A neuropathology case report of a woman with Down syndrome who remained cognitively stable: Implications for resilience to neuropathology

Abstract

INTRODUCTION

Aging adults with Down syndrome (DS) accumulate Alzheimer's disease (AD) neuropathology, including amyloid beta plaques and neurofibrillary tangles, by age 40.

METHODS

We present findings from an individual with DS who remained cognitively stable despite AD neuropathology. Clinical assessments, fluid biomarkers, neuroimaging, and neuropathological examinations were conducted to characterize her condition.

RESULTS

Her apolipoprotein E was ε2/ε3 and genome-wide association study data indicated mosaicism. Neuroimaging revealed stable yet elevated amyloid and moderately elevated tau levels, while neuropathology indicated intermediate AD neuropathologic change with Lewy body and cerebrovascular pathologies. The participant demonstrated stable cognitive functioning in her 60s, potentially attributed to genetic variations, cognitive resilience, and environmental enrichment.

DISCUSSION

These findings emphasize the complexity of AD progression in DS. Further investigation into factors influencing cognitive resilience in individuals with DS is warranted. Understanding the mechanisms underlying cognitive stability in DS could offer insights into resilience to AD neuropathology in people with DS and inform future interventions.

Highlights

• Findings from clinical assessments, fluid biomarkers, genotyping, neuroimaging, and neuropathological examinations of an individual with Down syndrome (DS) who remained cognitively stable despite Alzheimer's disease (AD) neuropathology are presented.
• Neuroimaging revealed stable yet elevated amyloid profiles and moderately elevated tau levels, while neuropathology indicated intermediate AD neuropathologic change with Lewy body and cerebrovascular pathologies.
• Despite the presence of AD pathology, the participant demonstrated intact cognitive functioning, potentially attributed to genetic variations, cognitive resilience, and environmental enrichment, emphasizing the complexity of AD progression in DS.

1 BACKGROUND

Aging adults with Down syndrome (DS) accumulate Alzheimer's disease (AD) neuropathology, including amyloid beta (Aβ) plaques and neurofibrillary tangles, by the age of 40 years.^{1, 2} Most older people with DS also develop mild cognitive impairment (MCI) or early signs of dementia between 48 and 56 years of age.^3-10 The Alzheimer Biomarker Consortium–Down Syndrome (ABC-DS) was established in 2015 with the goal to characterize biomarkers of AD in people with DS.¹¹ In this case report we describe a participant in ABC-DS who remained cognitively stable despite a significant neuropathology burden at an age at which up to 90% of people with DS develop the clinical features of MCI or dementia.^12-14

2 METHODS

2.1 Case description

We describe a woman in her 60s with apolipoprotein E (APOE) ε2/ε3 and trisomy 21 who remained cognitively stable up until her death. The participant was followed for 9 years in two National Institutes of Health–funded longitudinal studies of AD in DS before enrolling in the ABC-DS. Institutional review board approval and informed consent from the participant were obtained.

2.2 Clinical assessment

Full-scale IQ (FSIQ) was acquired from the medical records, in which assessments were conducted by a community provider using the Wechsler Adult Intelligence Scale, Revised Edition (WAIS-R)¹⁵ at two time points in her 30s. The Kaufman Brief Intelligence Test, 2nd Edition (KBIT-2¹⁶) was administered to the participant when she was in her 60s by an ABC-DS clinician. Overall cognitive function was assessed with the Down Syndrome Mental Status Examination (DSMSE)¹⁷ and the Rapid Assessment for Developmental Disabilities, 2nd Edition.¹⁸ Memory was evaluated with the Modified Cued Recall test.¹⁹ Attention and aspects of executive function were assessed with the Cats and Dogs Stroop²⁰ Naming and Switch tasks. Additionally, language, visuospatial abilities, and motor performance were evaluated. Dementia symptoms were assessed and characterized as the sum of cognitive and social scores from the Dementia Questionnaire for People with Learning Disabilities (DLD).²¹ The consensus diagnosis, based only on clinical and neuropsychological data, at both time points when the participant was in her 60s, was cognitively stable.¹¹

2.3 Fluid biomarkers

Cerebrospinal fluid (CSF) was collected from the participant following protocols consistent with previous studies.²² The participant underwent a lumbar puncture procedure, from which ≈ 10 to 20 mL of CSF was collected through gravity drip. Subsequently, the CSF samples were flash-frozen on dry ice before being shipped to the Fluid Biomarker Core at Washington University in St. Louis. Upon receipt, the samples were thawed and aliquoted into polypropylene tubes before being stored at −80°C. CSF biomarkers, including Aβ40, Aβ42, total tau (t-tau), and phosphorylated tau181 (p-tau181), were measured using an automated immunoassay LUMIPULSEG1200 (Fujirebio).

Peripheral blood samples were collected from the participant, with protocols for processing and analysis similar to previous studies.²³ Plasma biomarkers, including Aβ40, Aβ42, t-tau, p-tau181, p-tau217, glial fibrillary acidic protein (GFAP), and neurofilament light chain (NfL), were measured. Plasma Aβ40, Aβ42, GFAP, and NfL as well as p-tau181 were analyzed using Simoa Neurology 4-Plex E and Simoa p-Tau 181 assays (Quanterix), respectively.²⁴ Plasma p-tau217 concentration was measured using an immunoassay on a Meso Scale Discovery platform developed by Lilly Research Laboratories, calibrated with a synthetic p-tau217 peptide.^{25, 26} All fluid biomarker analyses were conducted by staff blinded to the clinical and imaging data.

2.4 Genotyping

Genomic DNA was extracted from peripheral blood collected and genotyped using Infinium General Screening Array V2, as previously described.²⁷ Mosaicism was assessed by plotting B allele frequencies against position on chromosome 21 using GenomeStudio (Illumina). Deviations of the expected 0, 0.3, 0.6, and 1 B allele frequencies were considered to show mosaicism.²⁸

2.5 Neuroimaging

Four ¹⁸F-AV-45 (florbetapir; amyloid) and two ¹⁸F-AV-1451 (flortaucipir; tau) scans were conducted during the last 5 years of the participant's life using the high resolution research tomograph (HRRT; Siemens; orientation = axial, voxel size = 1.2 mm³, matrix size = 256 × 256 × 207, reconstruction = OP-OSEM3D). The participant was injected with 10 ± 1.0 mCi of florbetapir or flortaucipir with an uptake time of ≈ 40 minutes for florbetapir and ≈ 70 minutes for flortaucipir while at rest. Image acquisition followed the Alzheimer's Disease Neuroimaging Initiative (ADNI)²⁹ protocol consisting of 4 × 5 minute frames collected 50 to 70 minutes (florbetapir) or 80 to 100 minutes (flortaucipir) after injection of the ligand. The positron emission tomography (PET) frames were realigned, averaged, and co-registered with their respective magnetic resonance imaging (MRI) scans. MRI segmentations were computed with FreeSurfer (FS6; RRID:SCR_001847). Regions of interest (ROIs) were extracted in the native MRI space from the FS6 Desikan–Killiany atlas³⁰ segmentations.  The PET counts were converted to standardized uptake value ratio (SUVR) units using the cerebellum cortex reference region. Correction for partial volume effects was performed using PETSurfer.³¹ ROI average values were calculated for meta-regions corresponding to each Braak staging (I–VI) region using the temporally closest MR scan FreeSurfer segmentations.³² Ante mortem MR scans at 3T were conducted using either a Philips Achieva or Siemens Prisma scanner with a body coil. The scan protocol included T1-weighted magnetization-produced rapid gradient echo (MPRAGE) at 1.0 mm resolution, T2-weighted fluid-attenuated inversion recovery at 5.0 mm resolution, and T2-star gradient echo (GRE) at 4.0 mm resolution.

RESEARCH IN CONTEXT

1. Systematic review: The authors conducted a literature review using PubMed and Google Scholar. Several case reports, all cited in the Discussion, describe individuals with Down syndrome (DS) over the past 3 decades.

2. Interpretation: Our comprehensive case description with deep phenotyping of a person with DS who did not develop dementia despite significant Alzheimer's disease (AD) neuropathology adds and expands upon the existing literature and suggests resilience may occur in DS.

3. Future directions: This article proposes potential factors influencing cognitive resilience in DS. Further investigation into these factors, including comorbidities and social functioning, is warranted. Understanding the mechanisms underlying cognitive stability in DS could provide insights into resilience to AD neuropathology in both people with DS and the general population and inform future interventions.

2.6 Post mortem MRI

The use of autopsy tissue for research was approved by the committee for oversight of research and clinical training involving decedents at the University of Pittsburgh and the University of California, Irvine. The post mortem interval was 15 hours. The right hemisphere was frozen, while the left hemisphere was fixed in 4% paraformaldehyde for 3 weeks and subsequently embedded in 1.5% (w/v) agar (Millipore Sigma, A5431) and 30% sucrose (Fisher, S5-3) hydrogel³³ in a 3D printed container^34-36 for post mortem MRI scanning. This scanning process used a 7T human MRI scanner, featuring a custom-built radiofrequency Tic-Tac-Toe head coil system equipped with 16 transmit channels and 32 receive channels.^37-39 Structural imaging encompassed the acquisition of T1-weighted MP2RAGE scans at a resolution of 0.37 mm isotropic, T2-weighted sampling perfection with application optimized contrast using different flip angle evolution (SPACE) imaging at a resolution of 0.41 mm, and T2-star GRE (susceptibility-weighted imaging [SWI]) at a resolution of 0.37 mm, specifically for detecting cerebral microhemorrhages. Post mortem T1 scans were used to align ante mortem T1 and gross images, facilitating comprehensive analysis.

2.7 Neuropathology

After the post mortem MRI was completed, the left hemisphere was cut into coronal slabs for neuropathological examinations. Tissue sampling and staining included all brain regions of the left hemisphere recommended by the 2012 National Institutes of Aging–Alzheimer's Association consensus criteria for the neuropathological evaluation of AD.^{40, 41} Immunohistochemical (IHC) staining for Aβ (BioLegend #803015, 1:1000) was performed to characterize the Thal phase.⁴² Tau IHC staining (Agilent #A0024, 1:3000) was performed to determine Braak neurofibrillary tangle (NFT) stage⁴³ to assess neuritic plaque density by Consortium to Establish a Registry for Alzheimer's Disease (CERAD) criteria.⁴⁴ According to the fourth consensus report of dementia with Lewy bodies consortium,⁴⁵ alpha-synuclein staining (Millipore Sigma #AB5038, 1:1000) was used to detect the presence of Lewy body-related pathology. A non-phospho-TDP-43 antibody (Proteintech #10782-2-AP, 1:2000) was used to detect the TDP-43 signal in the amygdala, hippocampus and/or entorhinal/inferior temporal cortex, as well as neocortex. Anti-IBA1 (Wako Fujifilm #019-19741, 1:1500) and anti-GFAP (Abcam #ab4648, 1:3000) antibodies with citrate buffer (pH 6.0 for 20 minutes at 95°C) for antigen retrieval were used to assess microglial and astrocytic activity in the hippocampus and in the frontal cortex.

3 RESULTS

3.1 Clinical assessment

The participant had an IQ of 69 indicating a mild level of intellectual disability (Table 1). Her body mass index (BMI) was recorded at 36.1, indicating obesity. Although her gait was slow with short steps, it was likely due to her osteoarthritis of bilateral knees and joint pain. The participant received private school education from childhood through adolescence at an institute licensed to educate students with intellectual disabilities and behavioral challenges. Until her passing, she maintained cognitive stability across visits, as evidenced by consistent performance on cognitive tests such as the DSMSE. Her Cued Recall memory scores remained stable, and she demonstrated minimal impairment in executive function, indicated by consistent Cats and Dogs Stroop Naming scores with no errors over recent years before her passing. Notably, her DLD scores in both cognitive and social domains were remarkably low, registering zero. Furthermore, she retained functional capacity, managing most of her own cooking and shopping until her death. Most of the clinical team arrived at a consensus diagnosis of cognitively stable at every cycle, although there was worsening in the DLD social scores showing increases, reflecting the onset of mild behavioral or psychiatric symptoms. However, she was reported to have appropriate social engagement and behaviors at the last visit prior to her death.

TABLE 1. Clinical data of the case.

		Visit 1	Visit 2	Visit 3	Visit 4	Visit 5	Visit 6	Visit 7	Visit 8
Cognition	FSIQ	WAIS-R = 69	–	–	–	–	–	–	KBIT-2 = 64
	DSMSE	–	84	88	90.5	84	85.5	91	83
Memory	Cued recall	–	–	–	–	36	36	35	30
Executive function	Cats and Dogs Stroop Naming time	–	–	–	–	11.5″	9.6″	10.3″	11.7″
	Cats and Dogs Stroop Naming errors	–	–	–	–	0	0	0	0
	Cats and Dogs Stroop Switch time	–	–	–	–	21.1″	20.1″	24.6″	20.3″
	Cats and Dogs Stroop Switch errors	–	–	–	–	0	0	1	0
Visuospatial	Block design	–	19	15	21	22	18	20	18
	VMI	–	22	22	22	23	22	22	19
Motor	Tinetti gait	–	–	–	–	12	12	11	10
Dementia symptoms	DLD cognitive	–	1	0	0	0	0	7	0
	DLD social	–	4	4	1	6	10	22	0

• Abbreviations: DLD, Dementia Questionnaire for People with Learning Disabilities; DSMSE, Down Syndrome Mental Status Examination; FSIQ, Full Scale IQ; KBIT-2, Kaufman Brief Intelligence Test 2nd edition; VMI, visual motor integration; WAIS-R, Wechsler Adult Intelligence Scale—Revised edition.

3.2 Fluid biomarkers

Analysis of CSF protein concentrations (Table 2) revealed elevated concentrations of Aβ40, resulting in a lower Aβ42/40 ratio. Levels of CSF p-tau181 and t-tau exceeded the manufacturer cutoffs established in the Amsterdam Dementia Cohort, which includes individuals with subjective cognitive decline, MCI, AD, and other forms of dementia.^46-48 However, it is worth noting that these levels were lower than the average observed in our previous study involving 341 participants with DS, similarly aged carriers of autosomal dominant AD mutations, and non-carrier siblings.²² Furthermore, her plasma levels of t-tau and GFAP exceeded those reported in published studies.^{23, 49, 50}

TABLE 2. CSF and plasma biomarkers of the case.

(pg/mL)	Time point 2	Time point 3	Fagan et al. Mean (SD)^22	Fujrebio cutoffs^46-48	Literature mean^23, 49, 50
CSF Aβ40	16723	–	13612 (3892)	–	>12134
CSF Aβ42	694	–	877 (287)	<600	–
CSF t-tau	627	–	644 (382)	>400	–
CSF p-tau181	74.4	–	93 (77)	>56.5	–
CSF Aβ42/40	0.042	–	0.064	<0.069	–
Plasma Aβ40	514	400	–	–	312
Plasma Aβ42	12	8.6	–	–	23
Plasma t-tau	2.4	2.6	–	–	1.5
Plasma p-tau181	2.0	2.0	–	–	22
Plasma p-tau217	0.29	–	–	–	0.91
Plasma NfL	16.1	25.3	–	–	23.7
Plasma GFAP	283	–	–	–	280

• Note: Numbers above or below the average are bolded.
• Abbreviations: Aβ, amyloid beta; CSF, cerebrospinal fluid; GFAP, glial fibrillary acidic protein; NfL, neurofilament light chain; p-tau, phosphorylated tau; SD, standard deviation; t-tau, total tau.

3.3 Genotyping

The B allele distribution obtained from the genome-wide association study (GWAS) data suggests the presence of ≈ 10% disomic cells. This indicates mosaicism at the time of peripheral blood collection.

3.4 Neuroimaging

In evaluating the amyloid PET ROI averages in the PET amyloid-specific regions, we found stable, yet elevated (SUVR range 1.0–1.7), amyloid profiles at which time the SUVR values increased with PET amyloid-specific stage IV regions (inferior temporal cortex; middle temporal cortex; temporal pole; thalamus; caudal, rostral, isthmus, posterior cingulate; insula) yielding the largest increases between time points 3 and 4 and PET amyloid-specific stage V regions (frontal cortex; parietal cortex; occipital cortex; transverse temporal cortex, superior temporal cortex; precuneus; banks of superior temporal sulcus; nucleus accumbens; caudate nucleus; putamen) yielding the highest SUVR of 1.8. These increases can be seen in Figure 1A, showing elevated amyloid PET signal. Further, we see the same profile in the superior frontal, rostral middle frontal, inferior parietal, and posterior cingulate regions. The magnitude of amyloid SUVR load in her final scan in the regions evaluated appears to be consistent with levels seen in DS with MCI as described in Keator et al.⁵¹ In contrast, tau PET ROIs of PET tau-specific regions were flat across the two time points with SUVRs in the range of 1.0 to 1.4, indicating moderately elevated, yet stable, tau. Ante mortem MRI T1-weighted MPRAGE indicated minimal brain atrophy and numerous unusual spherical lesions primarily involving the white matter and to a lesser extent the region of the caudate nuclei; the central portion of the lesions follow CSF signal on all sequences. Post mortem MRI of the left hemisphere revealed a hippocampal volume of 2577 mm³ and an amygdala volume of 768 mm³, both notably exceeding the group average (in ABC-DS post mortem MRI cohort of 23) of 2138 ± 611 mm³ and 401 ± 198 mm³, respectively. Based on the PET neuroimaging data, there may be a subtle increase in amyloid burden, particularly in the posterior cingulate, closer to the time of death, accompanied by minimal atrophy.

FIGURE 1

A, Representative images of longitudinal amyloid PET, tau PET, and MRI. B, Several cystic-appearing lesions detected in structural MRI were hypointense on both T1 and T2 FLAIR, with subtle peripheral T2 signal abnormality involving many of the lesions. By aligning ante mortem–post mortem gross images, abnormal lesions and regions with high amyloid and tau burden can be analyzed. FLAIR, fluid-attenuated inversion recovery; MRI, magnetic resonance imaging; PET, positron emission tomography.

3.5 Neuropathology

The fresh (whole) brain weight was 1083 g, exceeding the group average (in ABC-DS post mortem MRI cohort of 23) of 1043 ± 249 g. Grossly, mild atrophy was observed in the frontal cortex, parietal and temporal cortex, and hippocampus; however, this assessment may not be as precise as radiologic volumetric analysis. Immunohistochemistry determined that this case was Thal Phase 3 for Aβ deposition (A2; Figure 2A–C), Braak NFT Stage IV for neurofibrillary degeneration (B2; Figure 2D,E), and a moderate CERAD score for neocortical neuritic plaques (C2; Figure 2F), resulting in an intermediate AD neuropathologic change (A2B2C2) classification according to diagnostic criteria. Secondary neuropathology included Lewy body pathology and cerebrovascular pathology. Specifically, amygdala-predominant Lewy body pathology was identified (Figure 2G). Moderate cerebral amyloid angiopathy, notably affecting the gray matter (Figure 2H), was noted. Microcalcifications were observed in the basal ganglia, thalamus, and cerebellum (Figure 2I), along with mild arteriolosclerosis in the inferior parietal and midbrain regions (Figure 2J,K). Furthermore, microhemorrhage and macrophages in the medulla were observed (Figure 2L). No TDP-43 immunosignal was detected; hippocampal sclerosis was absent. Microglial marker IBA1 showed reactive microglia in the frontal cortex and the hippocampus (Figure 2M,N). Clusters of GFAP signals suggest reactive astroglia in the hippocampus possibly surrounding amyloid plaques (Figure 2O). Overall, the main diagnosis for this individual with DS in her 60s and a non-carrier status for APOE ε4 was intermediate AD neuropathologic change, with secondary diagnoses of Lewy body pathology and cerebrovascular pathology.

FIGURE 2

At autopsy, (A)–(C) amyloid beta deposition was observed in the frontal cortex and the hippocampal CA1 as well as the striatum, leading to a diagnosis of Thal phase 3. Additionally, (D), (E) neurofibrillary tangles were detected in the hippocampus and middle temporal gyrus, corresponding to Braak NFT stage IV. F, Nine neuritic plaques were detected in the hippocampus—a moderate Consortium to Establish a Registry for Alzheimer's Disease score. G, Lewy body pathology was evident in the amygdala. Cerebrovascular pathology includes (H) cerebral amyloid angiopathy in the frontal cortex, (I) microcalcification in the cerebellum, (J), (K) arteriolosclerosis in the inferior parietal and midbrain, and (L) microhemorrhage in the medulla. M, N, IBA1 staining shows reactive (arrowhead) and rod (arrow) microglia in the frontal gyrus and the hippocampus. O, Clusters of GFAP signals suggest reactive astroglia in the hippocampus possibly surrounding amyloid plaques. Scale bars represent 100 µm.

4 DISCUSSION

We describe a unique individual with DS, who had medical and cognitive test records over a 31-year period, and neuroimaging and fluid biomarker data during the last 10 years of her life. She maintained intact cognitive functioning despite showing intermediate AD neuropathology at autopsy. This case description contributes to the other reports of individuals with DS who did not develop dementia into their late 60s,⁵² 70s,^53-57 and 80s.⁵⁸

This case contributes to the expanding body of literature⁵⁹ aimed at understanding the phenomenon of resistance to cognitive decline among individuals with AD neuropathology who remain non-demented. Various compensatory mechanisms have been proposed, including the concept of “cognitive reserve.” Research suggests that individuals with higher levels of education tend to exhibit less cognitive impairment compared to those with lower education levels, potentially due to more advantageous lifestyle choices.^60-66 In our case, the individual possessed notably high levels of education compared to peers with DS from her generation. This enriched learning environment may have contributed to her cognitive reserve.

Another proposed compensatory mechanism is “brain reserve.” Individuals with larger brain reserves, characterized by greater synaptic density and a larger number of healthy neurons, may require more pathology to exhibit clinical dementia symptoms.^{67, 68} This delay in symptom manifestation may occur because substantial pathology accumulates before clinical symptoms become evident.^69-72 Our case exhibited a larger brain compared to typical individuals with DS in autopsy cases, suggesting a potential brain reserve effect.

A third potential compensatory mechanism is “genetic advantage.” Certain genetic mutations may confer resistance to dementia by inhibiting the formation of NFTs or enhancing the clearance of Aβ.^{73, 74} This genetic advantage may be particularly relevant in cases of non-demented individuals demonstrating intermediate AD neuropathologic changes (NDAD),^75-81 characterized by Braak NFT stage II through IV and moderate to frequent CERAD scores. Our case aligns with this profile, exhibiting features consistent with NDAD and intermediate AD neuropathologic changes.

In this case report, examination of longitudinal amyloid PET scans revealed an increase in cortical amyloid uptake compared to the cerebellum in several regions, including the superior frontal, rostral middle frontal, inferior parietal, and posterior cingulate areas. Tau PET ROIs exhibited a consistent level of tau accumulation, with SUVRs ranging from 1.0 to 1.4, indicating moderately elevated tau levels but remaining stable. However, it's important to note that this assessment occurred 3 years before the autopsy. There is a possibility of a subsequent accumulation of tau, potentially progressing toward Braak NFT Stage IV (B2) as observed by neuropathology.

Despite being cognitively stable, the subject's neuropathological outcomes suggest an intermediate level of AD neuropathologic change, with cerebrovascular pathology and amygdala-predominant Lewy body pathology as well as signals related to reactive microglia and astroglia. Lewy bodies in the amygdala in DS are not uncommon and depending on the cohort study prevalence ranges from 11% to 50%.^82-85 Several genes on chromosome 21 have been linked to neuroinflammation, including S100B, which can contribute to astrocytic reactivity.^{86, 87} Rod microglia and reactive microglia are found in DS brains before and after the development of AD neuropathology.^{88, 89}

In elderly people,⁹⁰ it is not uncommon to encounter cases in which AD neuropathological changes are found in individuals clinically diagnosed as non-demented. This case may be one of those instances in which clinical and pathological diagnoses do not align.

In DS, there are three genetic causes including the most common full trisomy 21, mosaicism, and partial trisomy.^91-93 A case report of partial trisomy 21 highlighted that the absence of amyloid precursor protein overexpression was associated with a lack of AD development.^{57, 93} Mosaicism for chromosome 21 at birth is linked to a phenotype characterized by less severe intellectual disability.⁹⁴ Because a blood karyotype was never completed, it is uncertain whether she had full trisomy 21 at birth. One possible explanation for her cognitive stability despite the presence of AD pathology is that she was full trisomy 21 at birth and acquired mosaicism throughout her life.^{27, 95} Alternatively, she might have been mosaic at birth, with cognitive stability primarily influenced by other factors.

The presence of APOE ε4 leads to a high risk for AD in the general population while the presence of APOE ε2 is thought to be protective.^96-99 In DS, multiple studies have assessed the impact of APOE genotype on the development of dementia. APOE ε2 is linked to a decreased risk of dementia in individuals with DS.^100-102 In a large cohort study, the APOE ε4 allele was associated with earlier clinical and biomarker changes of AD in DS. Thus, the presence of APOE ε2/ε3 in this case study may also be part of the underlying reason for protection from dementia.

Factors like greater cognitive resilience may also have been protective in the person described here,¹⁰³ as suggested by studies indicating that some individuals with DS maintain cognitive abilities through older ages.^{104, 105} IQ or level of intellectual disability was not related to risk or age at onset of AD for adults with DS when severity of intellectual disability was included as a covariate in the analysis.^106-108

In DS, we have a limited understanding of how to assess the impact of comorbidities in relation to biomarkers and other measures. Studies focusing on the late-onset AD population found that a higher Charlson Comorbidity Index, particularly BMI, is associated with elevated levels of plasma Aβ40 and t-tau.¹⁰⁹ This association may explain why this participant exhibited higher plasma Aβ40 levels compared to the published studies (Table 2). Additionally, studies in the general population suggested that the increase in comorbidities is related to increasing age. For example, the prevalence of hearing impairment and thyroid disorders in DS dramatically increases after age 60.¹¹⁰ However, in contrast, a 4-year prospective cohort study of neurotypical older adults with dementia found no association between Charlson Comorbidity Index and cognitive function.¹¹¹

This case report has one major limitation: we did not examine the human chromosome 21 region of trisomy/triplicated genes, which could provide insights into the cognitive and neuropathological status of this individual. Future experiments will include conducting a comprehensive omics investigation of blood and brain samples from this individual to determine which genes are triplicated in both the periphery and the brain and to identify any differences between the two. Age-matched disomic controls, as well as individuals with DS, will serve as comparators. As more individuals with DS reach older ages, we anticipate identifying more that remain cognitively stable to allow for studies of resilience to AD neuropathology. Given the full penetrance of AD neuropathology over the age of 40 years in people with trisomy 21, this may be an exciting cohort to include in resilience studies.

ACKNOWLEDGMENTS

The authors are grateful to the ABC-DS participant, her family and care providers, and the ABC-DS research and support staff for their contributions to this study. Funding to support this study was from the National Institutes of Health/National Institute on Aging (U19AG068054, P30AG066519, U01AG051412, RF1AG079519, P01AG025204, P01AG014449), and the National Institutes of Health/Eunice Kennedy Shriver National Institute of Child Health and Human Development (R01HD065160). L.F.A. was also supported by the Alzheimer Association and by the Jerome Lejeune Foundation.

CONFLICT OF INTEREST STATEMENT

Dr. Mapstone is an inventor on patents related to fluid biomarkers of neurological disease owned by the University of Rochester and Georgetown University. All other authors do not have any conflicts to disclose specific to this study. Author disclosures are available in the Supporting Information.

CONSENT STATEMENT

Institutional review board approval and informed consent were obtained during enrollment into the study by the participant according to the Declaration of Helsinki.