Alzheimer Dementia

Background

• Alzheimer dementia (AD) is a gradual progressive impairment in cognition and memory, that typically affects adults aged ≥ 65 years and interferes with function and daily activities.
• AD and related dementias occur in about 1%-2% of adults ≤ 65 years old, but the prevalence increases with age to 30%-50% by age 85.
• The neuropathology of Alzheimer dementia include neurofibrillary tangles (comprised of tau protein) and plaques (comprised of beta-amyloid protein).
• There are numerous potential risk factors for AD including cardiovascular risk factors (diabetes, hypertension, dyslipidemia, obesity, metabolic syndrome, and smoking tobacco), low physical activity, cerebrovascular injury, mid-life hearing loss, low cognitive reserve, female sex, family history, and the APOE epsilon-4 genetic variant.
• The typical disease pattern is a gradual progressive impairment in cognition and memory that interferes with function and daily activities. Other symptoms include anxiety and depressive symptoms, apathy and withdrawal, changes in sleep, impaired judgment, disorientation, confusion, aggression, agitation, other behavioral changes, delusions, hallucinations, and other neuropsychiatric changes.
• The median survival of adults diagnosed with dementia at age 60-69 years is about 6.7 years and lower in adults diagnosed at later ages.

Evaluation

• When taking a history:
  • Obtain clinical history from additional independent informant when available. (Strong recommendation)
  • Ask about pattern of overall changes in thinking, mood, behavior, and neurologic symptoms to help determine progression.
  • Ask about changes in function, activities of daily living, and more complex activities.
  • Ask about all medications and supplements used, especially anticholinergics, sedative-hypnotics, and narcotics.
  • Conduct a comprehensive review of past medical history to help identify risk factors for Alzheimer dementia (AD) and evaluate for other causes of symptoms.
• When conducting a physical, look for signs of parkinsonism and neurological signs, and consider assessing for pain using a structured observational tool.
• All patients should have:
  • Formal cognitive assessments (Strong recommendation)
  • Routine blood tests to assess for potential causes of symptoms: (Strong recommendation)
    • complete blood count with differential.
    • thyroid stimulating hormone.
    • vitamin B12.
    • homocysteine.
    • complete metabolic panel.
    • erythrocyte sedimentation rate.
    • c-reactive protein levels.
  • Additional blood tests based on individual patient and clinical suspicion.
  • Structural brain imaging to assess for:
    • hippocampal and cortical atrophy in temporal and parietal lobes.
    • infarcts, leukoaraiosis, and microhemorrhages.
    • other conditions such as hydrocephalus or mass lesions.
• Diagnosis is made clinically - National Institute on Aging and Alzheimer's Association (NIA-AA) workgroup diagnostic criteria for probable AD include
  • the patient meeting clinical criteria for dementia:
    • decline from previous level of functioning.
    • impaired ability to function at work or at usual activities.
    • detection and diagnosis of cognitive impairment.
    • ≥ 2 of impaired ability to acquire and recall new information, poor judgement, impaired visuospatial skills, impaired language, and personality or behavior changes.
    • symptoms not caused by major psychiatric disorder or delirium.
  • a history of gradual onset over months to years.
  • clear worsening of cognitive abilities.
  • the initial and most prominent cognitive deficits seen on patient's history and exam may be either amnestic (most common presentation) or nonamnestic (language, visuospatial, or executive dysfunction presentation).
  • no evidence of other disease (such as features of other causes of dementia) or medication effect that could be affecting cognitive abilities.
• The Diagnostic and Statistical Manual of Mental Disorders Fifth Edition (DSM-5) and International Statistical Classification of Disease-10 (ICD-10) also have diagnostic criteria.
• Consider specialized testing for select patients (such as if highly atypical presentation or rapid progression):
  • Blood tests for thyroid peroxidase and antithyroglobulin antibody levels.
  • Genetic testing with genetic counseling.
  • Single photon emission computed tomography (SPECT), fluorodeoxyglucose (FDG)-positron emission tomography (PET), or amyloid PET imaging.
  • Cerebrospinal fluid (CSF) analysis.
  • Biopsy.

Management

• Determine dementia severity to help guide management.
• Assess for safety risks (such as cooking, smoking, wandering, financial management, and medication management), driving capacity, need for advanced planning, and decision-making capacity.
• Review current medication use to identify and consider discontinuing redundant and potentially deleterious medications such as anticholinergics, benzodiazepines, diphenhydramine, and sedative hypnotics.
• Consider conservative management for all patients to improve cognitive symptoms, function, or other symptoms - exercise, counseling, cognitive stimulation or rehabilitation, occupational therapy, reminiscence therapy, and music-based therapies.
• Consider cholinesterase (AChE) inhibitors and/or memantine, taking into account expected therapeutic benefits vs. potential safety risks. (Strong recommendation)
  • Discuss realistic expectations for treatment effects and potential side effects with patient and caregivers.
  • AChE inhibitors donepezil, rivastigmine, and galantamine are FDA approved for the treatment of patients with Alzheimer dementia (AD) at all stages.
    • Contraindications include unstable or severe cardiac disease, uncontrolled epilepsy, unexplained syncope, and active peptic ulcer disease.
    • Initiate at low dose and slowly titrate over months to maximal clinical benefit as tolerated
      • Donepezil starting dose 5 mg orally once daily for ≥ 4-6 weeks.
      • Rivastigmine starting dose 1.5 mg orally twice daily for ≥ 2 weeks or 4.6 mg transdermal patch once daily for ≥ 4 weeks.
      • Galantamine starting dose 4 mg orally twice daily for ≥ 4 weeks.
    • Once started, discontinuation may be harmful and increase symptom severity.
  • Memantine is FDA approved for the treatment of patients with moderate-to-severe AD, with a starting dose of 5 mg orally once daily for ≥ 1 week.
  • Regularly monitor patient for medication response and adverse effects.
• Aducanumab was granted FDA-accelerated approval for treatment of Alzheimer disease in patients with mild cognitive impairment or mild dementia in June 2021 (FDA Press Release 2021 Jun 7).
• Lecanemab-irmb was granted FDA-accelerated approval for treatment of Alzheimer disease in patients with mild cognitive impairment or mild dementia in January 2023 (FDA Press Release 2023 Jan 6).
• Other medications may benefit patients with Alzheimer dementia, but evidence and/or benefit is limited and professional organizations either recommend against using these medications to treat Alzheimer dementia or do not have recommendations regarding their use.
  • Antidiabetic agents.
  • Antihypertensive medications.
  • Vitamin E supplements.
  • Ginkgo biloba and huperzine A.
  • Other medications - dextromethorphan/quinidine (for moderate-to-severe agitation), adjunct antidepressants, or dihydroergocristine.
• Antipsychotics should only be considered with extreme caution in highly selected patients.
• Brexpiprazole (Rexulti) is FDA approved for treatment of dementia-associated agitation due to Alzheimer disease.
• Many other medications have been tried but have very limited or no evidence demonstrating benefit. These include statins, BACE inhibitors, monoclonal antibodies, selective serotonin receptor antagonists, tau aggregation inhibitors, IV immunoglobulin, cannabinoids, and others.
• There is limited evidence demonstrating efficacy of invasive procedures such as brain stimulation and gene therapy, and very limited or no evidence demonstrating efficacy of cerebrospinal fluid shunting, intraventricular infusion, or tissue graft.
• Conduct regular patient follow-up visits to monitor response to treatment and disease progression using scales such as the Mini-Mental State Examination (MMSE).
• For some patients with advanced dementia, consider referral for hospice care.