Accurate placement of the macaque within the Alzheimer's disease (AD) research framework is essential to discover early-stage predictive biomarkers.
Objective
To assess utility of the aging macaque in advancing translational biomarker development for preclinical AD, we evaluated relative signal strength of comparable neuropathologic phenomena in macaques and patients.
Methods
We compared pathology in patient and macaque formalin-fixed paraffin embedded (FFPE) tissues using identical criteria. We quantified expression of amyloid-β (Aβ), pTau, and inflammatory and senescence markers across species. Distribution of AD-relevant markers were compared in FFPE and perfused frozen macaque brain to assess expression of labile proteins that could inform in-life fluid biomarkers.
Results
Aβ pathology in macaques closely approximated patient pathology. Complex plaque composition in macaques implied significant disruption of synaptic connectivity. In FFPE tissue, pretangle pTau immunoreactivity placed the macaque in Braak Stage 1b. In perfused frozen tissue, soluble pTau distribution approximated Braak Stage III-IV. In macaque, Aβ, pTau, and acetylcholinesterase labeling co-localized to AD-vulnerable circuits. Significant association of glial fibrillary acidic protein with Aβ occurred in humans only. The senescence marker p16 correlated positively with pTau expression and negatively with Aβ in patients only. Macaques lacked neuropathologic co-morbidities.
Conclusions
AD-relevant neuropathologic signals in the macaque support biomarker discovery in the areas of Aβ plaque evolution and associated synaptic disruption as well as early-stage tau phosphorylation. Relative protection from accumulation of senescence markers, fibrillar tau and neuropathologic co-morbidities in macaque implicate species difference in rates of biological brain aging. We provide over 4000 digital slides for further study.
StonebargerGABimonte-NelsonHAUrbanskiHF. The rhesus macaque as a translational model for neurodegeneration and Alzheimer's disease. Front Aging Neurosci2021; 13: 734173.
2.
UnoH. The incidence of senile plaques and multiple infarction in aged macaque brain. Neurobiol Aging1993; 14: 673–674.
Freire-CoboCEdlerMKVargheseM, et al.Comparative neuropathology in aging primates: a perspective. Am J Primatol2021; 83: e23299.
5.
Sukoff RizzoSJHomanicsGSchaefferDJ, et al.Bridging the rodent to human translational gap: marmosets as model systems for the study of Alzheimer's disease. Alzheimers Dement2023; 9: e12417.
6.
BonsNRiegerFPrudhommeD, et al.Microcebus murinus: a useful primate model for human cerebral aging and Alzheimer's disease?Genes Brain Behav2006; 5: 120–130.
7.
Diehl RodriguezRTavaresMCHBruckiSMD, et al.Bearded capuchin monkeys as a model for Alzheimer's disease. Sci Rep2024; 14: 6287.
8.
ArnstenAFTDattaDPreussTM. Studies of aging nonhuman primates illuminate the etiology of early-stage Alzheimer's-like neuropathology: an evolutionary perspective. Am J Primatol2021; 83: e23254.
9.
BoTLiJHuG, et al.Brain-wide and cell-specific transcriptomic insights into MRI-derived cortical morphology in macaque monkeys. Nat Commun2023; 14: 1499.
10.
GrahamLCNaldrettMJKohamaSG, et al.Regional molecular mapping of primate synapses during normal healthy aging. Cell Rep2019; 27: 1018–26.e4.
11.
StonebargerGAUrbanskiHFWoltjerRL, et al.Amyloidosis increase is not attenuated by long-term calorie restriction or related to neuron density in the prefrontal cortex of extremely aged rhesus macaques. Geroscience2020; 42: 1733–1749.
12.
MooreTLKillianyRJHerndonJG, et al.Executive system dysfunction occurs as early as middle-age in the rhesus monkey. Neurobiol Aging2006; 27: 1484–1493.
13.
DumitriuDHaoJHaraY, et al.Selective changes in thin spine density and morphology in monkey prefrontal cortex correlate with aging-related cognitive impairment. J Neurosci2010; 30: 7507–7515.
14.
WalkerLCJuckerM. The exceptional vulnerability of humans to Alzheimer's disease. Trends Mol Med2017; 23: 534–545.
15.
UemuraE. Age-related changes in the subiculum of Macaca mulatta: synaptic density. Exp Neurol1985; 87: 403–411.
16.
KeukerJILuitenPGFuchsE. Preservation of hippocampal neuron numbers in aged rhesus monkeys. Neurobiol Aging2003; 24: 157–165.
17.
Jack JrCRAndrewsJSBeachTG, et al.Revised criteria for diagnosis and staging of Alzheimer's disease: Alzheimer's association workgroup. Alzheimers Dement2024; 20: 5143–5169.
18.
Jack JrCRBennettDABlennowK, et al.NIA-AA Research framework: toward a biological definition of Alzheimer's disease. Alzheimers Dement2018; 14: 535–562.
19.
Jack JrCRWisteHJWeigandSD, et al.Age-specific and sex-specific prevalence of cerebral β-amyloidosis, tauopathy, and neurodegeneration in cognitively unimpaired individuals aged 50–95 years: a cross-sectional study. Lancet Neurol2017; 16: 435–444.
20.
DuboisBHampelHFeldmanHH, et al.Preclinical Alzheimer's disease: definition, natural history, and diagnostic criteria. Alzheimers Dement2016; 12: 292–323.
21.
ParnettiLChipiESalvadoriN, et al.Prevalence and risk of progression of preclinical Alzheimer's disease stages: a systematic review and meta-analysis. Alzheimers Res Ther2019; 11: 7.
22.
NodaAMurakamiYNishiyamaS, et al.Amyloid imaging in aged and young macaques with [11C]PIB and [18F]FDDNP. Synapse2008; 62: 472–475.
23.
NishiyamaSOhbaHKanazawaM, et al.Comparing α7 nicotinic acetylcholine receptor binding, amyloid-β deposition, and mitochondria complex-I function in living brain: a PET study in aged monkeys. Synapse2015; 69: 475–483.
24.
TsukadaHNishiyamaSOhbaH, et al.Comparing amyloid-beta deposition, neuroinflammation, glucose metabolism, and mitochondrial complex I activity in brain: a PET study in aged monkeys. Eur J Nucl Med Mol Imaging2014; 41: 2127–2136.
25.
FangXTWilliamsGCastnerS, et al.The aging rhesus macaque as a potential model for Alzheimer's disease/dementia: an in vivo study of [11C]PIB, [11C]UCB-j, [18F]MK-6240 and working memory performance. Alzheimers Dement2020; 16: e038467.
26.
MontineTJPhelpsCHBeachTG, et al.National institute on aging-Alzheimer's association guidelines for the neuropathologic assessment of Alzheimer's disease: a practical approach. Acta Neuropathol2012; 123: 1–11.
27.
BraakHThalDRGhebremedhinE, et al.Stages of the pathologic process in Alzheimer disease: age categories from 1 to 100 years. J Neuropathol Exp Neurol2011; 70: 960–969.
28.
MatsuoESShinRWBillingsleyML, et al.Biopsy-derived adult human brain tau is phosphorylated at many of the same sites as Alzheimer's disease paired helical filament tau. Neuron1994; 13: 989–1002.
29.
ChampagneDRochfordJPoirierJ. Effect of apolipoprotein E deficiency on reactive sprouting in the dentate gyrus of the hippocampus following entorhinal cortex lesion: role of the astroglial response. Exp. Neurol2005; 194: 31–42.
30.
MirraSSHartMNTerryRD. Making the diagnosis of Alzheimer's disease. A primer for practicing pathologists. Arch Pathol Lab Med1993; 117: 132–144.
31.
SchneiderCARasbandWSEliceiriKW. NIH Image to ImageJ: 25 years of image analysis. Nat. Methods2012; 9: 671–675.
32.
OtsuN. A threshold selection method from gray-level histograms. IEEE Trans Syst Man Cybern1979; 9: 62–66.
33.
PaxinosGHuangXFTogaAW. The rhesus monkey brain in stereotaxic coordinates. San Diego, CA: Academic Press, 2000.
34.
MoloneyCMLoweVJMurrayME. Visualization of neurofibrillary tangle maturity in Alzheimer's disease: a clinicopathologic perspective for biomarker research. Alzheimers Dement2021; 17: 1554–1574.
35.
BraakHAlafuzoffIArzbergerT, et al.Staging of Alzheimer disease-associated neurofibrillary pathology using paraffin sections and immunocytochemistry. Acta Neuropathol2006; 112: 389–404.
36.
BraakHBraakE. Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol1991; 82: 239–259.
37.
RobertsonELBoehnkeSELyraESNM, et al.Characterization of cerebrospinal fluid biomarkers associated with neurodegenerative diseases in healthy cynomolgus and rhesus macaque monkeys. Alzheimers Dement2022; 8: e12289.
38.
YueFLuCAiY, et al.Age-associated changes of cerebrospinal fluid amyloid-beta and tau in cynomolgus monkeys. Neurobiol Aging2014; 35: 1656–1659.
39.
LeslieSNKanyoJDattaD, et al.Simple, single-shot phosphoproteomic analysis of heat-stable tau identifies age-related changes in pS235- and pS396-tau levels in non-human primates. Front Aging Neurosci2021; 13: 767322.
40.
FrostGRLiYM. The role of astrocytes in amyloid production and Alzheimer's disease. Open Biol2017; 7: 170228.
41.
CallaghanMFFreundPDraganskiB, et al.Widespread age-related differences in the human brain microstructure revealed by quantitative magnetic resonance imaging. Neurobiol Aging2014; 35: 1862–1872.
42.
BronsonRTSchoeneWC. Spontaneous pallido-nigral accumulation of iron pigment and spheroid-like structures in macaque monkeys. J Neuropathol Exp Neurol1980; 39: 181–196.
43.
EverettJCollingwoodJFTjendana-TjhinV, et al.Nanoscale synchrotron X-ray speciation of iron and calcium compounds in amyloid plaque cores from Alzheimer's disease subjects. Nanoscale2018; 10: 11782–11796.
44.
SiddiqiZKemperTLKillianyR. Age-related neuronal loss from the substantia nigra-pars compacta and ventral tegmental area of the rhesus monkey. J Neuropathol Exp Neurol1999; 58: 959–971.
45.
ShoresMMWhiteSSVeithRC, et al.Tyrosine hydroxylase mRNA is increased in old age and norepinephrine uptake transporter mRNA is decreased in middle age in locus coeruleus of brown-Norway rats. Brain Res1999; 826: 143–147.
46.
Jack CRJ. Advances in Alzheimer's disease research over the past two decades. Lancet Neurol2022; 21: 866–869.
47.
KalininSWillardSLShivelyCA, et al.Development of amyloid burden in African green monkeys. Neurobiol Aging2013; 34: 2361–2369.
48.
CramerPEGentzelRCTanisKQ, et al.Aging African green monkeys manifest transcriptional, pathological, and cognitive hallmarks of human Alzheimer's disease. Neurobiol Aging2018; 64: 92–106.
49.
Ndung'uMHärtigWWegnerF, et al.Cerebral amyloid β(42) deposits and microvascular pathology in ageing baboons. Neuropathol Appl Neurobiol2012; 38: 487–499.
50.
GearingMTiggesJMoriH, et al.. beta-amyloid (A beta) deposition in the brains of aged orangutans. Neurobiol Aging1997; 18: 139–146.
51.
EdlerMKSherwoodCCMeindlRS, et al.Aged chimpanzees exhibit pathologic hallmarks of Alzheimer's disease. Neurobiol Aging2017; 59: 107–120.
52.
PerezSERaghantiMAHofPR, et al.Alzheimer's disease pathology in the neocortex and hippocampus of the western lowland gorilla (Gorilla gorilla gorilla). Comp Neurol2013; 521: 4318–4338.
53.
GiannakopoulosPSilholSJallageasV, et al.Quantitative analysis of tau protein-immunoreactive accumulations and beta amyloid protein deposits in the cerebral cortex of the mouse lemur, Microcebus murinus. Acta Neuropathol1997; 94: 131–139.
54.
IwaideSNakayamaYChambersJK, et al.Senile plaques and phosphorylated tau deposition in a super-aged rhesus monkey (Macaca mulatta). J Vet Med Sci2023; 85: 1296–1300.
55.
Milà-AlomàMAshtonNJShekariM, et al.Plasma p-tau231 and p-tau217 as state markers of amyloid-β pathology in preclinical Alzheimer's disease. Nat Med2022; 28: 1797–1801.
56.
La JoieRAyaktaNSeeleyWW, et al.Multisite study of the relationships between antemortem [(11)C]PIB-PET Centiloid values and postmortem measures of Alzheimer's disease neuropathology. Alzheimers Dement2019; 15: 205–216.
57.
LatimerCSShivelyCAKeeneCD, et al.A nonhuman primate model of early Alzheimer's disease pathologic change: implications for disease pathogenesis. Alzheimers Dement2019; 15: 93–105.
58.
DarusmanHSPandelakiJMulyadiR, et al.Poor memory performance in aged cynomolgus monkeys with hippocampal atrophy, depletion of amyloid beta 1–42 and accumulation of tau proteins in cerebrospinal fluid. In Vivo2014; 28: 173–184.
59.
DarusmanHSSajuthiDKalliokoskiO, et al.Correlations between serum levels of beta amyloid, cerebrospinal levels of tau and phospho tau, and delayed response tasks in young and aged cynomolgus monkeys (Macaca fascicularis). J Med Primatol2013; 42: 137–146.
60.
RosenRFWalkerLCLevineH. 3rd. PIB binding in aged primate brain: enrichment of high-affinity sites in humans with Alzheimer's disease. Neurobiol Aging2011; 32: 223–234.
61.
IkonomovicMDKlunkWEAbrahamsonEE, et al.Post-mortem correlates of in vivo PiB-PET amyloid imaging in a typical case of Alzheimer's disease. Brain2008; 131: 1630–1645.
62.
FarrellMEJiangSSchultzAP, et al.Defining the lowest threshold for amyloid-PET to predict future cognitive decline and amyloid accumulation. Neurology2021; 96: e619–e631.
63.
CurtisCGamezJESinghU, et al.Phase 3 trial of flutemetamol labeled with radioactive fluorine 18 imaging and neuritic plaque density. JAMA Neurol2015; 72: 287–294.
64.
IkonomovicMDBuckleyCJAbrahamsonEE, et al.Post-mortem analyses of PiB and flutemetamol in diffuse and cored amyloid-β plaques in Alzheimer's disease. Acta Neuropathol2020; 140: 463–476.
65.
WardRJZuccaFADuynJH, et al.The role of iron in brain ageing and neurodegenerative disorders. Lancet Neurol2014; 13: 1045–1060.
66.
BraakHDel TrediciK. The pathological process underlying Alzheimer's disease in individuals under thirty. Acta Neuropathol2011; 121: 171–181.
67.
WesselingHMairWKumarM, et al.Tau PTM profiles identify patient heterogeneity and stages of Alzheimer's disease. Cell2020; 183: 1699–713.e13.
68.
AggletonJPFriedmanDPMishkinM. A comparison between the connections of the amygdala and hippocampus with the basal forebrain in the macaque. Exp Brain Res1987; 67: 556–568.
69.
VanaLKanaanNMUgwuIC, et al.Progression of tau pathology in cholinergic Basal forebrain neurons in mild cognitive impairment and Alzheimer's disease. Am J Pathol2011; 179: 2533–2550.
70.
MacedoACTissotCTherriaultJ, et al.The use of tau PET to stage Alzheimer disease according to the Braak staging framework. J Nucl Med2023; 64: 1171–1178.
71.
LoweVJCurranGFangP, et al.An autoradiographic evaluation of AV-1451 tau PET in dementia. Acta Neuropathol Commun2016; 4: 58.
72.
AgueroCDhaynautMNormandinMD, et al.Autoradiography validation of novel tau PET tracer [F-18]-MK-6240 on human postmortem brain tissue. Acta Neuropathol Commun2019; 7: 37.
73.
HostetlerEDWaljiAMZengZ, et al.Preclinical characterization of 18F-MK-6240, a promising PET tracer for in vivo quantification of human neurofibrillary tangles. J Nucl Med2016; 57: 1599–1606.
74.
JackCRWisteHJAlgeciras-SchimnichA, et al.Predicting amyloid PET and tau PET stages with plasma biomarkers. Brain2023; 146: 2029–2044.
75.
NeddensJTemmelMFlunkertS, et al.Phosphorylation of different tau sites during progression of Alzheimer's disease. Acta Neuropathol Commun2018; 6: 52.
76.
BarthélemyNRBatemanRJHirtzC, et al.Cerebrospinal fluid phospho-tau T217 outperforms T181 as a biomarker for the differential diagnosis of Alzheimer's disease and PET amyloid-positive patient identification. Alzheimers Res Ther2020; 12: 26.
77.
BarthélemyNRSaefBLiY, et al.CSF Tau phosphorylation occupancies at T217 and T205 represent improved biomarkers of amyloid and tau pathology in Alzheimer's disease. Nat Aging2023; 3: 391–401.
78.
FerreiraPCLTherriaultJTissotC, et al.Plasma p-tau231 and p-tau217 inform on tau tangles aggregation in cognitively impaired individuals. Alzheimers Dement2023; 19: 4463–4474.
79.
Montoliu-GayaLBenedetALTissotC, et al.Mass spectrometric simultaneous quantification of tau species in plasma shows differential associations with amyloid and tau pathologies. Nat Aging2023; 3: 661–669.
80.
LombardiGPancaniSMancaR, et al.Role of blood P-tau isoforms (181, 217, 231) in predicting conversion from MCI to dementia due to Alzheimer's disease: a review and meta-analysis. Int J Mol Sci2024; 25: 12916.
81.
JanelidzeSMattssonNPalmqvistS, et al.Plasma P-tau181 in Alzheimer's disease: relationship to other biomarkers, differential diagnosis, neuropathology and longitudinal progression to Alzheimer's dementia. Nat. Med2020; 26: 379–386.
82.
DattaDLeslieSNWangM, et al.Age-related calcium dysregulation linked with tau pathology and impaired cognition in non-human primates. Alzheimers Dement2021; 17: 920–932.
83.
DattaDPeroneIWijegunawardanaD, et al.Nanoscale imaging of pT217-tau in aged rhesus macaque entorhinal and dorsolateral prefrontal cortex: evidence of interneuronal trafficking and early-stage neurodegeneration. Alzheimers Dement2024; 20: 2843–2860.
84.
CarlyleBCNairnACWangM, et al.cAMP-PKA phosphorylation of tau confers risk for degeneration in aging association cortex. Proc Natl Acad Sci U S A2014; 111: 5036–5041.
85.
BathlaSDattaDBolatD, et al.Dysregulated calcium signaling in the aged macaque entorhinal cortex associated with tau hyperphosphorylation. bioRxiv 2024; DOI: 2024.12.05.626721 [Preprint]. Posted December 09, 2024.
86.
JesterHMGosraniSPDingH, et al.Characterization of early Alzheimer's disease-like pathological alterations in non-human primates with aging: a pilot study. J Alzheimers Dis2022; 88: 957–970.
87.
BiskadurosAGlodzikLSaint LouisLA, et al.Longitudinal trajectories of Alzheimer's disease CSF biomarkers and blood pressure in cognitively healthy subjects. Alzheimers Dement2024; 20: 4389–4400.
88.
LuoJAgboolaFGrantE, et al.Sequence of Alzheimer disease biomarker changes in cognitively normal adults: a cross-sectional study. Neurology2020; 95: e3104–e3116.
89.
HaraYRappPRMorrisonJH. Neuronal and morphological bases of cognitive decline in aged rhesus monkeys. Age2012; 34: 1051–1073.
90.
KyleCTStokesJBennettJ, et al.Cytoarchitectonically-driven MRI atlas of nonhuman primate hippocampus: preservation of subfield volumes in aging. Hippocampus2019; 29: 409–421.
91.
DashSParkBKroenkeCD, et al.Brain volumetrics across the lifespan of the rhesus macaque. Neurobiol Aging2023; 126: 34–43.
92.
MeccaAPChenMKO'DellRS, et al.In vivo measurement of widespread synaptic loss in Alzheimer's disease with SV2A PET. Alzheimers Dement2020; 16: 974–982.
93.
BeckmanDOttSDonis-CoxK, et al.Oligomeric Aβ in the monkey brain impacts synaptic integrity and induces accelerated cortical aging. Proc Natl Acad Sci U S A2019; 116: 26239–26246.
94.
HärtigWBrücknerGSchmidtC, et al.Co-localization of beta-amyloid peptides, apolipoprotein E and glial markers in senile plaques in the prefrontal cortex of old rhesus monkeys. Brain Res1997; 751: 315–322.
95.
VillemagneVLHaradaRDoréV, et al.Assessing reactive astrogliosis with (18)F-SMBT-1 across the Alzheimer disease spectrum. J Nucl Med2022; 63: 1560–1569.
96.
PereiraJBJanelidzeSSmithR, et al.Plasma GFAP is an early marker of amyloid-β but not tau pathology in Alzheimer's disease. Brain2021; 144: 3505–3516.
97.
LengFHinzRGentlemanS, et al.Combined neuroinflammation and amyloid PET markers in predicting disease progression in cognitively impaired subjects. J. Alzheimers Dis2024; 100: 973–986.
98.
HillmerATHoldenDFowlesK, et al.Microglial depletion and activation: a [(11)C]PBR28 PET study in nonhuman primates. EJNMMI Res2017; 7: 59.
99.
AbdelhakAFoschiMAbu-RumeilehS, et al.Blood GFAP as an emerging biomarker in brain and spinal cord disorders. Nat Rev Neurol2022; 18: 158–172.
100.
Di MiccoRKrizhanovskyVBakerD, et al.Cellular senescence in ageing: from mechanisms to therapeutic opportunities. Nat Rev Mol Cell Biol2021; 22: 75–95.
101.
DaiLGaoFWangQ, et al.Molecules of senescent glial cells differentiate Alzheimer's disease from ageing. J Neurol Neurosurg Psychiatry2023; 94: 550–559.
102.
HuYFryattGLGhorbaniM, et al.Replicative senescence dictates the emergence of disease-associated microglia and contributes to Aβ pathology. Cell Rep2021; 35: 109228.
103.
OgrodnikMEvansSAFielderE, et al.Whole-body senescent cell clearance alleviates age-related brain inflammation and cognitive impairment in mice. Aging Cell2021; 20: e13296.
104.
DaiDLLiMLeeEB. Human Alzheimer's disease reactive astrocytes exhibit a loss of homeostastic gene expression. Acta Neuropathol Commun2023; 11: 127.
105.
MrdjenDAmouzgarMCannonB, et al.Spatial proteomics reveals human microglial states shaped by anatomy and neuropathology. Res Sq2023: 1–42. DOI: 10.21203/rs.3.rs-2987263/v1 [Preprint]. Posted 02 June 2023.
106.
PascoalTABenedetALAshtonNJ, et al.Microglial activation and tau propagate jointly across Braak stages. Nat Med2021; 27: 1592–1599.
107.
HamelinLLagardeJDorothéeG, et al.Distinct dynamic profiles of microglial activation are associated with progression of Alzheimer's disease. Brain2018; 141: 1855–1870.
108.
InoueYShueFBuG,et al.Pathophysiology and probable etiology of cerebral small vessel disease in vascular dementia and Alzheimer's disease. Mol Neurodegener2023; 18: 46.
109.
LiuYJZhaoJYHanWW, et al.Microvascular burden and long-term risk of stroke and dementia in type 2 diabetes mellitus. J Affect Disord2024; 354: 68–74.
110.
FilshteinTJDuggerBNJinLW, et al.Neuropathological diagnoses of demented Hispanic, Black, and Non-Hispanic white decedents seen at an Alzheimer's disease center. J Alzheimers Dis2019; 68: 145–158.
111.
ZhangXZhangRRaabS, et al.Rhesus macaques develop metabolic syndrome with reversible vascular dysfunction responsive to pioglitazone. Circ J2011; 124: 77–86.
112.
HuangXHuangSFuF, et al.Characterization of preclinical Alzheimer's disease model: spontaneous type 2 diabetic cynomolgus monkeys with systemic pro-inflammation, positive biomarkers and developing AD-like pathology. Alzheimers Res Ther2024; 16: 52.
113.
SperlingRAAisenPSBeckettLA, et al.Toward defining the preclinical stages of Alzheimer's disease: recommendations from the national institute on aging-Alzheimer's association workgroups on diagnostic guidelines for Alzheimer's disease. Alzheimers Dement2011; 7: 280–292.
114.
AgueroCDhaynautMAmaralAC, et al.Head-to-head comparison of [(18)F]-Flortaucipir, [(18)F]-MK-6240 and [(18)F]-PI-2620 postmortem binding across the spectrum of neurodegenerative diseases. Acta Neuropathol2024; 147: 25.
115.
ApplemanMLThomasJLWeissAR, et al.Effect of hormone replacement therapy on amyloid beta (Aβ) plaque density in the rhesus macaque amygdala. Front Aging Neurosci2023; 15: 1326747.
116.
UnoHWalkerLC. The age of biosenescence and the incidence of cerebral beta-amyloidosis in aged captive rhesus monkeys. Ann N Y Acad Sci1993; 695: 232–235.
117.
MartinLJSisodiaSSKooEH, et al.Amyloid precursor protein in aged nonhuman primates. Proc Natl Acad Sci U S A1991; 88: 1461–1465.
118.
ZhaoQLuJYaoZ, et al.Upregulation of Aβ42 in the brain and bodily fluids of rhesus monkeys with aging. J Mol Neurosci2017; 61: 79–87.
119.
WatowichMMChiouKLMontagueMJ, et al.Natural disaster and immunological aging in a nonhuman primate. Proc Natl Acad Sci U S A2022; 119: e2121663119.
120.
TianYECropleyVMaierAB, et al.Heterogeneous aging across multiple organ systems and prediction of chronic disease and mortality. Nat Med2023; 29: 1221–1231.
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