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Alzheimer Disease
Jill Ann Grimes, MD
image BASICS
DESCRIPTION
  • Alzheimer disease (AD) is the most common cause of dementia in the elderly.
  • Degenerative neurologic disease with progressive impairment in ≥2:
    • Memory, executive function, attention, language, or visuospatial skills
    • With significant interference in ability to function in work, home, or social interactions
  • New diagnostic criteria released in 2011 emphasize full spectrum of disease (1)[A]:
    • Preclinical AD (research purposes only: biomarkers present; subtle decline evident to patient but cognitive tests in “normal” range)
    • Mild cognitive impairment (MCI): Social, occupational, and functional skills are preserved despite significant decline in cognition.
    • Alzheimer dementia
  • System(s) affected: nervous
  • Synonym(s): presenile dementia; senile dementia of the Alzheimer type
Geriatric Considerations
Asymptomatic screening is not recommended.
EPIDEMIOLOGY
  • Predominant age: >65 years
  • 2/3 females, 1/3 males in United States
Incidence
1 in 8 Americans age >65 years (13%); nearly 50% once >85
Prevalence
>5.2 million in United States
  • 200,000 younger onset (<65 years)
ETIOLOGY AND PATHOPHYSIOLOGY
  • Unknown but involves amyloid beta accumulation initially, then synaptic dysfunction, neurodegeneration, and eventual neuronal loss
  • Age, genetics, systemic disease, behaviors (smoking), and other host factors may influence the response to amyloid beta and/or the pace of progression toward the clinical manifestations of AD.
Genetics
  • Positive family history in 50%, but 90% of AD is sporadic:
    • APOE4 increases risk but full unclear
  • Familial/autosomal dominant AD accounts for <5% AD:
    • Amyloid precursor protein (APP), presenilin-1 (PS-1), and presenilin-2 (PS-2)
RISK FACTORS
  • Aging, family history, APOE4, Down syndrome
  • Cardiovascular and carotid artery disease
  • Smoking (2- to 4-fold increase)
  • Head trauma
GENERAL PREVENTION
  • NSAIDs, estrogen, and vitamin E do NOT delay AD; insufficient evidence for statins (2)[A].
  • Intellectual challenge (puzzles) and regular physical exercise may offer preventive benefit.
  • Control vascular risk factors (e.g., hypertension); lowering cholesterol may retard pathogenesis of AD.
  • Ginkgo biloba may be beneficial for cognition but not activities of daily living.
  • Physical activities and omega-3 fatty acids may help to prevent or delay cognitive decline.
  • Ultrasound (US) may help to identify asymptomatic patients at increased risk with chronic brain hypoperfusion secondary to cardiovascular or carotid artery pathology.
COMMONLY ASSOCIATED CONDITIONS
  • Down syndrome
  • Depression
image DIAGNOSIS
Degenerative neurologic disease with progressive impairment in2 areas:
  • Memory, executive function, attention, language, or visuospatial skills AND
  • Significant interference in ability to function in work, home, or social interactions
PHYSICAL EXAM
  • Neurologic exam to rule out other causes
  • Folstein Mini-Mental State Exam (MMSE): copyrighted but available (http://www.aafp.org/afp/20010215/703.html)
  • Counting coins test: “If I gave you a nickel, quarter, dime, and penny, how much is that?”
  • No focal neurologic signs
  • Short-term memory loss
  • Acalculia (e.g., cannot balance checkbook)
  • Agnosia: inability to recognize objects
  • Apraxia: inability to carry out movements
  • Confabulation
  • Delusions
  • Impaired abstraction
  • Decreased attention to hygiene
  • Visuospatial distortion
  • Late signs: psychotic features, mutism
DIFFERENTIAL DIAGNOSIS
  • Depression
  • Vascular dementia, multi-infarct dementia
  • Lewy body disease
  • Dementia associated with Parkinson disease
  • Normal pressure hydrocephalus
  • Creutzfeldt-Jakob disease
  • End-stage multiple sclerosis
  • Brain tumor: primary or metastatic
  • Subdural hematoma
  • Progressive multifocal leukoencephalopathy
  • Metabolic dementia (hypothyroidism)
  • Drug reactions, alcoholism, other addictions
  • Dementia pugilistica
  • Toxicity from liver and kidney failure
  • Vitamin and other nutritional deficiencies
  • Vasculitis
  • Neurosyphilis
DIAGNOSTIC TESTS & INTERPRETATION
Neuropsychological testing: Order if clinical picture is confusing or to help determine level of independence for skills such as balancing checkbooks, driving, or managing medicines.
Initial Tests (lab, imaging)
  • To help rule out other causes of dementia
    • CBC, ESR
    • Chemistry panel
    • Thyroid-stimulating hormone
    • Folate and B12 levels
    • Venereal disease reaction level (VDRL) or rapid plasma reagin (RPR)
    • HIV antibody (selected cases)
    • APOE4 or biomarker testing is not routine.
  • Imaging: Controversy exists; may identify moderate cortical atrophy or ventricular enlargement.
    • Consider MRI or CT scan if
      • Cognitive decline is recent and rapid; age <60 years; history of stroke; gait disturbance or focal neurologic signs
      • Cancer, urinary incontinence, bleeding disorder, or current use of anticoagulants
    • Single-photon emission computed tomography (SPECT) and positron emission tomography (PET): only if diagnostic uncertainty after CT or MRI; insufficient evidence to use alone
    • Medicare pays for PET to distinguish AD from frontotemporal dementia under specific requirements; this should not be routine.
Follow-Up Tests & Special Considerations
Genetic testing for APOE4 or for familial AD types; discuss with genetic counselor
Test Interpretation
  • Gross: diffuse cerebral atrophy in hippocampus, amygdala, and some subcortical nuclei
  • Microscopic
    • Neuritic senile plaques
    • Neurofibrillary tangles
    • Pyramidal cell loss
    • Decreased cholinergic innervation (other neurotransmitters variably decreased)
    • Degeneration of locus ceruleus and basal forebrain nuclei of Meynert; amyloid angiopathy
image TREATMENT
GENERAL MEASURES
  • Optimize treatment of associated comorbid conditions (including hearing and vision loss).
  • Analyze environment for safety and security, and avoid sudden changes in environment.
  • Assess spouse/caregiver burnout.
  • Advance directives, living will, power of attorney
MEDICATION
First Line
2014 meta-analysis shows cholinesterase inhibitors (ChEIs) and memantine are “able to stabilize or slow decline in cognition, function, behavior, and global change” (3)[A].
  • Debate continues regarding the clinical significance and cost-effectiveness of AD medication.
  • P.39

  • ChEIs
    • Equally effective; all have potential for GI side effects; monitor for bradycardia/syncope; associated with abnormal dreams
    • When used for at least 6 months, provide mild benefit in cognition, ADL, and behavior. (No deterioration for 6 months is evidence of efficacy.)
    • Shown to reduce nursing home placement by 20% after 25 months of treatment
    • Best in mild to moderate disease (MMSE 10 to 24); may be effective in Lewy body dementia
    • Donepezil (Aricept): start at 5 mg/day PO; may increase to 10 mg/day after 1 month
    • Tablets disintegrating tablets; generic available
    • Caution with digoxin or beta-blockers (can cause 3rd-degree heart block)
    • Aricept 23-mg tablet approved in 2010
    • Rivastigmine (Exelon): start at 1.5 mg PO BID, increase by 1.5 mg BID every 2 weeks; maintenance 6 to 12 mg/day total
    • Capsule, solution, or patch (patch greatly reduces side effects)
    • Indicated for both AD and Parkinson dementia
    • Galantamine (Razadyne): start at 4 mg BID for 4 weeks, then increase by 4 mg BID every month with goal of 16 to 24 mg/day dose
    • Tablets, solution, extended-release (ER) capsule, and transdermal formulations (ER and transdermal have daily dosing)
  • N-methyl-D-aspartate (NMDA) receptor antagonists (for moderate to severe AD; MMSE 5 to 14)
    • Monotherapy or in combination with acetylcholinesterase inhibitors
    • Memantine (Namenda): start 5 mg/day, with titrate to target dose of 10 mg BID after 4 weeks
    • Often improves behavioral issues
    • Beneficial for cognition and physician's global impression; increases risk of somnolence, weight gain, confusion, hypertension, nervous system disorders, and falling (4)[A]
  • For depression (occurs in 1/3 of patients), SSRIs preferred first line.
  • Insomnia
    • Trazodone 25 to 100 mg at bedtime, zolpidem (Ambien) 5 mg at bedtime, zaleplon (Sonata) 5 to 10 mg at bedtime, ramelteon (Rozerem) 8 mg at bedtime
    • Avoid diphenhydramine in elderly due to negative cognitive effects and risk of urinary retention (males).
  • Moderate anxiety/restlessness: Consider low-dose, short-acting benzodiazepines, buspirone, or SSRIs (efficacy unproven).
  • Severe aggressive agitation
    • Behavioral techniques and environmental modification help more than medications for wandering, restlessness, uncooperativeness, hoarding, and irritability:
      • Consider changing environment, rewards, behavioral redirection, hearing aids, and bright light therapy.
    • Memantine (Namenda): start at 5 mg/day, with starter pack titrating to target dose of 10 mg BID after 4 weeks
    • Antipsychotics (both conventional and atypical) are associated with increased mortality and acute care hospital admissions in elderly patients with dementia.
    • Antiepileptic agents (carbamazepine valproate, lamotrigine) have been used for their mood stabilizing properties.
  • Precautions
    • Avoid anticholinergic drugs, such as tricyclic antidepressants and antihistamines.
    • Ginkgo biloba: Avoid anticoagulants and aspirin.
    • Benzodiazepines may produce paradoxical excitation or daytime drowsiness.
    • Triazolam (Halcion) can produce confusion, memory loss, and psychotic behavior.
    • Benzodiazepines may increase serum phenytoin concentration.
    • Cimetidine may increase benzodiazepine concentration.
    • Donepezil (Aricept): use with caution with anticholinergic medication, in sick sinus syndrome, or history of peptic ulcers
    • Paroxetine increases donepezil levels.
Second Line
Vitamin E, statins, estrogen, and NSAIDs should not be routinely recommended due to lack of evidence and safety concerns (1,2)[A].
ISSUES FOR REFERRAL
  • Assess driving safety (vision, spatial relations, hearing, judgment):
    • http://www.nhtsa.gov/people/injury/olddrive/Driving%20Safely%20Aging%20Web/
  • Support groups for patient and family: Alzheimer Association: http://www.alz.org/
ADDITIONAL THERAPIES
  • Exercise to reduce restlessness
  • Cognitive challenge; traditional and computerized training both effective
  • Occupational, music, aroma, and pet therapy
COMPLEMENTARY & ALTERNATIVE MEDICINE
  • Huperzine A 400 mg (herbal ChEIs) may improve cognition with minimal side effects (5)[A].
  • Ginkgo biloba extracts (120 mg/day) show conflicting efficacy in treatment of AD but may be beneficial.
  • Coenzyme Q10 is not effective.
  • Acupuncture continues to be assessed and may enhance effectiveness of drugs in treating Alzheimer disease.
image ONGOING CARE
FOLLOW-UP RECOMMENDATIONS
Patient Monitoring
  • Schedule regular follow-up (3 months) to assess medical complications, provide support for family, and assess need for placement.
  • Serial mental status testing is potentially helpful, but bedside tests (Folstein MMSE) offer wide variability and lack of sensitivity.
PATIENT EDUCATION
  • Alzheimer Association: http://www.alz.org/
  • Explain progressive nature of the disease and start advance directives planning as early as possible.
PROGNOSIS
Poor: Average survival from diagnosis is 4 to 8 years (diagnosis is often delayed).
REFERENCES
1. McKhann GM, Knopman DS, Chertkow H, et al. The diagnosis of dementia due to Alzheimer's disease: recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease. Alzheimers Dement. 2011;7(3):263-269.
2. McGuinness B, Craig D, Bullock R, et al. Statins for the treatment of dementia. Cochrane Database Syst Rev. 2014;8(7):CD007514.
3. Tan CC, Yu JT, Wang HF, et al. Efficacy and safety of donepezil, galantamine, rivastigmine, and memantine for the treatment of Alzheimer's disease: a systematic review and meta-analysis. J Alzheimers Dis. 2014;41(2):615-631.
4. Yang Z, Zhou X, Zhang Q. Effectiveness and safety of memantine treatment for Alzheimer's disease. J Alzheimers Dis. 2013;36(3):445-458.
5. Xing SH, Zhu CX, Zhang R, et al. Huperzine A in the treatment of Alzheimer's disease and vascular dementia: a meta-analysis. Evid Based Complement Alternat Med. 2014;2014:363985.
Additional Reading
  • Birks JS, Grimley Evans J. Rivastigmine for Alzheimer's disease. Cochrane Database Syst Rev. 2015;(4):CD001191.
  • Buckley JS, Salpeter SR. A risk-benefit assessment of dementia medications: systematic review of the evidence. Drugs Aging. 2015;32(6):453-467.
  • Ehret MJ, Chamberlin KW. Current practices in the treatment of Alzheimer disease: where is the evidence after the phase III trials? Clin Ther. 2015;37(8):1604-1616.
  • Zhou J, Peng W, Xu M, et al. The effectiveness and safety of acupuncture for patients with Alzheimer disease: a systematic review and meta-analysis of randomized controlled trials. Medicine (Baltimore). 2015;94(22):e933.
See Also
Substance Use Disorders; Hypothyroidism, Adult; Depression
Codes
ICD10
  • G30.9 Alzheimer's disease, unspecified
  • G30.0 Alzheimer's disease with early onset
  • G30.1 Alzheimer's disease with late onset
Clinical Pearls
  • Daily intellectual stimulation, such as puzzles, and moderate physical exercise may help prevent AD.
  • Imaging studies have low yield in patients with a history typical of AD.
  • Encourage families to join a chapter of the Alzheimer Association and to pursue advanced directive planning early in the course of the disease.
  • Atypical antipsychotic medications increase mortality.