Mild cognitive impairment (MCI) confers an increased risk of Alzheimer's disease (AD). The apolipoprotein E (APOE) ε4 allele is a major genetic risk factor for late-onset AD and is strongly associated with amyloid-β (Aβ) pathology. However, whether Aβ burden is associated with APOE ε4-related longitudinal changes in tau pathology, neurodegeneration, and cognitive decline in MCI remains incompletely understood.
Objective
To examine whether Aβ burden is associated with APOE ε4-related longitudinal changes in tau pathology, neurodegeneration, and cognition in MCI using ε4 carrier-based and genotype-stratified approaches.
Methods
Data from 396 individuals with MCI in the Alzheimer's Disease Neuroimaging Initiative were analyzed. Longitudinal changes in cerebrospinal fluid (CSF) tau biomarkers, neurodegeneration, and cognition were quantified using individual-specific slopes and examined in multiple linear regression models in relation to APOE ε4 carrier status and Aβ burden. Mediation analyses were used to quantify the associations between baseline Aβ burden and APOE ε4-related longitudinal changes across ε4 carrier-based and genotype-stratified analyses.
Results
APOE ε4 carriers showed greater longitudinal increases in CSF tau and more pronounced declines in glucose metabolism, regional brain volumes, and cognition. Baseline Aβ burden showed associations with APOE ε4-related longitudinal changes in CSF tau, cerebral glucose metabolism, brain atrophy, and memory and global cognition. A similar pattern was also observed in genotype-stratified analyses.
Conclusions
These longitudinal findings suggest that Aβ burden is closely associated with APOE ε4-related tau accumulation, neurodegeneration, and cognitive decline in individuals with MCI.
BloomGS. Amyloid-β and tau: the trigger and bullet in Alzheimer disease pathogenesis. JAMA Neurol2014; 71: 505–508.
2.
Andrade-GuerreroJSantiago-BalmasedaAJeronimo-AguilarP, et al.Alzheimer’s disease: an updated overview of its genetics. Int J Mol Sci2023; 24: 3754.
3.
PetersenRCSmithGEWaringSC, et al.Mild cognitive impairment: clinical characterization and outcome. Arch Neurol1999; 56: 303–308.
4.
AlbertMSDeKoskySTDicksonD, et al.The diagnosis of mild cognitive impairment due to Alzheimer’s disease: recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement2011; 7: 270–279.
5.
CorderEHSaundersAMStrittmatterWJ, et al.Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer’s disease in late onset families. Science1993; 261: 921–923.
6.
FarrerLACupplesLAHainesJL, et al.Effects of age, sex, and ethnicity on the association between apolipoprotein E genotype and Alzheimer disease. A meta-analysis. APOE and Alzheimer Disease Meta Analysis Consortium. JAMA1997; 278: 1349–1356.
7.
Mahoney-SanchezLBelaidiAABushAI, et al.The complex role of apolipoprotein E in Alzheimer’s disease: an overview and update. J Mol Neurosci2013; 60: 325–335.
8.
HuynhT-PVDavisAAUlrichJD, et al.Apolipoprotein E and Alzheimer’s disease: the influence of apolipoprotein E on amyloid-β and other amyloidogenic proteins. J Lipid Res2017; 58: 824–836.
9.
JackCRWisteHJWeigandSD, et al.Age, sex, and APOE ε4 effects on memory, brain structure, and β-amyloid across the adult life span. JAMA Neurol2015; 72: 511–519.
10.
MurphyKRLandauSMChoudhuryKR, et al.Mapping the effects of ApoE4, age and cognitive status on 18F-florbetapir PET measured regional cortical patterns of beta-amyloid density and growth. Neuroimage2013; 78: 474–480.
11.
FleisherASChenKLiuX, et al.Apolipoprotein E ε4 and age effects on florbetapir positron emission tomography in healthy aging and Alzheimer disease. Neurobiol Aging2013; 34: 1–12.
12.
LimYYMorminoEC and Alzheimer’s Disease Neuroimaging Initiative. APOE Genotype and early β-amyloid accumulation in older adults without dementia. Neurology2017; 89: 1028–1034.
13.
NeuSCPaJKukullW, et al.Apolipoprotein E genotype and sex risk factors for Alzheimer disease: a meta-analysis. JAMA Neurol2017; 74: 1178–1189.
14.
GeninEHannequinDWallonD, et al.APOE And Alzheimer disease: a major gene with semi-dominant inheritance. Mol Psychiatry2011; 16: 903–907.
15.
JagustWJLandauSM and Alzheimer’s Disease Neuroimaging Initiative. Apolipoprotein E, not fibrillar β-amyloid, reduces cerebral glucose metabolism in normal aging. J Neurosci2012; 32: 18227–18233.
16.
HostageCARoy ChoudhuryKDoraiswamyPM, et al.Dissecting the gene dose-effects of the APOE ε4 and ε2 alleles on hippocampal volumes in aging and Alzheimer’s disease. PLoS One2013; 8: e54483.
17.
LehmannMGhoshPMMadisonC, et al.Greater medial temporal hypometabolism and lower cortical amyloid burden in ApoE4-positive AD patients. J Neurol Neurosurg Psychiatry2014; 85: 266–273.
18.
DrzezgaAGrimmerTHenriksenG, et al.Effect of APOE genotype on amyloid plaque load and gray matter volume in Alzheimer disease. Neurology2009; 72: 1487–1494.
19.
JackCRPetersenRCXuYC, et al.Hippocampal atrophy and apolipoprotein E genotype are independently associated with Alzheimer’s disease. Ann Neurol1998; 43: 303–310.
20.
FanMLiuBZhouY, et al.Cortical thickness is associated with different apolipoprotein E genotypes in healthy elderly adults. Neurosci Lett2010; 479: 332–336.
21.
BelinsonHKariv-InbalZKayedR, et al.Following activation of the amyloid cascade, apolipoprotein E4 drives the in vivo oligomerization of amyloid-β resulting in neurodegeneration. J Alzheimers Dis2010; 22: 959–970.
22.
CicognolaCSalvadóGSmithR, et al.APOE4 Impact on soluble and insoluble tau pathology is mostly influenced by amyloid-beta. Brain2025; 148: 2373–2383.
23.
Brugulat-SerratASánchez-BenavidesGCacciagliaR, et al.APOE-ε4 modulates the association between regional amyloid deposition and cognitive performance in cognitively unimpaired middle-aged individuals. EJNMMI Res2023; 13: 18.
24.
DesikanRSFanCCWangY, et al.Genetic assessment of age-associated Alzheimer disease risk: development and validation of a polygenic hazard score. PLoS Med2017; 14: e1002258.
25.
ShawLMVandersticheleHKnapik-CzajkaM, et al.Cerebrospinal fluid biomarker signature in Alzheimer’s Disease Neuroimaging Initiative subjects. Ann Neurol2009; 65: 403–413.
LandauSMMintunMAJoshiAD, et al.Amyloid deposition, hypometabolism, and longitudinal cognitive decline. Ann Neurol2012; 72: 578–586.
28.
YuJ-TLiJ-QSucklingJ, et al.Frequency and longitudinal clinical outcomes of Alzheimer’s AT(N) biomarker profiles: a longitudinal study. Alzheimers Dement2019; 15: 1208–1217.
29.
RubinskiADewenterAZhengL, et al.Florbetapir PET-assessed demyelination is associated with faster tau accumulation in an APOE ε4-dependent manner. Eur J Nucl Med Mol Imaging2024; 51: 1035–1049.
30.
SelfWKHoltzmanDM. Emerging diagnostics and therapeutics for Alzheimer disease. Nat Med2023; 29: 2187–2199.
31.
LongJMHoltzmanDM. Alzheimer disease: an update on pathobiology and treatment strategies. Cell2019; 179: 312–339.
32.
TheendakaraVPeters-LibeuCABredesenDE, et al.Transcriptional effects of ApoE4: relevance to Alzheimer’s disease. Mol Neurobiol2018; 55: 5243–5254.
33.
TiraboschiPHansenLAMasliahE, et al.Impact of APOE genotype on neuropathologic and neurochemical markers of Alzheimer disease. Neurology2004; 62: 1977–1983.
34.
HashimotoTSerrano-PozoAHoriY, et al.Apolipoprotein E, especially apolipoprotein E4, increases the oligomerization of amyloid β peptide. J Neurosci2012; 32: 15181–15192.
35.
LiuC-CZhaoNFuY, et al.Apoe4 accelerates early seeding of amyloid pathology. Neuron2017; 96: 1024–1032.e3.
BarthelHGertzH-JDreselS, et al.Cerebral amyloid-β PET with florbetaben (18F) in patients with Alzheimer’s disease and healthy controls: a multicentre phase 2 diagnostic study. Lancet Neurol2011; 10: 424–435.
38.
JohnsonKASperlingRAGidicsinCM, et al.Florbetapir (F18-AV-45) PET to assess amyloid burden in Alzheimer’s disease dementia, mild cognitive impairment, and normal aging. Alzheimers Dement2013; 9: S72–S83.
39.
MorrisJCRoeCMXiongC, et al.APOE Predicts amyloid-beta but not tau Alzheimer pathology in cognitively normal aging. Ann Neurol2010; 67: 122–131.
40.
KimJBasakJMHoltzmanDM. The role of apolipoprotein E in Alzheimer’s disease. Neuron2009; 63: 287–303.
41.
ToledoJBZetterbergHvan HartenAC, et al.Alzheimer’s disease cerebrospinal fluid biomarker in cognitively normal subjects. Brain2012; 138: 2701–2715.
42.
DincerAChenCDMcKayNS, et al.APOE Ε4 genotype, amyloid-β, and sex interact to predict tau in regions of high APOE mRNA expression. Sci Transl Med2022; 14: eabl7646.
43.
JackCRWisteHJWeigandSD, 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.
44.
PascoalTAMathotaarachchiSMohadesS, et al.Amyloid-β and hyperphosphorylated tau synergy drives metabolic decline in preclinical Alzheimer’s disease. Mol Psychiatry2017; 22: 306–311.
45.
TherriaultJBenedetALPascoalTA, et al.APOEε4 potentiates the relationship between amyloid-β and tau pathologies. Mol Psychiatry2021; 26: 5977–5988.
46.
LimYYYassiNBransbyL, et al.CSF Aβ42 and tau biomarkers in cognitively unimpaired Aβ- middle-aged and older APOE ε4 carriers. Neurobiol Aging2023; 129: 209–218.
47.
BarthélemyNRLiYJoseph-MathurinN, et al.A soluble phosphorylated tau signature links tau, amyloid and the evolution of stages of dominantly inherited Alzheimer’s disease. Nat Med2020; 26: 398–407.
48.
Mattsson-CarlgrenNAnderssonEJanelidzeS, et al.Aβ deposition is associated with increases in soluble and phosphorylated tau that precede a positive Tau PET in Alzheimer’s disease. Sci Adv2020; 6: eaaz2387.
49.
MattssonNSchöllMStrandbergO, et al.18F-AV-1451 And CSF T-tau and P-tau as biomarkers in Alzheimer’s disease. EMBO Mol Med2017; 9: 1212–1223.
50.
MartensYAZhaoNLiuC-C, et al.Apoe cascade hypothesis in the pathogenesis of Alzheimer’s disease and related dementias. Neuron2022; 110: 1304–1317.
51.
FrisoniGBFoxNCJackCR, et al.The clinical use of structural MRI in Alzheimer disease. Nat Rev Neurol2010; 6: 67–77.
52.
HashimotoMYasudaMTanimukaiS, et al.Apolipoprotein E epsilon 4 and the pattern of regional brain atrophy in Alzheimer’s disease. Neurology2001; 57: 1461–1466.
53.
ZhangCKongMWeiH, et al.The effect of ApoE ε 4 on clinical and structural MRI markers in prodromal Alzheimer’s disease. Quant Imaging Med Surg2020; 10: 464–474.
54.
HostageCAChoudhuryKRMurali DoraiswamyP, et al.Mapping the effect of the apolipoprotein E genotype on 4-year atrophy rates in an Alzheimer disease-related brain network. Radiology2014; 271: 211–219.
55.
MorraJHTuZApostolovaLG, et al.Automated mapping of hippocampal atrophy in 1-year repeat MRI data from 490 subjects with Alzheimer’s disease, mild cognitive impairment, and elderly controls. Neuroimage2009; 45: S3–S15.
56.
LemaîtreHCrivelloFDufouilC, et al.No epsilon4 gene dose effect on hippocampal atrophy in a large MRI database of healthy elderly subjects. Neuroimage2005; 24: 1205–1213.
57.
LeungKKBartlettJWBarnesJ, et al.Cerebral atrophy in mild cognitive impairment and Alzheimer disease: rates and acceleration. Neurology2013; 80: 648–654.
58.
SchuffNWoernerNBoretaL, et al.MRI Of hippocampal volume loss in early Alzheimer’s disease in relation to ApoE genotype and biomarkers. Brain2009; 132: 1067–1077.
59.
CohenADMowreyWWeissfeldLA, et al.Classification of amyloid-positivity in controls: comparison of visual read and quantitative approaches. Neuroimage2013; 71: 207–215.
60.
LuPHThompsonPMLeowA, et al.Apolipoprotein E genotype is associated with temporal and hippocampal atrophy rates in healthy elderly adults: a tensor-based morphometry study. J Alzheimers Dis2011; 23: 433–442.
61.
TaylorJLScanlonBKFarrellM, et al.APOE-epsilon4 and aging of medial temporal lobe gray matter in healthy adults older than 50 years. Neurobiol Aging2014; 35: 2479–2485.
62.
DuA-TSchuffNChaoLL, et al.Age effects on atrophy rates of entorhinal cortex and hippocampus. Neurobiol Aging2006; 27: 733–740.
63.
ParanjpeMDChenXLiuM, et al.The effect of ApoE ε4 on longitudinal brain region-specific glucose metabolism in patients with mild cognitive impairment: a FDG-PET study. Neuroimage Clin2019; 22: 101795.
64.
LiWLiRYanS, et al.Effect of APOE ε4 genotype on amyloid-β, glucose metabolism, and gray matter volume in cognitively normal individuals and amnestic mild cognitive impairment. Eur J Neurol2023; 30: 587–596.
65.
OssenkoppeleRSmithROhlssonT, et al.Associations between tau, Aβ, and cortical thickness with cognition in Alzheimer disease. Neurology2019; 92: e601–e612.
66.
BennettDASchneiderJAWilsonRS, et al.Amyloid mediates the association of apolipoprotein E e4 allele to cognitive function in older people. J Neurol Neurosurg Psychiatry2005; 76: 1194–1199.
67.
NicholsEBrickmanAMCasalettoKB, et al.AD And non-AD mediators of the pathway between APOE genotype and cognition. Alzheimers Dement2023; 19: 2508–2519.
68.
OriáRBSmithCJAshfordJW, et al.Pros and cons of APOE4 homozygosity and effects on neuroplasticity, malnutrition, and infections in early life adversity, Alzheimer’s disease, and Alzheimer’s prevention. J Alzheimers Dis2024; 100: S179–S185.
69.
LottITHeadE. Dementia in down syndrome: unique insights for Alzheimer disease research. Nat Rev Neurol2019; 15: 135–147.
70.
BlessedGTomlinsonBERothM. The association between quantitative measures of dementia and of senile change in the cerebral grey matter of elderly subjects. Br J Psychiatry1968; 114: 797–811.
71.
BukhariHGlotzbachAKolbeK, et al.Small things matter: implications of APP intracellular domain AICD nuclear signaling in the progression and pathogenesis of Alzheimer’s disease. Prog Neurobiol2017; 156: 189–213.
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