Alzheimer's disease associated with Down syndrome: a genetic form of dementia

Abstract

Adults with Down syndrome develop the neuropathological hallmarks of Alzheimer's disease and are at very high risk of developing early-onset dementia, which is now the leading cause of death in this population. Diagnosis of dementia remains a clinical challenge because of the lack of validated diagnostic criteria in this population, and because symptoms are overshadowed by the intellectual disability associated with Down syndrome. In people with Down syndrome, fluid and imaging biomarkers have shown good diagnostic performances and a strikingly similar temporality of changes with respect to sporadic and autosomal dominant Alzheimer's disease. Most importantly, there are no treatments to prevent Alzheimer's disease, even though adults with Down syndrome could be an optimal population in whom to conduct Alzheimer's disease prevention trials. Unprecedented research activity in Down syndrome is rapidly changing this bleak scenario that will translate into disease-modifying therapies that could benefit other populations.

Figure 1:. Lifelong accumulation of Alzheimer’s disease neuropathology.

Intraneuronal amyloid accumulation starts in the first decade of life (blue dotted line, 1- frontal cortex). Extracellular diffuse plaques (blue line) start in teenagers and are systematically observed after 30 years of age (2- cingulate gyrus). Amyloid deposition progresses with the accumulation of compact neuritic plaques (3- superior temporal gyrus) in the fourth decade. Tau pathological changes are observed starting in the third decade, with subsequent appearance of neurofibrillary tangles in the fourth decade (NFT) (4- superior temporal gyrus). After 40 years pathological diagnostic criteria for Alzheimer’s disease are fulfilled (green line,3, 4) and pathological changes continue to increase in severity in old age (5- frontal cortex). Amyloid and tau deposition can be detected through in vivo biomarkers. Cerebrospinal fluid changes occur almost 10 years before they are detectable in PET. After age 40, the prevalence of dementia increases exponentially affecting more than 90% of the adults in those older than 60 years of age (red line).

Figure 2.. Case study.

The upper row shows the cortical atrophy (difference map between the first and las MRI scan) and both the amyloid and tau PET SUVRs using the Pittsburgh compound B and flortaucipir ligands respectively. The lower row shows the longitudinal intra-individual trajectory of the biomarker changes with respect the described changes with age in Down syndrome as described by Fortea & colleagues. The plotted changes with age for the CAMCOG-DS were those described in individuals with mild intellectual disability. Coloured dots indicate the different timepoints for assessment and black dots indicate the timepoint in which the displayed neuroimage was performed.

Figure 3:. Integrated models of the natural history of Down syndrome-associated Alzheimer’s disease (DSAD) and autosomal dominant Alzheimer’s disease (ADAD).

Comparison of the clinical and biomarker changes (standardised differences) as a function of age in Down syndrome (left) and autosomal dominant Alzheimer’s disease (right). The DSAD model is based on the study published by Fortea & colleagues and includes a hypothetical for tau uptake in PET (***green dotted line) based on the scarce data in Down syndrome. The ADAD model is based on that published by Bateman & colleagues. We have added the trajectory of plasma neurofilament light based on a large recent study (*orange line), and the hypothetical trajectory of Tau deposition measured by Tau-PET (***green dotted line). We have inverted the trajectory of the clinical dementia rating scale sum of boxes (CDR-SOB) to more easily compare the cognitive changes in ADAD and DSAD.

Figure 4.. Framework for clinical trials in Down syndrome.

The two upper arrows for the AT(N) reflect the different timings for the earliest changes in CSF and PET, which in turn would affect the definition of primary or secondary prevention trials (third arrow). The model includes the different clinical outcomes reflecting the clinical progression of Alzheimer disease in Down syndrome. Subtle memory/executive deficits can appear from 35 years of age, prodromal Alzheimer’s disease appears with a mean age of presentation of 50·8 years (*) while dementia presents with a mean age of onset of 53·8 (**) years of age. The Gaussians below the X-axis reflect de density of prodromal and AD dementia diagnosis in Fortea et al paper. The vertical dotted lines reflect the earliest biomarker changes for the amyloid and tau biomarkers. The lower arrow summarizes the age spans in which different types of intervention trials could be performed in adults with Down syndrome, following the new Food and Drug Administration guidanceº.