The pattern of amyloid accumulation in the brains of adults with Down syndrome

Annus, Tiina; Wilson, Liam R.; Hong, Young T.; Acosta‐Cabronero, Julio; Fryer, Tim D.; Cárdenas-Blanco, Arturo; Smith, Robert V.; Boros, István; Coles, Jonathan P.; Aigbirhio, Franklin I.; Menon, David; Zaman, Shahid; Nestor, Peter J.; Holland, Anthony

doi:10.1016/j.jalz.2015.07.490

Cited by 152 publications

(206 citation statements)

References 43 publications

(59 reference statements)

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“…In a sample of 12 adults with DS without clinical AD, Florbetapir-PET was not significantly associated with cognitive functioning (Rafii et al, 2015). Chronological age was strongly associated with PiB - or Florbetapir-PET retention in several previous cross-sectional studies (Annus et al, 2016; Hartley et al, 2014; Nelson et al, 2011; Sabbagh et al, 2015), such that the effect of normative age-related decline may have been indistinguishable from the effect of amyloid-β accumulation.…”

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confidence: 71%

“…The study also builds on previous cross-sectional studies in DS (e.g., Annus et al, 2016; Nelson et al, 2011) by including an extensive neuropsychological battery. Across the 3 years, adults with DS evidenced increased amyloid-β accumulation in the AVS and across the neocortex (details see Lao et al, under review).…”

Section: Discussionmentioning

confidence: 99%

“…Analyses then examined the association between change in neuropsychological measures (from Cycle 1 to Cycle 2) and change in both global and AVS-only PiB retention (from Cycle 1 to Cycle 2) as a continuous variable, without controlling for chronological age (Pearson correlations) and then controlling for chronological age (multiple linear regressions). The AVS was analyzed individually because this region reveals the earliest presence of elevated PiB binding in the DS population (Annus et al, 2016; Hartley et al, 2014; Nelson et al, 2011; Lao et al, 2016). Finally, one-way analyses of variance (ANOVAs) and Bonferroni-corrected post-hoc comparisons examined differences in neuropsychological measures by PiB categorization status (consistently PiB−, consistently PiB+, and converted from PiB− to PiB+).…”

Section: Data Analysis Planmentioning

confidence: 99%

“…However, conclusions are limited due to cross-sectional designs (Annus et al, 2016; Handen et al, 2012; Hartley et al, 2014; Nelson et al, 2011), small sample sizes (Handen et al, 2012), and restricted neuropsychological batteries of cognitive functioning (Nelson et al, 2011). In the largest cross-sectional study, and the one with the most extensive battery of directly-administered neuropsychological measures, Hartley et al (2014) found a negative association between neocortical PiB retention and verbal and visual episodic memory, executive functioning, and expressive language in 63 adults with DS (aged 30–50 years) who did not exhibit clinical signs of AD.…”

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confidence: 99%

“…In addition to assessing neocortical PiB retention, we examined PiB retention in the striatum, as it is the brain region with the earliest amyloid-β accumulation in the DS population (Annus et al, 2016; Lao et al, 2016). PiB retention was evaluated as both a continuous variable and dichotomous variable by categorizing adults with DS as PiB + versus PiB−, in line with previous studies (Annus et al, 2016; Hartley et al, 2014; Nelson et al, 2011; Lao et al, 2016). Analyses were conducted with and without controlling for chronological age to separate out the effects of normative aging from those of amyloid-β accumulation.…”

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confidence: 99%

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Cognitive decline and brain amyloid-β accumulation across 3 years in adults with Down syndrome

Hartley

Handen

Devenny

et al. 2017

Neurobiology of Aging

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Adults with Down syndrome (DS) have a high incidence of Alzheimer’s disease (AD), providing a unique opportunity to explore the early, preclinical stages of AD neuropathology. We examined change in brain amyloid-β accumulation via the PET tracer [11C] Pittsburgh compound B (PiB) across two data collection cycles, spaced 3 years apart, and decline in cognitive functioning in 58 adults with DS without clinical AD. PiB retention increased in the anterior cingulate gyrus, precuneus cortex, parietal cortex and anterior ventral striatum. Across the two cycles, 14 (27.5%) participants were consistently PiB+, 31 (60.8%) were consistently PiB−, and 6 (11.7%) converted from PiB− at Cycle 1 to PiB+ at Cycle 2. Increased global amyloid-β was related to decline in verbal episodic memory, visual episodic memory, executive functioning, and fine motor processing speed. Participants who were consistently PiB+ demonstrated worsening of episodic memory, whereas participants who were consistently PiB− evidenced stable or improved performance. Amyloid-β accumulation may be a contributor to or biomarker of declining cognitive functioning in preclinical AD in DS.

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confidence: 71%

Section: Discussionmentioning

confidence: 99%

Section: Data Analysis Planmentioning

confidence: 99%

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confidence: 99%

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confidence: 99%

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Cognitive decline and brain amyloid-β accumulation across 3 years in adults with Down syndrome

Hartley

Handen

Devenny

et al. 2017

Neurobiology of Aging

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Association of Apolipoprotein E ɛ4 Allele With Clinical and Multimodal Biomarker Changes of Alzheimer Disease in Adults With Down Syndrome

et al. 2021

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IMPORTANCE Alzheimer disease (AD) is the leading cause of death in individuals with Down syndrome (DS). Previous studies have suggested that the APOE ε4 allele plays a role in the risk and age at onset of dementia in DS; however, data on in vivo biomarkers remain scarce.OBJECTIVE To investigate the association of the APOE ε4 allele with clinical and multimodal biomarkers of AD in adults with DS.

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Safety, Tolerability, and Immunogenicity of the ACI-24 Vaccine in Adults With Down Syndrome

et al. 2022

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IMPORTANCE Individuals with Down syndrome (DS) are at high risk of developing Alzheimer disease due to an increased dose of the amyloid precursor protein gene, APP, which leads to increased levels of full-length APP and its products, including amyloid-β (Aβ). The liposome-based antiamyloid ACI-24 vaccine is intended to treat neurological disorders caused by misfolded Aβ pathological protein. However, the safety, tolerability, and immunogenicity of the ACI-24 vaccine among adults with DS have not been fully examined.OBJECTIVE To assess the safety and tolerability of the ACI-24 vaccine among adults with DS as well as its ability to induce immunogenicity measured by anti-Aβ immunoglobulin G titers. DESIGN, SETTING, AND PARTICIPANTSThis multicenter double-blind placebo-controlled dose-escalation phase 1b randomized clinical trial was conducted at 3 US academic medical centers with affiliated Down syndrome clinics between March 30, 2016, and June 29, 2020. A total of 20 adults with DS were screened; of those, 16 adults were eligible to participate. Eligibility criteria included men or women aged 25 to 45 years with cytogenetic diagnosis of either trisomy 21 or complete unbalanced translocation of chromosome 21. Between April 27, 2016, and July 2, 2018, participants were randomized 3:1 into 2 dose-level cohorts (8 participants per cohort, with 6 participants receiving the ACI-24 vaccine and 2 receiving placebo) in a 96-week study. Participants received 48 weeks of treatment followed by an additional 48 weeks of safety follow-up. INTERVENTIONSParticipants were randomized to receive 7 subcutaneous injections of ACI-24, 300 μg or 1000 μg, or placebo. MAIN OUTCOMES AND MEASURESPrimary outcomes were measures of safety and tolerability as well as antibody titers. RESULTS Among 16 enrolled participants, the mean (SD) age was 32.6 (4.4) years; 9 participants were women, and 7 were men. All participants were White, and 1 participant had Hispanic or Latino ethnicity. Treatment adherence was 100%. There were no cases of meningoencephalitis, death, or other serious adverse events (AEs) and no withdrawals as a result of AEs. Most treatment-emergent AEs were of mild intensity (110 of 132 events [83.3%]) and unrelated or unlikely to be related to the ACI-24 vaccine (113 of 132 events [85.6%]). No amyloid-related imaging abnormalities with edema or cerebral microhemorrhage and no evidence of central nervous system inflammation were observed on magnetic resonance imaging scans. Increases in anti-Aβ immunoglobulin G titers were observed in 4 of 12 participants (33.3%) receiving ACI-24 (2 receiving 300 μg and 2 receiving 1000 μg) compared with 0 participants receiving placebo. In addition, a greater increase was observed in plasma Aβ1-40 and Aβ1-42 levels among individuals receiving ACI-24.CONCLUSIONS AND RELEVANCE In this study, the ACI-24 vaccine was safe and well tolerated in adults with DS. Evidence of immunogenicity along with pharmacodynamic and target engagement were observed, and anti-Aβ antibody titers were not associated with a...

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The pattern of amyloid accumulation in the brains of adults with Down syndrome

Cited by 152 publications

References 43 publications

Cognitive decline and brain amyloid-β accumulation across 3 years in adults with Down syndrome

Cognitive decline and brain amyloid-β accumulation across 3 years in adults with Down syndrome

Association of Apolipoprotein E ɛ4 Allele With Clinical and Multimodal Biomarker Changes of Alzheimer Disease in Adults With Down Syndrome

Safety, Tolerability, and Immunogenicity of the ACI-24 Vaccine in Adults With Down Syndrome

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