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INTRODUCTION Both micro‐ and macrostructural white matter (WM) abnormalities, particularly those related to axonal degeneration, are associated with cognitive decline in adults with Down syndrome (DS) prior to a diagnosis of Alzheimer disease. Neurofilament light chain (NfL) is a support protein within myelinated axons released into blood following axonal damage. In this study we investigated cross‐sectional relationships between WM microstructural changes as measured by diffusion tensor imaging (DTI) and plasma NfL concentration in adults with DS without dementia. METHODS Thirty cognitively stable (CS) adults with DS underwent diffusion‐weighted MRI scanning and plasma NfL measurement. DTI measures of select WM tracts were derived using automatic fiber tracking, and associations with plasma NfL were assessed using Spearman correlation coefficients. RESULTS Higher Plasma NfL was associated with greater altered diffusion measures of select tracts. DISCUSSION Early increases in plasma NfL may reflect early white matter microstructural changes prior to dementia in DS. Highlights The onset of such WM changes in DS has not yet been widely studied. WM microstructural properties correlated with plasma neurofilament light chain (NfL). NfL may reflect early, selective WM changes in adults with DS at high risk of developing AD.

Adults with Down syndrome (DS) have an exceptionally high frequency of Alzheimer disease (AD) with a wide variability in onset, from 40 to 70 years of age. Equally prevalent in DS is hypothyroidism. In this study, we sought to quantify the relationship between the two. A total of 232 adults with DS and AD were stratified into three AD onset age groups: early (<47 years), typical (48–59), and late (>59). Among patients with available data, differences in the distributions of demographics, hypothyroidism variables (presence, age of onset), thyroid function tests, thyroid autoantibodies, and APOE genotypes were assessed (e.g., chi-squared, Mann–Whitney tests). Spearman and partial Spearman correlations and ordinal logistic regression models were constructed to quantify the association between ages of AD and hypothyroidism onset with and without covariate adjustments. We observed a positive association between the ages of AD and hypothyroidism onset after accounting for APOE-Ɛ4 (correlation: 0.44, 0.24, 0.60; odds ratio: 1.09, 1.05–1.14). However, an early age of hypothyroidism onset and the presence of the APOE-Ɛ4 allele were independently associated with the early age of AD onset. Similar findings were observed when accounting for other factors. Our study provides evidence for the importance of hypothyroidism and associated pathological mechanisms for risk of AD in DS.

Accurate identification of the prodromal stage of Alzheimer’s disease (AD), known as mild cognitive impairment (MCI), in adults with Down syndrome (MCI-DS) has been challenging because there are no established diagnostic criteria that can be applied for people with lifelong intellectual disabilities (ID). As such, the sequence of cognitive decline in adults with DS has been difficult to ascertain, and it is possible that domain constructs characterizing cognitive function in neurotypical adults do not generalize to this high-risk population. The present study examined associations among multiple measures of cognitive function in adults with DS, either prior to or during the prodromal stage of AD to determine, through multiple statistical techniques, the measures that reflected the same underlying domains of processing. Participants included 144 adults with DS 40–82 years of age, all enrolled in a larger, multidisciplinary study examining biomarkers of AD in adults with DS. All participants had mild or moderate lifelong intellectual disabilities. Overall AD-related clinical status was rated for each individual during a personalized consensus conference that considered performance as well as health status, with 103 participants considered cognitively stable (CS) and 41 to have MCI-DS. Analyses of 17 variables derived from 10 tests of cognition indicated that performance reflected three underlying factors: language/executive function, memory, and visuomotor. All three domain composite scores significantly predicted MCI-DS status. Based upon path modeling, the language/executive function composite score was the most affected by prodromal AD. However, based upon structural equation modeling, tests assessing the latent construct of memory were the most impacted, followed by those assessing visuomotor, and then those assessing language/executive function. Our study provides clear evidence that cognitive functioning in older adults with DS can be characterized at the cognitive domain level, but the statistical methods selected and the inclusion or exclusion of certain covariates may lead to different conclusions. Best practice requires investigators to understand the internal structure of their variables and to provide evidence that their variables assess their intended constructs.

INTRODUCTION Lipoprotein a (Lp(a)) is a low‐density lipoprotein (LDL)‐like particle that has been associated with risk for vascular inflammation, atherogenesis, calcification, and thrombosis in the general population but is also a risk factor for Alzheimer disease (AD). OBJECTIVE The aim of this study was to conduct a retrospective study of lipoprotein a, Lp(a), levels in adults with Down syndrome (DS) and at risk for Alzheimer's disease (AD). METHODS Lp(a) serum concentrations were collected from 96 adults as part of a routine clinical assessment. A comprehensive medical chart review was conducted, including clinical laboratory values that could contribute to cognitive dysfunction (e.g., thyroid function tests, C‐reactive protein(CRP), vitamin B12, lipid profiles, and vitamin D levels). Generalized linear regression models were constructed to quantify the relationship between each medical condition or laboratory value and Lp(a) level. RESULTS There was insufficient evidence for an increased risk for earlier age of onset of AD in those with elevated Lp(a) plasma levels (≥50 mg/dL). DISCUSSION Adults with DS may have unique neuro‐ and cardio‐ protective factors that deserve future investigation. Highlights Lipoprotein a (Lp(a)) elevations in Down syndrome (DS) are not associated with higher risk for Alzheimer's disease (AD). Lp(a) elevations are not associated with typical vascular risk factors in DS. Distinct neuro‐ and cardio‐ protective factors may play a role in DS that may provide novel insights.

Variable (Range of Scores) Domain CS (n = 103) MCI-DS (n = 41) Mann–Whitney U (p-Value) Block Design (0–54) Visuomotor 23.79 (10.49) 17.37 (12.78) 3.11 (0.002) Boston Naming (0–27) Language 15.88 (5.51) 13.23 (6.91) 2.04 (0.041) Category Fluency (0–17) EF 8.23 (3.18) 6.82 (3.68) 2.21 (0.027) Cats and Dogs Switch (--17.00–61.80) † EF 9.80 (11.22) 5.05 (11.21) 1.82 (0.069) Cued Recall (3–35) Memory 28.61 (6.83) 21.38 (9.22) 4.43 (0.0001) DSMSE Language (3–52) Language 37.10 (9.07) 30.80 (9.63) 3.28 (0.001) DSMSE Memory (0–23) Memory 14.08 (4.68) 9.80 (4.57) 4.62 (0.0001) DSMSE Visual Spatial (2–8) Visuomotor 6.18 (1.09) 5.59 (1.01) 2.98 (0.003) mMMSE-DS Anomia (4–20) Language 18.18 (2.20) 16.49 (4.19) 1.55 (0.122) mMMSE-DS Concentration (0–6) EF 3.69 (2.10) 2.39 (2.14) 3.15 (0.002) mMMSE-DS Fine Motor (1–10) Visuomotor 8.04 (1.29) 7.05 (2.28) 2.58 (0.010) mMMSE-DS Orientation (5–30) EF 25.46 (5.33) 20.87 (6.41) 4.75 (0.0001) Purdue Pegboard Both Hands (0–8) Visuomotor 2.62 (1.82) 1.51 (1.71) 3.14 (0.002) RADD-2 Digit Span Forward (0–8) EF 4.02 (1.66) 2.97 (1.80) 2.84 (0.005) RADD-2 Expressive Lang. (0–12) Language 7.56 (2.51) 6.80 (2.99) 1.08 (0.279) RADD-2 Sensorimotor (0–7) Visuomotor 6.70 (0.50) 5.85 (1.50) 3.87 (0.0001) RADD-2 Similarities (0–4) Language 2.51 (1.49) 1.56 (1.47) 3.40 (0.001) Rivermead Recognition (0–10) Memory 5.42 (3.77) 2.21 (3.40) 3.90 (0.0001) Selective Reminding Test (1–24) Memory 15.50 (5.62) 9.18 (4.32) 5.70 (0.0001) Tinetti Gait (4–12) Visuomotor 10.75 (1.62) 10.37 (1.88) 1.47 (0.143) VMI (1–25) Visuomotor 15.45 (3.22) 13.98 (3.40) 1.75 (0.081) † Cats and Dogs is measured in seconds; all other scores are measured in points (number correct). Cognitive Domain Predictor Variable Estimate SE CR Standardized Regression Weight p-Value Structural Language/EF Sex −0.010 0.075 −0.13 −0.01 0.893 Language/EF PID −0.413 0.067 −6.15 −0.41 <0.001 Language/EF MCI-DS −0.238 0.074 −3.23 −0.24 0.001 Memory Sex 0.008 0.076 0.11 0.01 0.916 Memory PID −0.241 0.075 −3.21 −0.24 0.001 Memory MCI-DS −0.471 0.67 −7.07 −0.47 <0.001 Visuomotor Sex −0.093 0.081 −1.14 −0.09 0.255 Visuomotor PID −0.302 0.077 −3.91 −0.30 <0.001 Visuomotor MCI-DS −0.303 0.78 −3.90 −0.30 <0.001 Measurement Language/EF Boston Naming 0.879 0.023 38.18 0.88 <0.001 Language/EF DSMSE Language 0.878 0.023 37.81 0.88 <0.001 Language/EF mMMSE Anomia 0.742 0.041 18.14 0.74 <0.001 Language/EF mMMSE Concentration 0.724 0.043 16.53 0.72 <0.001 Language/EF RADD-2 Digit Span Forward 0.782 0.036 21.93 0.78 <0.001 Language/EF RADD-2 Expressive Language 0.874 0.023 37.52 0.87 <0.001 Language/EF RADD-2 Receptive Language 0.683 0.047 16.53 0.68 <0.001 Language/EF RADD-2 Similarities 0.760 0.038 20.05 0.76 <0.001 Memory Cued Recall 0.673 0.053 12.65 0.67 <0.001 Memory DSMSE Memory 0.858 0.032 27.09 0.86 <0.001 Memory Rivermead Recognition 0.702 0.051 13.87 0.70 <0.001 Memory Selective Reminding Test 0.845 0.033 25.65 0.85 <0.001 Visuomotor Block Design 0.849 0.033 26.09 0.85 <0.001 Visuomotor DSMSE Visual Spatial 0.797 0.038 17.05 0.80 <0.001 Visuomotor Purdue Pegboard 0.615 0.59 10.39 0.62 <0.001 Visuomotor RADD Sensorimotor 0.624 0.058 10.70 0.62 <0.001 Visuomotor VMI 0.708 0.048 14.77 0.71 <0.001 CR = critical ratio, EF = executive function, MCI = mild cognitive impairment, PID = premorbid level of ID, SE = standard error.

INTRODUCTION Gut dysbiosis has been found to play a role in sporadic Alzheimer's disease (AD) but has not been explored in Down syndrome (DS), despite the strong relationship between DS and early AD. Here, we compared the gut microbiomes of 20 adults with DS, either cognitively stable or with mild cognitive impairment. METHODS DNA from stool samples was profiled using 16S rRNA sequencing. RESULTS Cognitive status was associated with a significant difference in overall microbiome composition (p < 0.01) and with significant differences in the abundance of Bacteroidaceae, Enterobacteriaceae, and Christensenellaceae. CONCLUSION Just as in sporadic AD, AD in DS is associated with gut dysbiosis. Our work suggests that this is an important area for future investigation, one that may provide a novel and important target for therapeutic intervention. Highlights Alterations in the gut microbiome are present in adults with Down syndrome (DS) with mild cognitive impairment (MCI). Increased taxa in DS‐MCI that contribute to inflammation and disrupt blood–brain barrier. Suggests a possible role of gut dysbiosis in Alzheimer's disease in adults with DS.

SIGNAL is a multicenter, randomized, double-blind, placebo-controlled phase 2 study (no. NCT02481674) established to evaluate pepinemab, a semaphorin 4D (SEMA4D)-blocking antibody, for treatment of Huntington’s disease (HD). The trial enrolled a total of 265 HD gene expansion carriers with either early manifest (EM, n  = 179) or late prodromal (LP, n  = 86) HD, randomized (1:1) to receive 18 monthly infusions of pepinemab ( n  = 91 EM, 41 LP) or placebo ( n  = 88 EM, 45 LP). Pepinemab was generally well tolerated, with a relatively low frequency of serious treatment-emergent adverse events of 5% with pepinemab compared to 9% with placebo, including both EM and LP participants. Coprimary efficacy outcome measures consisted of assessments within the EM cohort of (1) a two-item HD cognitive assessment family comprising one-touch stockings of Cambridge (OTS) and paced tapping (PTAP) and (2) clinical global impression of change (CGIC). The differences between pepinemab and placebo in mean change (95% confidence interval) from baseline at month 17 for OTS were −1.98 (−4.00, 0.05) (one-sided P  = 0.028), and for PTAP 1.43 (−0.37, 3.23) (one-sided P  = 0.06). Similarly, because a significant treatment effect was not observed for CGIC, the coprimary endpoint, the study did not meet its prespecified primary outcomes. Nevertheless, a number of other positive outcomes and post hoc subgroup analyses—including additional cognitive measures and volumetric magnetic resonance imaging and fluorodeoxyglucose–positron-emission tomography imaging assessments—provide rationale and direction for the design of a phase 3 study and encourage the continued development of pepinemab in patients diagnosed with EM HD. The SIGNAL Phase 2 study of pepinemab immunotherapy in early Huntington’s disease (HD) did not meet its coprimary clinical efficacy endpoints, but had a favorable safety profile and showed a significant treatment-related reduction in caudate brain atrophy and reversal of the characteristic decline in brain metabolic activity that is typical of HD progression.

Prior authorization criteria for Federal Drug Administration (FDA) approved immunotherapeutics, among the class of anti‐amyloid monoclonal antibodies (mAbs), established by state drug formulary committees, are tailored for adults with late‐onset Alzheimer's disease. This overlooks adults with Down syndrome (DS), who often experience dementia at a younger age and with different diagnostic assessment outcomes. This exclusion may deny DS adults access to potential disease‐modifying treatments. To address this issue, an international expert panel convened to establish adaptations of prescribing criteria suitable for DS patients and parameters for access to Centers for Medicare & Medicaid Services (CMS) registries. The panel proposed mitigating disparities by modifying CMS and payer criteria to account for younger onset age, using alternative language and assessment instruments validated for cognitive decline in the DS population. The panel also recommended enhancing prescribing clinicians' diagnostic capabilities for DS and initiated awareness‐raising activities within healthcare organizations. These efforts facilitated discussions with federal officials, aimed at achieving equity in access to anti‐amyloid immunotherapeutics, with implications for national authorities worldwide evaluating these and other new disease‐modifying therapeutics for Alzheimer's disease.

INTRODUCTION Late‐onset Alzheimer's disease (LOAD) has a strong genetic component. Participants in Long‐Life Family Study (LLFS) exhibit delayed onset of dementia, offering a unique opportunity to investigate LOAD genetics. METHODS We conducted a whole genome sequence analysis of 3475 LLFS members. Genetic associations were examined in six independent studies (N = 14,260) with a wide range of LOAD risk. Association analysis in a sub‐sample of the LLFS cohort (N = 1739) evaluated the association of LOAD variants with beta amyloid (Aβ) levels. RESULTS We identified several single nucleotide polymorphisms (SNPs) in tight linkage disequilibrium within the MTUS2 gene associated with LOAD (rs73154407, p = 7.6 × 10−9). Association of MTUS2 variants with LOAD was observed in the five independent studies and was significantly stronger within high levels of Aβ42/40 ratio compared to lower amyloid. DISCUSSION MTUS2 encodes a microtubule associated protein implicated in the development and function of the nervous system, making it a plausible candidate to investigate LOAD biology. Highlights Long‐Life Family Study (LLFS) families may harbor late onset Alzheimer's dementia (LOAD) variants. LLFS whole genome sequence analysis identified MTUS2 gene variants associated with LOAD. The observed LLFS variants generalized to cohorts with wide range of LOAD risk. The association of MTUS2 with LOAD was stronger within high levels of beta amyloid. Our results provide evidence for MTUS2 gene as a novel LOAD candidate locus.