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 (Aβ) 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.
- AD is the leading cause of dementia and the sixth most common cause of death in the US. 
Incidence and prevalence increase with age.
- ∼ 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.
Genetic factors 
|Overview of genetic factors in Alzheimer disease|
|Amyloid precursor protein (APP) gene|
|Presenilin-1|| || |
|Presenilin-2 || || |
Other risk factors 
- Age (strongest predisposing factor for regular AD)
- Family history of dementia (strongest predisposing factor for early-onset AD)
- Low socioeconomic and/or educational status
- Diabetes, obesity, dyslipidemia
- Hypertension, peripheral atherosclerosis, and cerebrovascular disease
- African American or Hispanic descent (compared to White individuals)
- Lack of physical activity (independent risk factor)
- Traumatic brain injuries
- Environmental factors (e.g., secondhand smoke)
- Sleep deprivation
The following pathophysiological mechanisms contribute to AD: 
- Senile plaques (neuritic plaques)
- Neurofibrillary tangles
- Reduced cholinergic function
- Common symptoms of cognitive impairment
- Less common symptoms
- Behavioral changes
- Mood disorders (e.g., symptoms of depression)
- Urinary incontinence
- Anxiety and mutism
- Hallucinations and paranoia
Patients with mild to moderate AD are often able to maintain a social facade and preserve certain skills (e.g., dressing, hygiene routines).
- Consider AD in patients with dementia or . (See “Diagnosis of major neurocognitive disorder.”)
- Establish the diagnosis based on clinical criteria and neuropsychological testing.
- Consider advanced testing in consultation with neurology, e.g.:
- A definitive diagnosis requires neurohistopathological confirmation (not usually done).
Diagnostic criteria for Alzheimer disease 
|DSM-5 diagnostic criteria for major neurocognitive disorder due to Alzheimer disease |
|Probable major neurocognitive disorder due to AD||Possible major neurocognitive disorder due to AD|
| || |
MRI brain 
- Indication: all patients as part of the
- Supportive findings
Advanced studies 
- Consider in selected cases under specialist guidance.
- May be indicated for patients with:
- Progressive unexplained mild cognitive impairment
- Possible AD
- 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
- Used to:
- Amyloid-β (Aβ)-PET 
- To assess prognosis based on ↑ tau uptake signal in temporal and parietal cortices
- CSF analysis
- Electroencephalogram (EEG) 
Patients with preclinical Alzheimer disease are asymptomatic but have measurable brain changes (e.g., abnormal Aβ 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. 
- Cerebral atrophy
- Amyloid beta (Aβ): stains with Congo red under polarization
- Tau protein: intracellular neurofibrillary tangles that stain with Gallyas silver
- Hirano bodies
The differential diagnoses listed here are not exhaustive.
General principles 
- There is currently no curative therapy for AD.
- Management should include:
- Overall goals
- Maintain function
- Delay symptom progression
Pharmacological treatment 
Recommendations are based on disease severity, which is based on symptoms , functional status, and cognitive assessment.
Pharmacological therapies provide only modest delay in the progression of cognitive decline. Treatment choices should be a shared decision.
|Antidementia medications |
|Indications||Mechanism of action||Adverse effects|
|Acetylcholinesterase inhibitors (AChEIs)|| |
NMDA receptor antagonist: memantine
|Aβ monoclonal antibody: aducanumab || || |
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 at each visit thereafter. 
- Similar to management in other
- Includes lifestyle modifications, e.g., maintaining and a predictable schedule
- May require management of common comorbidities, e.g.:
- See “Management of major neurocognitive disorder” for further details.
The mean survival time is ∼ 3 to 10 years after diagnosis.