Alzheimer disease

Last updated: September 13, 2023

Summarytoggle arrow icon

Alzheimer disease (AD) is a progressive neurodegenerative disorder and the leading cause of dementia. The clinical spectrum of AD ranges from preclinical to severe. Risk factors include age > 65 years and genetic factors. The main histopathological features are extraneuronal β-amyloid () plaques and intraneuronal tau protein neurofibrillary tangles. The most common initial presentation is short-term memory loss, which insidiously progresses to dementia with deficits in other cognitive domains. Patients commonly have neuropsychiatric symptoms (e.g., depression, anxiety, and apathy) alongside cognitive deficits. The diagnosis is based on clinical criteria. Specialized imaging (PET-CT) and cerebrospinal fluid (CSF) analysis can be used to help clarify diagnostic uncertainty. There is no curative therapy; patients should receive supportive management. Pharmacotherapy (e.g., cholinesterase inhibitors and/or memantine) are modestly effective at slowing symptom progression. Average survival following diagnosis usually ranges from 3 to 10 years.

Epidemiologytoggle arrow icon

  • AD is the leading cause of dementia and the sixth most common cause of death in the US. [1]
  • Incidence and prevalence increase with age.
    • Incidence
      • ∼ 400:100,000 in individuals between 65 and 74 years of age
      • ∼ 3200:100,000 in individuals 75–84 years of age
      • ∼ 7600:100,000 in individuals ≥ 85 years of age
    • Prevalence: A total number of ∼ 5.8 million individuals in the US have AD.
      • 65–74 years of age: 1 million individuals (17%)
      • 75–84 years of age: 2.7 million individuals (47%)
      • ≥ 85 years of age: 2.1 million individuals (36%)
  • Sex: >
  • Early-onset (before the age of 65) familial AD represents ∼ 10% of all AD cases

Epidemiological data refers to the US, unless otherwise specified.

Etiologytoggle arrow icon

Genetic factors [1][2]

Overview of genetic factors in Alzheimer disease
Genes Proteins Characteristics
Amyloid precursor protein (APP) gene
  • Linked to 10–15% of early-onset familial AD cases
  • Since the APP gene is located on chromosome 21, individuals with trisomy 21 have an increased risk of early-onset AD due to APP. overexpression
  • Age at disease onset usually resembles parental age at disease onset (median ∼ 49 years).
  • PSEN1
  • Earlier onset compared to AD due to mutations of other genes (median is ∼ 43 years)
  • Linked to ∼ 50% of familial AD cases
Presenilin-2 [3]
  • PSEN2
  • Mutations cause the rarest form of familial AD.
  • Later onset (average ∼ 54 years)
Apo ε
  • Risk of late-onset AD increases with the number of carried Apo ε4 alleles.
  • Apo ε2 alleles may have a protective effect (reduce the risk of late-onset sporadic AD).
  • Apo ε3 alleles neither decrease nor increase risk of developing AD.

Other risk factors [1][2]

Pathophysiologytoggle arrow icon

The following pathophysiological mechanisms contribute to AD: [2]

  • Senile plaques (neuritic plaques)
    • Extracellular
    • Located in the grey matter of the brain
    • Aβ protein is the main component of the plaques.
    • Enzymatic cleavage of transmembranous APP by β-secretase and γ-secretase → Aβ peptide aggregation formation of insoluble plaquesneurotoxic effect
  • Neurofibrillary tangles
    • Intracellular
    • Tangles are composed of hyperphosphorylated tau protein (an insoluble microtubule-associated protein).
    • Phosphorylation (hyperphosphorylation) of tau formation of intracellular fibrils → neurotoxic effect (number of tangles correlates with the degree of cognitive impairment) [4]
  • Reduced cholinergic function
    • Acetylcholine deficiency is related to the degeneration of cholinergic neurons and likely plays a role in the decline of cognitive abilities.
    • Other neurotransmitter systems (e.g., noradrenergic transmission) are affected less severely.

Clinical featurestoggle arrow icon

Cognitive [2]

Noncognitive [2]

Patients with mild to moderate AD are often able to maintain a social facade and preserve certain skills (e.g., dressing, hygiene routines).

Diagnosticstoggle arrow icon

Approach [5][6][7]

Diagnostic criteria for Alzheimer disease [9]

DSM-5 diagnostic criteria for major neurocognitive disorder due to Alzheimer disease [9][10][11]
Probable major neurocognitive disorder due to AD Possible major neurocognitive disorder due to AD
  • All of the following:
    • Objective impairment in learning and memory and ≥ 1 other cognitive domain
    • Steady cognitive decline with no plateaus
    • No evidence of other causes
  • OR evidence of a causative genetic mutation
  • Absence of any features indicating probable AD

MRI brain [7][8]

Advanced studies [8][12]

PET Scan

  • FDG-PET [13]
    • Used to:
      • Differentiate between types of dementia, as well as between AD subtypes
      • Assess severity and prognosis
    • Supportive finding: ↓ glucose metabolism in temporal and parietal cortices
  • Amyloid-β ()-PET [13]
    • A negative result reduces the probability of AD.
    • Supportive finding: amyloid uptake signal
  • Tau-PET [14]
    • To assess prognosis based on tau uptake signal in temporal and parietal cortices

Additional studies

Patients with preclinical Alzheimer disease are asymptomatic but have measurable brain changes (e.g., abnormal on PET-CT or CSF analysis). There is often a duration of several years between the onset of mild cognitive symptoms and the diagnosis of dementia. [16]

Pathologytoggle arrow icon




Differential diagnosestoggle arrow icon

See “Differential diagnosis of subtypes of dementia.”

The differential diagnoses listed here are not exhaustive.

Treatmenttoggle arrow icon

General principles [6]

  • There is currently no curative therapy for AD.
  • Management should include:
  • Overall goals
    • Maintain function
    • Delay symptom progression

Pharmacological treatment [6][7]

Recommendations are based on disease severity, which is based on symptoms , and the results of a functional status assessment and a cognitive assessment.

Pharmacological therapies provide only modest delay in the progression of cognitive decline. Treatment choices should be a shared decision.

Antidementia medications [6][17][18]
Indications Mechanism of action Adverse effects
Acetylcholinesterase inhibitors (AChEIs)



NMDA receptor antagonist: memantine

  • Moderate to severe AD
  • Often used in combination with donepezil
monoclonal antibody: aducanumab [19][20]

Cholinesterase inhibitors affect the sinoatrial and atrioventricular nodes and increase the risk of bradycardia, syncope, and heart block. Check heart rate and obtain a 12-lead ECG prior to initiating a cholinesterase inhibitor, and screen for bradyarrhythmias at each visit thereafter. [21]

Think “Gallantly Down the River“ to remember the centrally acting AChE inhibitors used in the treatment of dementia: Galantamine, Donepezil, and Rivastigmine.

Supportive management

Avoid drugs with strong anticholinergic effects (e.g., diphenhydramine).

Complicationstoggle arrow icon

We list the most important complications. The selection is not exhaustive.

Prognosistoggle arrow icon

The mean survival time is ∼ 3 to 10 years after diagnosis.

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Preventiontoggle arrow icon

Referencestoggle arrow icon

  1. The Alzheimer's Association. 2020 Alzheimer's disease facts and figures. Alzheimer's & Dementia. 2020; 16 (3): p.391-460.doi: 10.1002/alz.12068 . | Open in Read by QxMD
  2. Kasper DL, Fauci AS, Hauser SL, Longo DL, Lameson JL, Loscalzo J. Harrison's Principles of Internal Medicine. McGraw-Hill Education ; 2015
  3. Jayadev S, Leverenz JB, Steinbart E, et al. Alzheimer’s disease phenotypes and genotypes associated with mutations in presenilin 2. Brain. 2010; 133 (4): p.1143-1154.doi: 10.1093/brain/awq033 . | Open in Read by QxMD
  4. Nelson PT, Alafuzoff I, Bigio EH, et al. Correlation of Alzheimer Disease Neuropathologic Changes With Cognitive Status: A Review of the Literature. Journal of Neuropathology & Experimental Neurology. 2012; 71 (5): p.362-381.doi: 10.1097/nen.0b013e31825018f7 . | Open in Read by QxMD
  5. Falk N, Cole A, Meredith TJ. Evaluation of Suspected Dementia.. Am Fam Physician. 2018; 97 (6): p.398-405.
  6. Arvanitakis Z, Shah RC, Bennett DA. Diagnosis and Management of Dementia: Review. JAMA. 2019; 322 (16): p.1589.doi: 10.1001/jama.2019.4782 . | Open in Read by QxMD
  7. Knopman DS, Amieva H, Petersen RC, et al. Alzheimer disease. Nat Rev Dis Primers. 2021; 7 (1).doi: 10.1038/s41572-021-00269-y . | Open in Read by QxMD
  8. Villa C, Lavitrano M, Salvatore E, Combi R. Molecular and Imaging Biomarkers in Alzheimer’s Disease: A Focus on Recent Insights. J Pers Med. 2020; 10 (3): p.61.doi: 10.3390/jpm10030061 . | Open in Read by QxMD
  9. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. American Psychiatric Publishing ; 2013: p. 947
  10. Sachdev PS, Blacker D, Blazer DG, et al. Classifying neurocognitive disorders: the DSM-5 approach. Nat Rev Neurol. 2014; 10 (11): p.634-642.doi: 10.1038/nrneurol.2014.181 . | Open in Read by QxMD
  11. 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): p.263-269.doi: 10.1016/j.jalz.2011.03.005 . | Open in Read by QxMD
  12. Keith A. Johnson, Satoshi Minoshima, Nicolaas I. Bohnen, Kevin J. Donohoe, Norman L. Foster, Peter Herscovitch, Jason H. Karlawish, Christopher C. Rowe, Maria C. Carrillo, Dean M. Hartley, Saima Hedrick, Virginia Pappas, William H. Thies. Appropriate use criteria for amyloid PET: A report of the Amyloid Imaging Task Force, the Society of Nuclear Medicine and Molecular Imaging, and the Alzheimer's Association. Alzheimer's & Dementia. 2013; 9 (1).doi: 10.1016/j.jalz.2013.01.002 . | Open in Read by QxMD
  13. Marcus C, Mena E, Subramaniam RM. Brain PET in the Diagnosis of Alzheimer’s Disease. Clin Nucl Med. 2014; 39 (10): p.e413-e426.doi: 10.1097/rlu.0000000000000547 . | Open in Read by QxMD
  14. Ossenkoppele R, Smith R, Mattsson-Carlgren N, et al. Accuracy of Tau Positron Emission Tomography as a Prognostic Marker in Preclinical and Prodromal Alzheimer Disease. JAMA Neurol. 2021; 78 (8): p.961.doi: 10.1001/jamaneurol.2021.1858 . | Open in Read by QxMD
  15. Tsolaki A, Kazis D, Kompatsiaris I, Kosmidou V, Tsolaki M. Electroencephalogram and Alzheimer’s Disease: Clinical and Research Approaches. Int J Alzheimers Dis. 2014; 2014: p.1-10.doi: 10.1155/2014/349249 . | Open in Read by QxMD
  16. Alzheimer's Association. 2021 Alzheimer's disease facts and figures. Alzheimer's & Dementia. 2021; 17 (3): p.327-406.doi: 10.1002/alz.12328 . | Open in Read by QxMD
  17. APA Work Group on Alzheimer's Disease and other Dementias., Rabins PV, Blacker D, et al. American Psychiatric Association practice guideline for the treatment of patients with Alzheimer's disease and other dementias. Second edition.. Am J Psychiatry. 2007; 164 (12 Suppl): p.5-56.
  18. Peter V. Rabins, Barry W. Rovner, Teresa Rummans, Lon S. Schneider, Pierre N. Tariot. Guideline Watch (October 2014): Practice Guideline for the Treatment of Patients With Alzheimer's Disease and Other Dementias. FOCUS. 2017; 15 (1): p.110-128.doi: 10.1176/appi.focus.15106 . | Open in Read by QxMD
  19. Cummings J, Salloway S. Aducanumab: Appropriate use recommendations. Alzheimer's & Dementia. 2021.doi: 10.1002/alz.12444 . | Open in Read by QxMD
  20. Day GS, Scarmeas N, Dubinsky R, et al. Aducanumab Use in Symptomatic Alzheimer Disease Evidence in Focus: Report of the AAN Guidelines Subcommittee. Neurology. 2022: p.10.1212/WNL.0000000000200176.doi: 10.1212/wnl.0000000000200176 . | Open in Read by QxMD
  21. Young S, Chung E, Chen MA. Cardiovascular Complications of Acetylcholinesterase Inhibitors in Patients with Alzheimer’s Disease: A Narrative Review. Ann Geriatr Med Res. 2021; 25 (3): p.170-177.doi: 10.4235/agmr.21.0079 . | Open in Read by QxMD

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