Alzheimer Disease

As the most common cause of dementia, Alzheimer disease affects not only many individuals but also their families. Alzheimer disease is a progressive neurodegenerative disease that causes brain atrophy and presents with a decline in memory, cognition, and social skills. Several genetic defects and risk factors have been described, although there is no clear cause in the majority of cases. The main pathologic features are neuritic plaques, extracellular deposits of amyloid peptides, and neurofibrillary tangles. The clinical features are memory impairment, loss of executive function and judgment, impaired cognitive function, and behavioral changes. Diagnosis is based on clinical examination, neuropsychiatric testing, and imaging. There is no curative therapy, but symptomatic management with medications may slow progression; these include cholinesterase inhibitors, the N-methyl-D-aspartate (NMDA) receptor antagonist memantine, and a recently approved anti-amyloid monoclonal antibody.

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Overview

Definition

Alzheimer disease is a progressive neurodegenerative disease that causes brain atrophy and a decline in cognition, memory, and social skills.

Epidemiology

  • Leading cause of dementia in adults > 65 years
  • Incidence: women > men
  • Incidence increases exponentially after age 65. 
  • Prevalence of Alzheimer disease after age 70 in the United States: 9.7%
  • Familial Alzheimer disease called “early-onset” Alzheimer disease:
    • Rare (< 1% of cases)
    • Caused by genetic mutations
    • Autosomal dominant

Etiology

Although the cause of Alzheimer disease is unknown, several genetic defects and risk factors have been identified.

  • Genetic factors: 
    • Amyloid precursor protein gene: 
      • Located on chromosome 21
      • Associated with approximately 1% of all early-onset Alzheimer disease and 0.1% of total Alzheimer disease cases
      • Age at onset of Alzheimer disease in individuals with this mutation is 45–66 years.
    • Presenilin-1 (PSEN1) mutation: 
      • Located on chromosome 14 
      • Linked to 50% of all familial Alzheimer disease cases
      • Age at onset: 28–62 years
    • Presenilin-2 (PSEN2) mutation: 
      • Located on chromosome 1 
      • Causes the rarest form of familial Alzheimer disease
      • Age at onset: 40–85 years
    • Apolipoprotein E gene (APOE ε4) mutation: 
      • Located on chromosome 19 
      • May increase Alzheimer disease risk by impairing beta-amyloid clearance in the brain
      • Age at onset is later than those listed above (> 60 years).
  • Other risk factors: 
    • Age
    • Familial history of Alzheimer disease
    • Head trauma
    • Sleep deprivation
    • Diabetes
    • Dyslipidemia
    • Obesity
    • Hypertension 
    • Peripheral atherosclerosis

Pathophysiology

The pathogenesis of Alzheimer disease is unclear; however, there is an increase in beta-amyloid peptides and aggregation of the tau protein.

  • Pathways likely involved in Alzheimer disease:
    • Mutations in the genes PSEN1 or PSEN2 may increase the production of amyloid or neurotoxic forms of beta-amyloid found outside neurons.
    • Tau (aids in microtubule assembly and stabilization): hyperphosphorylation →  aggregates → abnormal helical form of tau  → found inside neurofibrillary tangles
  • Gross pathologic changes:
    • Cortical atrophy with widening cerebral sulci
    • Compensatory ventricular enlargement 
  • Microscopic pathologic changes found in the hippocampus:
    • Neurofibrillary tangles = bundles of filaments in the cytoplasm of neurons 
      • Paired helical filaments that contain hyperphosphorylated tau
      • Severity of Alzheimer disease directly correlates to the number of neurofibrillary tangles. 
    • Beta-amyloid “neuritic” plaques = focal, spherical collections of silver-staining neuritic processes
    • Amyloid angiopathy → granulovacuolar degeneration
  • Low acetylcholine → decrease in cognitive ability
  • Autopsy studies in people > 85 years show pathologic findings of Alzheimer disease in ⅓ of individuals with no clinical diagnosis of dementia before death.
    • More than half of brains from cases of Alzheimer disease show “mixed pathology” or brain changes of ≥ 1 other causes of dementia.
    • Concomitant cerebrovascular disease is common.
    • Lewy body disease is also seen.
Alzheimers brain

Depiction of the gross pathology seen with Alzheimer disease

Image: “Alzheimers brain” by National Institutes of Health. License: Public Domain

Clinical Presentation

Interviewing family members is essential to obtain a history of cognitive and behavioral changes.

Memory impairment

Memory impairment is the most common early symptom of Alzheimer disease.

  • Described as anterograde long-term episodic amnesia
  • Insidious onset with slow gradual progression 
  • In earlier stages of presentation: episodic memory is affected = memory of events occurring at a time and place
  • In later stages of memory impairment:
    • Procedural learning and remote memory 
    • Semantic memory = memory for facts, vocabulary, and concepts
    • Immediate recall 

Impaired executive function and judgment

  • Subtle to prominent impairment occurs in early Alzheimer disease.
  • Ability to complete tasks declines
  • Reduced insight into deficits (anosognosia) ↑ over time 
  • Associated with behavioral changes

Impairment in cognitive domains

  • Develop and progress insidiously
  • Visuospatial impairments: seen relatively early in the disease
  • Language deficits and primary progressive aphasia: manifest later

Motor function impairment

  • Apraxia = difficulty performing purposeful movements
    • Usually occurs after deficits in memory and language are apparent
    • Initially presents with difficulty performing complex, multistep activities
    • Later → difficulty with dressing, using utensils, and other self-care tasks 
  • Shuffling gait with generalized muscle rigidity
  • Slowness and awkwardness of movement

Behavioral and psychological symptoms

  • Sleep disturbances
  • Apathy/social disengagement
  • Irritability
  • Agitation, aggression, wandering, and psychosis: difficult for family members
  • Delusions in later stages: common themes of theft, infidelity, or misidentification

Other signs and symptoms

  • Focal, nonmotor seizures with impaired awareness (usually in the later stages) in 10%–20% of cases 
  • Olfactory dysfunction

Diagnosis

The typical duration of symptomatic Alzheimer disease is 8–10 years, but the course ranges from 1 to 25 years.

History and examination

  • Detailed history, including the perspective of an informant (e.g., spouse or adult child)
  • Neuropsychological assessment
  • Mental status scales to evaluate cognition:
    • Mini–Mental State Examination (MMSE)
    • Montreal Cognitive Assessment (MoCA)
    • Alzheimer disease assessment scale-cognitive behavior subscale (ADAS-Cog)
    • Clinical Dementia Rating Scale (CDR)

National Institute on Aging and the Alzheimer’s Association (NIA-AA) diagnostic guidelines

  • Initial diagnostic criteria presented in 1984, revised in 2011:
    • Recognizes that Alzheimer disease presents on a spectrum with a preclinical stage, followed by early cognitive impairment, and then marked dementia
    • Expands the criteria beyond memory loss to other cognitive aspects
  • Criteria for probable Alzheimer disease dementia require the presence of dementia and:
    • Interference with ability to function at work or usual activities
    • Decline from a previous level of functioning 
    • Not explained by delirium or major psychiatric disorder
    • Cognitive impairment established by history taking from the individual and a knowledgeable informant
    • Cognitive impairment involving ≥ 2 of the following: 
      • Impaired ability to acquire and remember new information
      • Impaired reasoning and handling of complex tasks, poor judgment
      • Impaired visuospatial abilities
      • Impaired language functions
      • Changes in personality, behavior, or comportment
    • Other clinical criteria:
      • Insidious onset
      • Clear history of progression
      • Initial and most prominent cognitive deficits are memory, language, or visuospatial cognitive deficits.
      • No other clear diagnosis of vascular dementia, dementia with Lewy bodies, or frontotemporal dementia

Other testing

  • Labs to evaluate for other causes of dementia:
    • CBC
    • Chemistries
    • Thyroid function
    • Vitamin B12 
  • Imaging to rule out other pathology
    • MRI findings:
      • Generalized and focal atrophy
      • White matter lesions
      • Reduced hippocampal volume or medial temporal lobe atrophy 
    • Amyloid PET imaging: Tracers may be used as qualitative assessments of beta-amyloid plaque density.

Management

There is no cure for Alzheimer disease, but medications may delay functional decline. Individualized treatment decisions are made in conjunction with individuals and caregivers after discussion of potential benefits, risks, and costs.

  • Supportive care
    • Lifestyle modifications:
      • Regular sleep cycle
      • It is imperative for the individual to stop driving when executive function is lost.
    • Maintain good physical health.
    • Memory training (e.g., puzzles, interactive games) 
  • Pharmacologic treatment
    • Cholinesterase inhibitors: used with mild to moderate symptoms
      • Donepezil
      • Rivastigmine
      • Galantamine
    • N-methyl-D-aspartate (NMDA) antagonist: 
      • Memantine
      • Used for moderate to severe dementia
    • Low-dose antipsychotics: only as a last resort to control agitation and hallucinations
    • Selective serotonin reuptake inhibitors to treat concomitant depression
    • Monoclonal antibody against beta-amyloid: aducanumab (approved June 2021)
      • For mild cognitive impairment due to Alzheimer disease
      • Produced a substantial reduction in brain amyloid levels in studies, but benefits on clinical end points have been inconsistent
  • Genetic testing in families with a history of early-onset Alzheimer disease

Differential Diagnosis

  • Vascular dementia: also known as multi-infarct dementia. Vascular dementia is caused by damage to the blood vessels and affects parts of the brain. The condition presents with abrupt cognitive decline and stepwise deterioration. Asymmetric focal deficits are the hallmark of this disease. Lacunar defects are seen on CT/MRI. Treatment includes risk factor reduction and managing hypertension, diabetes, and hyperlipidemia and recommending smoking cessation.
  • Dementia with Lewy bodies: Dementia, visual hallucinations, parkinsonism, cognitive fluctuations, dysautonomia, sleep disorders, and neuroleptic sensitivity are major symptoms of dementia with Lewy bodies. Diagnosed by white atrophic lesions seen on MRI. Treatment is supportive.
  • Frontotemporal dementia: neuropathologically and clinically heterogeneous disorder characterized by focal degeneration of the frontal and/or temporal lobes. Frontotemporal dementia manifests between the ages of 45 and 70. The behavioral variant is most common and presents as early changes in behavior and apathy. Increased amyloid-beta protein is the primary indicator for frontotemporal dementia, and changes in the temporal lobe can be seen on PET scans. Treatment is supportive.

References

  1. Seeley, W. W., Miller, B. L. (2018). Alzheimer’s disease. In: Jameson, J.L., et al. (Eds.), Harrison’s Principles of Internal Medicine, 20th ed., vol. 2. McGraw-Hill, pp. 3108–3114.
  2. Wolk, D. A., Dickerson, B. C. (2020). Clinical features and diagnosis of Alzheimer disease. UpToDate. Retrieved August 3, 2021, from https://www.uptodate.com/contents/clinical-features-and-diagnosis-of-alzheimer-disease
  3. Keene, C. D., Montine, T. J., Kuller, L. H. (2018). Epidemiology, pathology, and pathogenesis of Alzheimer disease. UpToDate. Retrieved August 3, 2021, from https://www.uptodate.com/contents/epidemiology-pathology-and-pathogenesis-of-alzheimer-disease
  4. Lakhan, S. E. (2021). Alzheimer Disease. Medscape. Retrieved August 3, 2021, from https://emedicine.medscape.com/article/1134817
  5. Kumar, A., et al. Alzheimer disease. StatPearls. Retrieved August 3, 2021, from https://www.ncbi.nlm.nih.gov/books/NBK499922/
  6. Maccioni, R.B., González, A., Andrade, V., Cortés, N., Tapia, J.P., Guzmán-Martínez, L. (2018). Alzheimer’s disease in the perspective of neuroimmunology. Open Neurol J 12:50–56. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6040210/
  7. Atri, A. (2019). The Alzheimer’s Disease Clinical Spectrum: Diagnosis and Management. Medical Clinics of North America, vol. 103, no. 2. Elsevier, pp. 263–293. https://doi.org/10.1016/j.mcna.2018.10.009
  8. Alzheimer’s Association. (2021). Alzheimer’s disease facts and figures. https://www.alz.org/media/Documents/alzheimers-facts-and-figures.pdf

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