Alzheimer disease

Across forms, the disorder typically begins with subtle failure of episodic memory, often recognised as mild cognitive impairment, and slowly progresses to incapacitating
dementia. Further common findings include confusion, impaired judgement, language disturbance, agitation, withdrawal, and hallucinations. Less frequent features comprise seizures, parkinsonian signs, increased muscle tone, myoclonus, and incontinence. The typical clinical duration is 8 to 10 years, with a range from 1 to 25 years. Approximately 95% of cases are late-onset, with onset after 60 to 65 years of age; around 5% are early-onset, with onset before 60 to 65 years. The clinical and genetic detail for the is given on its dedicated page; is also covered within the panel.

Alzheimer disease is the commonest cause of dementia. A single reliable Alzheimer-specific prevalence figure is not available; harmonised European prevalence estimates for all-cause dementia in adults aged 65 years and over vary strongly between countries, ranging from approximately 4.5% to 22.7% across populations and differing with childhood education.

Alzheimer disease has genetically distinct early-onset and late-onset forms. Early-onset familial Alzheimer disease is caused by germline pathogenic variants in PSEN1 (14q24.2), APP (21q21.3), and PSEN2 (1q42.13). These variants disturb amyloid precursor protein processing and increase the production or relative ratio of aggregation-prone beta-amyloid peptides, driving extracellular amyloid plaque deposition; downstream of this amyloid pathology, intraneuronal tau-containing neurofibrillary tangles form and progressive neurodegeneration follows. Late-onset disease is geneticallycomplex; the APOE ε4 allele acts as a susceptibility factor that increases lifetime risk but is not by itself causative.

Inheritance varies by form. Early-onset familial Alzheimer disease is inherited in an autosomal dominant manner, and each child of an affected individual has a 50% chance of inheriting the familial pathogenic variant. Late-onset Alzheimer disease is genetically complex, with multifactorial contributions from susceptibility alleles such as APOE ε4 together with environmental factors. Further detail on the is given on its dedicated page; is also covered within the panel.

The clinical diagnosis of Alzheimer disease relies on a combination of cognitive assessment, neuroimaging, and biomarker evaluation, structured by the . The defines the disease by the presence of beta-amyloid and tau pathology; the integrate clinical phenotype with biomarker evidence. Cerebrospinal-fluid beta-amyloid and tau concentrations, together with emerging blood-based markers, support biomarker confirmation. Amyloid PET, FDG PET, and structural MRI showing cortical atrophy contribute to diagnostic certainty. Neuropathological confirmation by beta-amyloid plaques and intraneuronal neurofibrillary tangles remains the histopathological reference standard.

Main differential diagnoses include:

• Frontotemporal dementia: early personality and behavioural changes or progressive language impairment with relative preservation of episodic memory; MAPT, GRN, C9orf72
• Dementia with Lewy bodies or Parkinson disease dementia: visual hallucinations, parkinsonism, fluctuating cognition, and REM-sleep behaviour disorder; SNCA, GBA1, LRRK2
• (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy): recurrent subcortical ischaemic strokes, migraine with aura, and characteristic white-matter MRI changes; NOTCH3

• Genetic testing supports establishing the diagnosis by identifying the underlying pathogenic variant, clarifying the genetic aetiology and providing a basis for genetic counselling.
• A confirmed result supports condition-specific surveillance and management options, which the treating physicians decide together with the affected individual.
• A known familial variant supports predictive testing of at-risk relatives, so they can clarify their personal risk and access surveillance and counselling where indicated.

• Bird TD. Alzheimer disease overview. 1998 Oct 23 [updated 2018 Dec 20]. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024. Available from: PMID:20301340.
• Börsch-Supan A, Douhou S, Otero MC, Tawiah BB. Harmonized prevalence estimates of dementia in Europe vary strongly with childhood education. Sci Rep. 2025;15(1):14024. doi:10.1038/s41598-025-97691-z. PMID:.
• Dickerson BC, Atri A, Clevenger C, Karlawish J, Knopman D, Lin PJ, et al. The Alzheimer’s Association clinical practice guideline for the Diagnostic Evaluation, Testing, Counseling, and Disclosure of Suspected Alzheimer’s Disease and Related Disorders (DETeCD-ADRD): executive summary of recommendations for specialty care. Alzheimers Dement. 2025;21(1). doi:10.1002/alz.14337. PMID:
• van der Molen LH, Boenink M, van Lente H, Richard E. Changing definitions of disease: transformations in the diagnostic criteria for Alzheimer disease. Alzheimers Dement. 2025;21(4). doi:10.1002/alz.70133. PMID: