Late-onset Alzheimer disease

Late-onset Alzheimer disease typically manifests after age 60 to 65 years and accounts for approximately 95% of all Alzheimer disease cases. The disorder begins with subtle and often poorly recognised failure of memory, frequently described as mild cognitive impairment, and slowly becomes more severe and eventually incapacitating.

Additional clinical features include confusion, poor judgement, language disturbance, visual complaints, agitation, withdrawal, and hallucinations. The clinical course is highly variable between individuals, with progressive cognitive and functional decline leading to complete dependence on carers.

Alzheimer disease is the most common cause of dementia, and the late-onset form rises steeply in prevalence with advancing age. As a single-cohort illustration of the contribution of the APOE ε4 risk allele, in a southern Greek case-control cohort the APOE ε4 allele frequency was 20.6% in individuals with Alzheimer disease dementia compared with 6.7% in controls.

Late-onset Alzheimer disease is a complex disorder with a substantial polygenic contribution; 75 risk loci, of which 42 were newly identified, have been reported in a large European-ancestry genome-wide association study. The APOE locus on 19q13.32 represents the strongest common germline risk factor, and the ε4 allele is consistently over-represented in affected individuals relative to controls. This APOE ε4 allele acts as a susceptibility factor that increases lifetime risk but is not by itself causative. The molecular pathology is driven by progressive accumulation of extracellular β-amyloid plaques and intraneuronal neurofibrillary tangles containing hyperphosphorylated tau, accompanied by amyloid angiopathy and neurodegeneration.

Late-onset Alzheimer disease does not follow a single Mendelian inheritance pattern; it is a complex disorder driven by polygenic and environmental contributions. First-degree relatives of affected individuals have an increased lifetime risk in comparison to the general population.

The clinical diagnosis is supported by biochemical and imaging biomarkers, in line with the , which define and stage the disease on a biomarker basis. Cerebrospinal-fluid β-amyloid and tau concentrations, complemented by emerging plasma β-amyloid assays, support the clinical evaluation. Structural MRI or CT typically shows cerebral cortical atrophy; amyloid PET demonstrates cortical amyloid deposition, with tau PET imaging emerging. Definitive diagnosis rests on neuropathological identification of extracellular β-amyloid plaques and intraneuronal neurofibrillary tangles; cerebral amyloid angiopathy is a frequently associated finding rather than a defining criterion.

Main differential diagnoses include:

• with Lewy bodies: fluctuating cognition, recurrent visual hallucinations and spontaneous parkinsonism early in the course, often with REM-sleep behaviour disorder; SNCA, GBA1, LRRK2 (susceptibility)
• Frontotemporal dementia: early prominent behavioural and personality change or progressive aphasia with relatively preserved episodic memory in early stages; MAPT, GRN, C9orf72
• (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy): subcortical ischaemic events, migraine with aura and mood disturbance preceding cognitive decline, with characteristic white-matter changes on MRI; NOTCH3

• Genetic testing supports establishing the diagnosis by identifying the underlying pathogenic or risk-conferring variant, clarifying the genetic aetiology and providing a basis for genetic counselling.
• The APOE ε4 allele is a susceptibility (risk) allele, not a diagnostic or predictive marker at the individual level; carriage neither confirms nor excludes the diagnosis, so its interpretation belongs within 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.

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• Papastefanopoulou V, Stanitsa E, Koros C, Simoudis A, Florou-Hatziyiannidou C, Beratis I, et al. APOE allele frequency in Southern Greece: exploring the role of geographical gradient in the Greek population. Geriatrics (Basel). 2022;8(1):1. PMID: .
• Jack CR Jr, Andrews JS, Beach TG, Buracchio T, Dunn B, Graf A, et al. Revised criteria for diagnosis and staging of Alzheimer’s disease: Alzheimer’s Association Workgroup. Alzheimers Dement. 2024;20(8):5143-5169. PMID: .
• Bellenguez C, Küçükali F, Jansen IE, Kleineidam L, Moreno-Grau S, Amin N, et al. New insights into the genetic etiology of Alzheimer disease and related dementias. Nat Genet. 2022;54(4):412-436. PMID: .