Alzheimer’s Disease

Introduction

Alzheimer’s disease (AD) is a progressive and eventually fatal dementia of unknown cause characterized by loss of cognitive and physical functioning, commonly with behavior symptoms.

• Dominantly inherited forms of AD are fewer than 1% of cases. More than half of young-onset, dominantly inherited cases are attributed to alterations on chromosomes 1, 14, or 21. Genetic susceptibility to late-onset AD is primarily linked to the apolipoprotein E (APOE) genotype, but an interaction of multiple genes with the environment may be at play.
• Risk factors associated with AD include age, decreased reserve capacity of the brain, head injury, Down syndrome, depression, mild cognitive impairment, and risk factors for vascular disease, including hypertension, elevated low-density lipoprotein cholesterol, low high-density lipoprotein cholesterol, and diabetes.
• Signature findings include intracellular neurofibrillary tangles (NFTs), extracellular amyloid plaques in the cortex and medial temporal lobe, and degeneration of neurons and synapses and cortical atrophy. Density of NFTs correlates with severity of dementia.
• Proposed mechanisms for these changes include (1) β-amyloid protein aggregation, leading to formation of plaques; (2) hyperphosphorylation of tau protein, leading to NFTs; (3) synaptic failure and depletion of neurotrophin and neurotransmitters; (4) mitochondrial dysfunction; and (5) oxidative stress.
• Of neurotransmitter deficits, loss of cholinergic activity is most prominent, and it correlates with AD severity. Cholinergic cell loss seems to be a consequence of AD pathology, not the cause of it.

Clinical Presentation

Cognitive decline is gradual and includes memory loss, aphasia, apraxia, agnosia, disorientation, and impaired executive function. Other symptoms include depression, psychotic symptoms, aggression, motor hyperactivity, uncooperativeness, wandering, and combativeness. Patients become increasingly unable to care for themselves.

Stages of AD

Mild (MMSE score 26–18) Patient has difficulty remembering recent events. Ability to manage finances, prepare food, and carry out other household activities declines. May get lost while driving. Begins to withdraw from difficult tasks and to give up hobbies. May deny memory problems.

Moderate (MMSE score 17–10) Patient requires assistance with activities of daily living. Frequently disoriented with regard to time (date, year, and season). Recall for recent events is severely impaired. May forget some details of past life and names of family and friends. Functioning may fluctuate from day to day. Patient generally denies problems. May become suspicious or tearful. Loses ability to drive safely. Agitation, paranoia, and delusions are common.

Severe (MMSE score 9–0) Patient loses ability to speak, walk, and feed self. Incontinent of urine and feces. Requires care 24 hours a day, 7 days a week.

MIMSE, Mini-Mental Status Examination,

Diagnosis

• The diagnostic criteria of the National Institute on Aging and the Alzheimer’s Association view AD as a spectrum beginning with an asymptomatic preclinical phase progressing to the symptomatic preclinical phase and then to the dementia phase. AD is a clinical diagnosis, based largely on identified symptoms and difficulty with activities of daily living revealed by patient and caregiver interviews.
• In the future, improved brain imaging and validated biomarkers of disease will enable a more sophisticated diagnosis with identified cognitive strengths and weaknesses and neuroanatomic localization of deficits.
• Patients with suspected AD should have a history and physical examination with appropriate laboratory tests (serum B12, folate, thyroid panel, blood cell counts, serum electrolytes, and liver function tests), and computed tomography or magnetic resonance imaging may aid diagnosis. To exclude other diagnoses, cerebrospinal fluid analysis or an electroencephalogram can occasionally be justified.
• Obtain information on medication use; alcohol or other substance use; family medical history; and history of trauma, depression, or head injury. Rule out medication use (e.g., anticholinergics, sedatives, hypnotics, opioids, antipsychotics, and anticonvulsants) as contributors to dementia symptoms. Rule out medications that could contribute to delirium (e.g., digoxin, nonsteroidal anti-inflammatory drugs [NSAIDs], histamine 2 [H2] receptor antagonists, amiodarone, antihypertensives, and corticosteroids).
• The Folstein Mini-Mental State Examination (MMSE) can help establish a history of deficits in two or more areas of cognition at baseline against which to evaluate change in severity over time. The average expected decline in an untreated patient is 2 to 4 points per year,

TREATMENT

• Goals of Treatment: The goal of treatment in AD is to maintain functioning as long as possible, with a secondary goal to treat the psychiatric and behavioral sequelae.
• For mild to moderate AD, consider use of a cholinesterase inhibitor, and titrate to maintenance dose. For moderate to severe AD, consider adding memantine, and titrate to maintenance dose. Alternatively, consider memantine or cholinesterase inhibitor alone. Treat behavior symptoms with support and behavior interventions, and use pharmacological management only if necessary.

NONPHARMACOLOGIC THERAPY

• Sleep disturbances, wandering, urinary incontinence, agitation, and aggression should be managed with behavioral and environmental interventions whenever possible
• On initial diagnosis, the patient and caregiver should be educated on the course of illness, available treatments, legal decisions, changes in lifestyle that will become necessary, and other quality-of-life issues.

PHARMACOTHERAPY OF COGNITIVE SYMPTOMS

• Managing blood pressure, cholesterol, and blood sugar may reduce the risk of developing AD.
• Reasonable expectations of treatment may be a slowed decline in abilities and delayed long-term care placement.
• Those who respond to treatment may lose the benefits when medication is stopped. Cholinesterase When switching from one cholinesterase inhibitor to another, 1 week washout is generally sufficient.
• No comparative trials have assessed the effectiveness of one agent over another. Donepezil, rivastigmine, and galantamine are indicated in mild to moderate AD; donepezil is also indicated for severe AD.
• If the decline in MMSE score is more than 2 to 4 points after treatment for 1 year with the initial agent, it is reasonable to change to a different cholinesterase inhibitor. Otherwise, treatment should be continued with the initial medication throughout the course of the illness. The three cholinesterase inhibitors have similar efficacy in mild to moderate AD, and duration of benefit lasts 3 to 12 months. Because of their short half-lives, if rivastigmine or galantamine treatment is interrupted for several days or longer, retitrate starting at the lowest dose.
• The most frequent adverse effects include mild to moderate gastrointestinal (GI) symptoms (nausea, vomiting, and diarrhea), urinary incontinence, dizziness, headache, syncope, bradycardia, muscle weakness, salivation, and sweating. Abrupt discontinuation can cause worsening of cognition and behavior in some patients

Other Drugs

• Memantine (Namenda) blocks glutamatergic neurotransmission by antagonizing N-methyl-d-aspartate receptors, which may prevent excitotoxic reactions. It is used as monotherapy and in combination with a cholinesterase inhibitor. It is indicated for treatment of moderate to severe AD, but not for mild AD. It is not metabolized by the liver but is primarily excreted unchanged in the urine. Dosing must be adjusted in patients with renal impairment. It is usually well tolerated; side effects include constipation, confusion, dizziness, and headache.
• Guidelines recommend low-dose aspirin in AD patients with significant brain vascular disease.
• Trials do not support the use of estrogen to prevent or treat dementia.
• Vitamin E is under investigation for prevention of AD and is not recommended for treatment of AD.
• Because of the incidence of side effects and a lack of supporting evidence, neither NSAIDs nor prednisone is recommended for treatment or prevention of AD.
• Trials of statin drugs have not shown significant benefit in prevention or treatment of AD.
• Because of limited efficacy data, the potential for adverse effects (e.g., nausea, vomiting, diarrhea, headache, dizziness, restlessness, weakness, and hemorrhage), and poor standardization of herbal products, ginkgo biloba is not recommended for prevention or treatment of AD.
• Do not use ginkgo biloba in individuals taking anticoagulants or antiplatelet drugs, and use cautiously in those taking NSAIDs.
• Huperzine A has not been adequately evaluated and is not currently recommended for treatment of AD.

PHARMACOTHERAPY OF NONCOGNITIVE SYMPTOMS

• Pharmacotherapy for noncognitive symptoms targets psychotic symptoms, inappropriate or disruptive behavior, and depression.
• General guidelines include the following: (1) Use environmental interventions first and pharmacotherapy only when necessary; (2) identify and correct underlying causes of disruptive behaviors when possible; (3) start with reduced doses and titrate slowly; (4) monitor closely; (5) periodically attempt to taper and discontinue medication; and (6) document carefully.
• Avoid anticholinergic psychotropic medications as they may worsen cognition. Cholinesterase Inhibitors and Memantine
• Cholinesterase inhibitors and memantine have shown modest improvement of behavioral symptoms over time but may not significantly reduce acute agitation. Antipsychotics
• Antipsychotic medications have traditionally been used for disruptive behaviors and neuropsychiatric symptoms, but the risks and benefits must be carefully weighed.
• A meta-analysis found that only 17% to 18% of dementia patients showed a modest treatment response with atypical antipsychotics. Adverse events (e.g., somnolence, extrapyramidal symptoms, abnormal gait, worsening cognition, cerebrovascular events, and increased risk of death [see black-box warning]) offset advantages. Another systematic review and meta-analysis found small but significant improvement in behavioral symptom scores in patients treated with aripiprazole, olanzapine, and risperidone.
• Typical antipsychotics may also produce a small increased risk of death, and more severe extrapyramidal effects and hypotension than the atypical.
• Antipsychotic treatment in AD patients should rarely be continued beyond 12 weeks Antidepressants
• Depression and dementia share many symptoms, and the diagnosis of depression can be difficult, especially later in the course of AD.
• A selective serotonin reuptake inhibitor (SSRI) is usually given to depressed patients with AD, and the best evidence is for sertraline and citalopram. Tricyclic antidepressants are usually avoided. Miscellaneous Therapies
• Use of benzodiazepines is not advised except on an “as needed” basis for infrequent episodes of agitation.
• Carbamazepine, valproic acid, and gabapentin may be alternatives, but evidence is conflicting.