This work believes this is the first evidence demonstrating an association between these clinically relevant biomarkers of Alzheimer’s disease and phenotypes of brain aging in nonhuman primates, underscoring their importance as models of aging and neurodegenerative disease.
Abstract
Chimpanzees share a number of age-related brain changes with humans, such as reductions in neurons and increases in neuropathology. To date, there are no published studies of peripheral biomarkers related to Alzheimer’s pathology and their associations with age and cortical atrophy in chimpanzees. Here we examined cross-sectional differences and longitudinal changes in biomarkers of pathological protein aggregation, neuroinflammation, and microglial function measured in serum. We examined the relationships between biomarkers and clinically relevant biomarker ratios with both age and cortical atrophy. We found linear and quadratic relationships between age and several biomarkers and ratios. Most biomarkers increased with age. While controlling for sex, we found significant negative associations between age and sulci surface area, mean depth, and gray matter thickness and a positive association with fold opening. Aβ42 and Aβ40 showed higher biomarker values associated with lower surface area, mean depth, and gray matter thickness and higher fold opening values. The clinically relevant biomarker ratios were also associated with cortical atrophy – Aβ42/Aβ40 was negatively associated with gray matter thickness, and pTau217/Aβ42 (both total and brain-derived) was positively associated with surface area and gray matter thickness and negatively associated with fold opening. Consistent with our hypotheses and previous findings in humans, many peripheral biomarkers associated with neurodegeneration and Alzheimer’s disease increase as chimpanzees age. We believe this is the first evidence demonstrating an association between these clinically relevant biomarkers of Alzheimer’s disease and phenotypes of brain aging in nonhuman primates, underscoring their importance as models of aging and neurodegenerative disease.
Many nonhuman primate species recapitulate the neuropathological features of sporadic Alzheimer’s disease (AD) to varying degrees. As with humans, the assessment of AD-related pathology in nonhuman primates has historically relied on the use of postmortem brain tissues. In vivo alternatives, such as PET imaging tracers and fluid biomarkers, have been developed for use in humans but require further validation in nonhuman primates before replacing postmortem analyses. Here we employed the Nucleic Acid-Linked Immuno-Sandwich Assay (NULISATM) CNS Disease panel to compare age-related changes in plasma biomarkers in two nonhuman primate species (rhesus monkeys and baboons). In addition, we examined whether amyloid and tau biomarkers were associated with brain atrophy, as measured by gray matter volume. We found significant associations between age and multiple biomarkers of neurodegeneration for both species, as well as significant differences in the patterns of these associations between the two species. For the phosphorylated tau measures, though rhesus monkeys had higher values, baboons showed significant and stronger associations with age. By contrast, rhesus monkeys exhibited an earlier age-related decline in Aβ42/Aβ40 ratio than baboons. Finally, in both species, lower Aβ42/Aβ40 ratios were associated with lower gray matter volumes. This is the first systematic comparative study of age-related changes in neurodegeneration biomarkers in two closely related nonhuman primates using comparable age ranges and sample sizes, and the same multiplex assay. Future studies should examine longitudinal changes in these biomarkers as well as validate the plasma findings using cerebral spinal fluid.
M. M. Mulholland, Elizabeth R. Magden, H. Scholtzova et al.· bioRxiv· 0 citations
Background Although blood-based biomarkers are now available for diagnosing Alzheimer’s disease (AD), the best biomarker for AD-specific neurodegeneration and cognitive decline remains unclear. This study aimed to determine the relative importance of four plasma biomarkers—phosphorylated tau (p-tau) 217, p-tau181, neurofilament light chain (NfL), and glial fibrillary acidic protein (GFAP)—in AD-specific neurodegeneration and cognition. Methods We analyzed cross-sectional data from two independent, ethnically distinct cohorts spanning the clinical spectrum from cognitively unimpaired to dementia: 150 participants from the SAMD cohort (100% Asian) and 284 participants from the ADNI cohort (94.0% White). Plasma biomarker levels were quantified using Single-Molecule Array (Simoa) assays. We employed dominance analysis to determine the hierarchical contributions of these biomarkers to AD signature regions of interest (ROI) thickness (entorhinal, inferior temporal, middle temporal, and fusiform regions), total cognition, and memory, stratified by amyloid-PET status. Three sensitivity analyses were further conducted to validate the findings across these cohorts, mitigating potential biases arising from differences in demographic characteristics and clinical severity. All analyses were adjusted for age, sex, education, and APOE ε4 status. Results The dominance hierarchy differed markedly according to the amyloid status. Plasma GFAP and p-tau217 emerged as the dominant predictors for AD signature ROI thickness and cognitive impairment in amyloid-positive participants. Specifically, GFAP demonstrated superior dominance in explaining cortical atrophy within the SAMD cohort, whereas p-tau217 was the dominant predictor in the ADNI cohort. P-tau217 generally outperformed the others in explaining total cognition and memory in the amyloid (+) group. In contrast, among amyloid (−) participants, plasma NfL showed greater explanatory power than GFAP for both neurodegeneration and cognitive decline across both cohorts. Conclusion The efficacy of plasma biomarkers in reflecting AD-related neurodegeneration varies significantly depending on the presence of amyloid pathology. While GFAP and p-tau217 are robust indicators of AD-associated changes linked to plaque pathology, NfL better reflects non-specific neurodegeneration involving axonal damage. Consequently, a stratified approach based on amyloid status is essential for the optimal application of blood-based biomarkers in monitoring disease progression and evaluating therapeutic efficacy in future clinical trials and precision medicine.
Keun You Kim, Hyunsun Ham, E. Yoon et al.· The journal of prevention of...· 0 citations
In light of the evidence that nonhuman primates naturally develop Alzheimer's disease neuropathologies, there is a renewed interest in research on the comparative biology of aging, including neurological changes across the age groups in species with diverse lifespans. In this paper, we examined age‐related differences in two measures of cortical folding, mean depth and fold opening, in a sample of chimpanzees (Pan troglodytes) and olive baboons (Papio anubis). We found significant species differences in the slope and pattern of age‐related changes in cortical folding. As predicted, chimpanzees showed negative linear associations between age and mean depth and positive linear associations between age and fold opening, as we see in humans. However, contrary to our hypotheses, baboons showed positive quadratic associations between age and mean depth and negative quadratic associations between age and fold opening. Additionally, within the baboons but not the chimpanzees, significant sex differences were found in age‐related differences in cortical folding. Here, male baboons showed significant linear associations between age, sulci depth, and fold opening, much like male and female chimpanzees. However, for female baboons, slopes of age‐related differences in fold opening were flat or showed slight quadratic associations. It is possible that variation in primate social systems and/or reproductive aging may influence sex and species differences in brain aging. Longitudinal studies on primate brain aging, as well as comparative research with additional taxa, could shed light on the causes and implications of these differences.
William D Hopkins, Angela M. Achorn, M. M. Mulholland et al.· American Journal of Primatol...· 0 citations
Plasma phosphorylated tau-217 (p-tau217) is one of the most accurate blood-based biomarkers for Alzheimer's disease (AD), yet whether its diagnostic and correlational properties vary with age at onset has not been systematically examined. We measured eight plasma biomarkers (tau, amyloid, neurodegeneration, neuroinflammation) via automated chemiluminescence immunoassay in a Chinese memory clinic cohort (n = 604; amyloid positron emission tomography (PET) reference), with validation in the Alzheimer's Disease Neuroimaging Initiative (ADNI) (n = 1,615; amyloid and tau PET). Diagnostic accuracy and biomarker–clinical correlations were compared between early-onset (EO < 65 years) and late-onset (LO ≥ 65 years) subgroups. Overall accuracy was high (primary area under the curve (AUC) 0.923; ADNI 0.904). In ADNI, p-tau217 showed higher accuracy in EO than LO (AUC 0.940 vs 0.892, P = 0.012), most pronounced at age 60 and absent by 70. The optimal biomarker shifted from tau-centric markers in LO to Aβ42/Aβ40 in EO. Tau biomarker–clinical correlations diverged sharply by onset age and were stronger in EO for cognitive and neuropsychiatric outcomes, whereas glial fibrillary acidic protein (GFAP) and neurofilament light chain (NfL) showed no age-dependent heterogeneity. Opposing-direction associations were observed for p-tau217%, which correlated negatively with onset age in AD but positively in Non-AD cognitive impairment. In an exploratory analysis, baseline p-tau217 was associated with longitudinal cognitive decline, numerically greater in EO though based on a small subgroup. Cross-ethnic generalizability was supported by the ADNI-Asian subgroup. This cross-ethnic, cross-platform study demonstrates that the diagnostic accuracy, biomarker–clinical correlation architecture, and optimal analyte selection of plasma p-tau217 vary systematically with age at onset, most markedly for tau-related measures. These findings challenge universal threshold paradigms and support age-stratified biomarker interpretation in clinical practice and therapeutic trial design.
Boru Jin, Aitong Li, Feng Xu et al.· Alzheimer's Research & Thera...· 0 citations
Background Chronic inflammation contributes to neurodegeneration and cerebrovascular injury, yet it remains unclear whether inflammatory biomarkers influence white matter hyperintensity (WMH) volume and cognition independent of Alzheimer's disease (AD) plasma biomarkers. Objective This study examined whether inflammatory biomarkers were associated with WMH volume and multidomain cognitive performance independent of AD plasma biomarkers, and whether WMH volume mediated associations between IL-6 and cognition. Methods Using data from 1806 participants in the Health and Aging Brain Study–Health Disparities (HABS-HD), we examined associations between log transformed plasma inflammatory biomarkers (IL-10, TNF-α, IL-6, and IL-5) and WMH volume and cognitive performance (memory, executive function, processing speed, language). Multivariable linear regression models adjusted for demographic and vascular risk factors were repeated with additional adjustment for AD biomarkers (p-Tau181, NfL, total tau, Aβ42/40). Mediation analyses were included to test whether WMH meditated the association between IL-6 and cognitive domains. Results Higher IL-6 levels were consistently associated with increased WMH volume in base and AD-adjusted regression models. Increased levels of IL-6 were also associated with poorer performance in all cognitive domains, but these associations did not survive multiple comparisons correction. WMH partially mediated the association between IL-6 and memory (23%) and processing speed (19%). Conclusions Elevated IL-6 is independently linked to cerebrovascular injury and poorer cognition beyond classical AD biomarkers, supporting a vascular–inflammatory pathway distinct from amyloid and tau pathology. These findings underscore the importance of integrating inflammatory and neurodegenerative markers to elucidate heterogeneous mechanisms of brain aging across diverse populations.
A. Dharmapuri, Soumilee Chaudhuri, J. Contreras et al.· Journal of Alzheimer's Disea...· 0 citations
BackgroundAlzheimer's disease (AD) is increasingly prevalent in Latin America. Neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP) are promising biomarkers of neurodegeneration, but their relationship with white matter (WM) integrity remains unclear.ObjectiveTo investigate associations between fluid neurodegeneration biomarkers and WM microstructure in a Brazilian cohort of individuals across the AD continuum and cognitively healthy controls.MethodsNinety-one participants were included: 27 cognitively healthy controls (mean age = 68.3 ± 5.2 years) and 64 amyloid-positive individuals with mild cognitive impairment or AD dementia (mean age = 70.6 ± 6.9 years). AD participants were characterized by low cerebrospinal fluid (CSF) Aβ42 concentrations (<540 pg/mL) and altered Aβ42/p-Tau and Aβ42/t-Tau ratios. Serum and CSF concentrations of NfL and GFAP were measured using single-molecule array technology and examined in relation to diffusion tensor imaging metrics, including fractional anisotropy, mean diffusivity, radial diffusivity, and axial diffusivity (AxD).ResultsWithin the clinical AD group, higher serum NfL levels were associated with lower AxD in the left cingulum tract (r = -0.372, p = 0.007). In cognitively healthy controls, serum NfL showed positive correlations with AxD and mean diffusivity in the right cingulum (r = 0.650, p = 0.001 and r = 0.607, p = 0.003, respectively). No significant associations were observed between serum or CSF GFAP concentrations and diffusion tensor imaging metrics.ConclusionsSerum NfL was associated with anatomically specific WM microstructural changes, with differing patterns across clinical groups.
T. Magalhães, R. Casseb, A. Moraes et al.· Journal of Alzheimer's Disea...· 0 citations