.
    
  • If rash with patch, switch to oral agent.
    
  • Use caution if prescribing oral Rivastigmine given high rate of gastrointestinal side effects.
    
  • If patient develops new urinary incontinence after initiation of ACHEI, consider changing dose    or weaning before prescribing Antimuscarinic.
    
• Ongoing Therapy
  
  • Continue ACHEI throughout disease course unless signs of intolerability emerge or at end       stage disease when patient has lost all meaningful function and is free of behavioral                    symptoms.
    
  • If behavioral symptoms emerge as disease progresses, consider weaning ACHEI before                 adding medication for behavioral symptoms because ACHEIs can be too activating in some              patients.

Memantine (Namenda) Initiation and Management

Initiation and Management 

• Diagnosis of Alzheimer’s Disease, Lewy Body Dementia, or Vascular Dementia: Memantine is  FDA approved for moderate to severe dementia. Consider initiation of Memantine with q progression to moderate stage disease OR if there are new neuropsychiatric features, consider the addition of Memantine.
  
  • Continue on ACHEI medication and add memantine.
    
  • Start Memantine at 5 mg qAM and titrate up to goal dose of 10 mg BID if on immediate              release form or start at 7 mg XR qday and titrate up to goal dose of 28 mg per day XR               formulation.
    
  • Use titration kit for first month or titrate up as follows:

• Immediate release: 5 mg daily x 1 week then 5 mg BID x 1 week then 5 mg qAM and 10 mg qpm x 1 week then 10 mg BID thereafter OR

• Extended Release: 7 mg XR daily x 1 week then 14 mg XR daily x 1 week then 21 mg XR daily x 1 week then 28 mg XR daily thereafter .
  
  • Common side effects: headache, dizziness, increased confusion, depression or agitation, somnolence, constipation, hallucinations.
    
• Ongoing therapy
  
  • Continue Memantine throughout disease course unless signs of intolerability emerge or at         end stage disease when patient has lost all meaningful function and is free of behavioral             symptoms.
    
  • If behavioral symptoms emerge as disease progresses, consider weaning Memantine before     adding medication for behavioral symptoms as it can cause agitation and behavioral                    symptoms in some patients.

Targeted Management of Common Symptoms of Dementia

Depression and Anxiety

• Patients with dementia may develop apathy, sleep impairment, and social withdrawal. These              symptoms may suggest the presence of depression but may also be a consequence of their       cognitive impairment. Patients may also become depressed in reaction to slipping mental capacity or as a direct biologic consequence of the underlying neuroligic disorder.
  
• Few studies guide selection of antidepressant medications in dementia but SSRIs are the preferred   starting point (avoid ricyclic antidepressants because of anticholinergic effects).
  
• Selection of a specific SSRI is generally based upon the side effect profile, drug interactions,           targeted symptoms, and cost. Note that there is an increased risk of hyponatremia in patients on SSRIs, specifically if combined with diuretics. Use with caution and check labs after starting therapy.
  
• Sertraline (Zoloft) and Escitalopram (Lexapro) or Citalopram (Celexa) (not to exceed 20 mg in older adults, caution re: QT prolongation risk) are commonly used. Fluoxetine (Prozac) can also be helpful if a more activating option is needed but use with caution because of long half life and multidrug        interactions. Duloxetine can be helpful if there is a coexisting pain component.
  
• Paroxetine (Paxil) (because of anticholinergic properties) is the LEAST desirable SSRI in dementia.
  
• The atypical antidepressants such as Venlafaxine (Effexor) and Bupropion (Wellbutrin) may also be   effective but have not been well studied in Alzheimer’s Disease. Both are beneficial if more               activation is needed but caution re: risk of elevated blood pressure with Venlafaxine. 

Neuropsychiatric/Behavioral Symptoms

(Delusions, Hallucinations, Paranoia, Agitation, Aggression, Apathy, Disinhibition)

• Neuropsychiatric symptoms are common in dementia but may be under-reported. Clinicians              should regularly inquire about delusions, hallucinations, paranoia, agitation, aggression,              apathy, and disinhibition at each visit.
  
• Identifying the genesis of the abnormal behavior is critical to effective management. Unmet            needs (food, water, etc.), a concomitant medical illness, uncontrolled pain, sleep disturbance,          medication toxicity, and other causes of delirium should be considered and ruled out whenever new behavioral disturbances arise. If no cause for delirium found, consider disease progression. 

• Treating underlying causes of behavioral symptoms and a focus on nonpharmacologic       interventions such as structured stimulating activities, exercise, sleep hygiene, reassurance,       and redirection (see Table 2 below) is ideal in this population. If psychotic symptoms are not          bothersome to the patient and are not placing others at risk, pharmacologic treatment is not       necessary.
  
• If pharmacologic intervention is indicated (due to failure of nonpharm strategies or behaviors having negative impact on quality of life or there is a risk to patient/caregiver safety), pharmacologic      interventions may be indicated:
  
  • Start with a cholinesterase inhibitor in patients who are not already on one due to some               evidence of efficacy in treating behavioral symptoms of dementia.
    
  • Memantine may also be considered in moderate to late stages (some studies show that            treatment with Memantine may reduce agitation/aggression, irritability, and other behavioral  disturbances); be mindful that it can also increase confusion and mood disturbance as well.
    
  • If patient is already on a cholinesterase inhibitor or Memantine, consider weaning off one or     both of these as they can be activating or cause behavioral symptoms in some instances           but monitor for cognitive decline.
    
• Selective serotonin reuptake inhibitors (SSRIs), have been shown to be useful in the manage         ment of agitation and paranoia in patients with Alzheimer’s Disease, as the symptoms are often        driven by a mood disorder that is poorly verbalized. *Note: avoid use of       Paroxetine (Paxil) due to its anticholin ergic properties.
  
• As an alternative, trazodone (starting dose 25 mg at bedtime, consider slow up titration) is well        tolerated and is often used for sleep onset and to treat behavioral symptoms in patients with             dementia. 

• Mood stabilizing drugs have also been used with mixed results and side effect concerns. Lamo        trigine (Lamictal) is the preferred first choice (be mindful of need for slow titration and risk of rash including Stevens-Johnson’s Syndrome).
  
  • Other options include: Divalproex Sodium (Depakote) and Carbamazepine (Tegretol) but             they have more worrisome side effect profiles.
    
• Atypical neuroleptics – may increase mortality and are not approved for the treatment of  behavioral disorders in patients with dementia by the FDA. They should not be used routinely to treat neuro psychiatric symptoms of dementia. However, their benefits often still outweigh their risks in patients with dementia when treatment of psychotic symptoms including hallucinations, paranoia, and delusions is critical to patient and caregiver safety, wellbeing, and quality of life.  *Inform the patients and families of the potential risks, including increased mortality.
  
  • Quetiapine (Seroquel) – tends to have least amount of parkinsonian and cognitive side              effects and can be titrated up from 25 mg with large dosing range. It is the weakest of the          antipsychotics so higher doses may be needed to manage more severe psychotic symptoms     or patient may need to be switched to another antipsychotic (Risperidone or Olanzapine).           Quetiapine can cause increased sedation but should never be used solely to help with sleep.
    
  • Risperidone (Risperdal) and Olanzapine (Zyprexa) have also been used but caution due to     risk of extrapyramidal symptoms and metabolic side effects (e.g., weight gain, diabetes,            and hypercholesterolemia). Start with low doses and slowly titrate up until symptoms                   are managed.
    
  • Pimavanserin (Nuplazid) is a newer alternative antipsychotic agent with some limited evi           dence of efficacy in this setting; it is typically started at 34 mg daily. Cost/insurance coverage   may be a barrier.

  Sleep Disturbances

• Sleep disturbances and disorders are important to recognize and treat in patients with dementia, as they are a major contributor to caregiver distress and are associated with an increased                   likelihood of institutionalization.
  
• Multiple contributing factors — age- and dementia-related changes in sleep and circadian                 rhythms, primary sleep disorders, institutional and environmental factors, and comorbid illnesses      and medications.
  
• The best way to detect and diagnose sleep-wake disturbances in patients with dementia is to          routinely ask about them. Caregiver or bed partner interview is crucial. Presenting sleep                  symptoms include: