The landscape of autosomal-dominant Alzheimer's disease: global distribution and age of onset

Abstract

We present a comprehensive global analysis of genetic variants associated with autosomal-dominant Alzheimer's disease (ADAD). A total of 550 variants in the APP, PSEN1 and PSEN2 genes were identified, of which 279 were classified as pathogenic or likely pathogenic based on American College of Medical Genetics and Genomics and the Association for Molecular Pathology criteria, utilizing data from the Dominantly Inherited Alzheimer Network (DIAN), literature and public databases. Symptomatic age at onset (AAO) data were estimated for 227 of these variants, allowing detailed characterization of their frequency, pathogenicity and AAO. Importantly, 226 variants met eligibility criteria for inclusion in disease-modifying clinical trials. Furthermore, we demonstrated the predictive value of mean variant AAO and parental AAO in predicting symptomatic AAO, validated against converters who became symptomatic during follow-up in the DIAN Observational Study. This dataset provides critical insights into the global landscape of ADAD and reveals the genetic and AAO heterogeneity of ADAD variants while refining variant trial eligibility criteria.

Keywords: amyloid precursor protein; pathogenicity; presenilin-1; presenilin-2; prevalence.

Figure 1

Systematic review flow chart. Flow chart outlines the sequential steps in the systematic literature review.

Figure 2

Dominantly Inherited Alzheimer Network–Trials Unit (DIAN-TU) algorithm to classify variant trial eligibility. Algorithm to assess eligibility for DIAN-TU trials. This model was modified from a previously proposed algorithm.^, GnomAD frequency is used to determine whether APP, PSEN1 and PSEN2 variants represent rare or common polymorphisms. Autosomal-dominant Alzheiemer's disease (ADAD) pathogenic variant PSEN1 A79 V allele frequency is used as a cut-off reference to define rare variants. Additional supportive criteria include: (a) whether other variants at the same residue have previously been confirmed as pathogenic; (b) whether a given presenilin variant is at a residue conserved between PSEN1 and PSEN2; (c) the number of unrelated families in which the variant is present at a consistent age at onset and evidence of AD biomarkers; (d) the number of generations with early-onset AD (<65 years); and (e) in silico predictions (CADD, REVEL score or comparable computational score). **The presence of multiple affected family members is considered supportive evidence but not required for variant review or trial inclusion. APP, PSEN1 and PSEN2 de novo variants are also assessed for pathogenicity by the Clinical-Genetic Committee using the DIAN algorithm. Families that exhibit multigenerational incidences of biomarker-confirmed Alzheimer’s dementia and age of onset under 40 years are automatically deemed eligible for inclusion in the trial while additional evidence is systematically gathered. CADD = Combined Annotation Dependent Depletion; REVEL = rare exome variant ensemble learne; GnomAD = Genome Aggregation Database.

Figure 3

Global distribution of pathogenic autosomal-dominant Alzheimer's disease variants. Number of pathogenic variants in APP, PSEN1 or PSEN2 by country. The map displays PSEN1 variants in green, APP variants in yellow and PSEN2 variants in red. The colours indicate the presence of different genetic variants among various countries but not the distribution within each country. The count of variants within individual genes is represented numerically.

Figure 4

Individual symptomatic age at onset (AAO) versus variant AAO and accuracy assessment of AAO.  Top: Each affected individual participant’s symptomatic AAO (n = 2110) on the y-axis, plotted against values predicted from variant AAO on the x-axis. Top left: All individuals combined, regardless of gene type. Data points are coloured/shaped according to each variant for autosomal-dominant Alzheimer’s disease. Top right: All individuals according to gene (PSEN1, PSEN2, APP). Bottom left: Relationship between converter and variant AAO, and (bottom right) between converter and parental AAO. Blue filled squares = PSEN1; red filled circles = PSEN2; green filled triangles = APP. Regression lines and adjusted R² values show the strength of the association between individual AAO and variant AAO. Converters are participants who transitioned from being asymptomatic to symptomatic during follow-up in the Dominantly Inherited Alzheimer Nework observational study.