Early-onset Alzheimer disease

Early-onset Alzheimer’s disease specifically accounts for approximately 5% of all Alzheimer’s disease, and early-onset familial Alzheimer disease for less than 2%. Progressive Alzheimer-type dementia presents with insidious episodic-memory impairment. Language, visuospatial, executive and behavioural decline follow, with agitation, withdrawal and visual hallucinations; seizures, myoclonus, parkinsonism, increased muscle tone, incontinence and mutism may emerge in advanced disease. Inter-individual variability is considerable: typical clinical duration is 8-10 years (range 1-25 years).

The estimated age-standardised prevalence of Alzheimer’s disease is 41.1 per 100,000 population worldwide and 54.1 per 100,000 population in Europe.

Germline heterozygous pathogenic variants in three genes account for EOFAD. PSEN1 (~45% of EOFAD families), APP (~12.5%), and PSEN2 (~5%) encode components of the γ-secretase complex (PSEN1, PSEN2) and the amyloid precursor protein (APP); variants alter APP processing, increase generation and aggregation of β-amyloid (notably the Aβ42 isoform), and drive formation of extracellular β-amyloid plaques and intraneuronal neurofibrillary tangles composed of tau protein, with subsequent progressive neurodegeneration.

EOFAD is inherited in an autosomal dominant manner. Each child of an affected individual has a 50% chance of inheriting the pathogenic variant.

The clinical diagnosis rests on consensus criteria, supported by biomarker and imaging findings. The NIA-AA core clinical criteria establish the clinical diagnosis of Alzheimer’s disease. The and the provide additional biomarker-based diagnostic frameworks. Supportive investigations include cerebrospinal fluid biomarkers (reduced Aβ42 with elevated total tau and phosphorylated tau), plasma β-amyloid and phosphorylated-tau assays, structural MRI showing cortical and medial temporal atrophy, and amyloid and tau PET imaging.

Main differential diagnoses include:

• Frontotemporal (including frontotemporal dementia with parkinsonism-17, FTDP-17): Prominent early behavioural change or progressive language disturbance with relative sparing of episodic memory; significant clinical overlap with PSEN1-related early-onset AD; MAPT, GRN, C9orf72
• Diffuse Lewy body disease (dementia with Lewy bodies): Fluctuating cognition, recurrent visual hallucinations, spontaneous parkinsonism and REM sleep behaviour disorder; SNCA, GBA1
• : Rapidly progressive dementia over weeks to months with prominent myoclonus, ataxia and characteristic EEG/MRI changes (cortical ribboning, basal ganglia DWI hyperintensities); PRNP

• Establishing the diagnosis: A confirmed molecular diagnosis brings diagnostic certainty, ends the diagnostic odyssey, and provides the basis for genetic counselling and individualised follow-up.
• Clinical management: A confirmed molecular diagnosis is the prerequisite for targeted medical care; the specifics of clinical management are determined by the treating physicians in consultation with the affected individual.
• Family member testing: Identification of the familial pathogenic variant enables predictive testing of at-risk relatives and is the prerequisite for cascade testing within the family.

• 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, Gripp KW, Amemiya A, editors. GeneReviews^® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2026. PMID: 20301340.
• Hendriks S, Peetoom K, Bakker C, van der Flier WM, Papma JM, Koopmans R, et al. Global prevalence of young-onset dementia: a systematic review and meta-analysis. JAMA Neurol. 2021;78(9):1080-1090. PMID: .
• McKhann GM, Knopman DS, Chertkow H, Hyman BT, Jack CR Jr, Kawas CH, 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):263-269. PMID: .
• Zampatti S, Ragazzo M, Peconi C, Luciano S, Gambardella S, Caputo V, et al. Genetic counselling improves the molecular characterisation of dementing disorders. J Pers Med. 2021;11(6):474. PMID: .