Preclinical Alzheimer’s disease (AD) is defined by cerebral amyloid-β positivity (Aβ+) in cognitively normal (CN) older adults.
Objective:
To estimate the risk of progression to the symptomatic stages of AD due to PET Aβ+ and the extent that progression was influenced by other demographic, genetic, and clinical characteristics in a large prospective study.
Methods:
Fine-Gray subdistribution modeling was used to examine the risk of progression from CN to MCI/dementia due to Aβ+, APOEɛ4 carriage, and their interaction in the Australian Imaging, Biomarkers and Lifestyle (AIBL) flagship study of aging CN cohort (n = 599) over 8 years.
Results:
17.7% Aβ+ and 8.1% Aβ–progressed over 8 years (OR: 2.43). Risk of progression for Aβ+ was 65–104% greater than Aβ–. Aβ+ APOEɛ4 carriers were at 348% greater risk than all other participants. Significant risk factors of progression in Aβ+ were age (HR: 1.05), PET SUVR (HR: 2.49) and APOE ɛ4 carriage (HR: 2.63); only age was a significant risk factor in Aβ–(HR: 1.09). Aβ–progressors were not near the threshold for Aβ+. These relationships were not moderated by hypertension, diabetes, obesity, or stroke/TIA.
Conclusion:
Aβ+ is an important prognostic marker for progression from CN to MCI/dementia in older adults and APOEɛ4 carriage provides further predictive value in the presence of Aβ+. These data suggest that Aβ-associated clinical progression is consistent with clinical-pathological models of AD, whereas progression in the absence of elevated Aβ deposition may be the result of neuropathological processes other than AD that accumulate with age.
JackCRJr, KnopmanDS, JagustWJ, PetersenRC, WeinerMW, AisenPS, ShawLM, VemuriP, WisteHJ, WeigandSD, LesnickTG, PankratzVS, DonohueMC, TrojanowskiJQ (2013) Update on hypothetical model of Alzheimer’s disease biomarkers. Lancet Neurol12, 207–216.
2.
SperlingRA, AisenPS, BeckettLA, BennettDA, CraftS, FaganAM, IwatsuboT, JackCR, KayeJ, MontineTJ, ParkDC, ReimanEM, RoweCC, SiemersE, SternY, YaffeK, CarrilloMC, ThiesB, Morrison-BogoradM, WagsterMV, PhelpsCH (2011) 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 Dement7, 280–292.
BakerJE, LimYY, PietrzakRH, HassenstabJ, SnyderPJ, MastersCL, MaruffP (2017) Cognitive impairment and decline in cognitively normal older adults with high amyloid-β: A meta-analysis. Alzheimers Dement (Amst)6, 108–121.
6.
StorandtM, MintunMA, HeadD, MorrisJC (2009) Cognitive decline and brain volume loss as signatures of cerebral amyloid-β peptide deposition identified with Pittsburgh Compound B. Arch Neurol66, 1476–1481.
7.
ChetelatG, VillemagneVL, VillainN, JonesG, EllisKA, AmesD, MartinsRN, MastersCL, RoweCC; AIBL Research Group (2012) Accelerated cortical atrophy in cognitively normal elderly with high beta-amyloid deposition. Neurology78, 477–484.
ChételatG, La JoieR, VillainN, PerrotinA, De La SayetteV, EustacheF, VandenbergheR (2013) Amyloid imaging in cognitively normal individuals, at-risk populations and preclinical Alzheimer’s disease. Neuroimage Clin2, 356–365.
10.
RobertsRO, AakreJA, KremersWK, VassilakiM, KnopmanDS, MielkeMM, AlhuraniR, GedaYE, MachuldaMM, ColomaP, SchaubleB, LoweVJ, JackCR, PetersenRC (2018) Prevalence and outcomes of amyloid positivity among persons without dementia in a longitudinal, population-based setting. JAMA Neurol75, 970–979.
11.
SperlingRA, RentzDM, JohnsonKA, KarlawishJ, DonohueM, SalmonDP, AisenP (2014) The A4 Study: Stopping AD before symptoms begin? Sci Transl Med6, 228fs13–228fs13.
BurnhamSC, BourgeatP, DoréV, SavageG, BrownB, LawsS, MaruffP, SalvadoO, AmesD, MartinsRN, MastersCL, RoweCC, VillemagneVL (2016) Clinical and cognitive trajectories in cognitively healthy elderly individuals with suspected non-Alzheimer’s disease pathophysiology (SNAP) or Alzheimer’s disease pathology: A longitudinal study. Lancet Neurol15, 1044–1053.
15.
DonohueMC, SperlingRA, PetersenR, SunC-K, WeinerMW, AisenPS (2017) Association between elevated brain amyloid and subsequent cognitive decline among cognitively normal persons. JAMA317, 2305.
16.
DeegDJH (2002) Attrition in longitudinal population studies: Does it affect the generalizability of the findings? An introduction to the series. J Clin Epidemiol55, 213–215.
17.
VosSJ, XiongC, VisserPJ, JasielecMS, HassenstabJ, GrantEA, CairnsNJ, MorrisJC, HoltzmanDM, FaganAM (2013) Preclinical Alzheimer’s disease and its outcome: A longitudinal cohort study. Lancet Neurol12, 957–965.
VerghesePB, CastellanoJM, HoltzmanDM (2011) Roles of apolipoprotein E in Alzheimer’s disease and other neurological disorders. Lancet Neurol10, 241–252.
MorminoEC, BetenskyRA, HeddenT, SchultzAP, WardA, HuijbersW, RentzDM, JohnsonKA, SperlingRA; Alzheimer’s Disease Neuroimaging Initiative; Australian Imaging Biomarkers and Lifestyle Flagship Study of Ageing; Harvard Aging Brain Study (2014) Amyloid and APOE ɛ4 interact to influence short-term decline in preclinical Alzheimer disease. Neurology82, 1760–1767.
22.
ThaiC, LimYY, VillemagneVL, LawsSM, AmesD, EllisKA, Rainey-SmithSR, MartinsRN, MastersCL, RoweCC, MaruffP, ChambersB, ChiuE, ClarnetteR, DarbyD, DavisonM, DragoJ, DrysdaleP, GilbertJ, LimK, LautenschlagerN, LoGiudiceD, McCardleP, McFarlaneS, ManderA, MeroryJ, O’ConnorD, ScholesR, SamuelM, TrivediD, WoodwardM (2015) Amyloid-related memory decline in preclinical Alzheimer’s disease is dependent on APOE ɛ4 and is detectable over 18-months. PLoS One10, 1–10.
23.
VemuriP, LesnickTG, PrzybelskiSA, KnopmanDS, LoweVJ, Graff-RadfordJ, RobertsRO, MielkeMM, MachuldaMM, PetersenRC, JackCR (2017) Age, vascular health, and Alzheimer disease biomarkers in an elderly sample. Ann Neurol82, 706–718.
24.
VemuriP, LesnickTG, PrzybelskiSA, KnopmanDS, PreboskeGM, KantarciK, RamanMR, MachuldaMM, MielkeMM, LoweVJ, SenjemML, GunterJL, RoccaWA, RobertsRO, PetersenRC, JackCR (2015) Vascular and amyloid pathologies are independent predictors of cognitive decline in normal elderly. Brain138, 761–771.
25.
RobertsRO, GedaYE, KnopmanDS, ChaRH, PankratzVS, BoeveBF, IvnikRJ, TangalosEG, PetersenRC, RoccaWA (2008) The Mayo Clinic Study of Aging: Design and sampling, participation, baseline measures and sample characteristics. Neuroepidemiology30, 58–69.
26.
EllisKA, BushAI, DarbyDG, De FazioD, FosterJK, HudsonP, LautenschlagerNT, LenzoN, MartinsRN, MaruffP, MastersCL, MilnerA, PikeKE, RoweCC, SavageG, SzoekeC, TaddeiK, VillemagneVL, WoodwardM, AmesD (2009) The Australian Imaging, Biomarkers and Lifestyle (AIBL) study of aging: Methodology and baseline characteristics of 1112 individuals recruited for a longitudinal study of Alzheimer’s disease. Int Psychogeriatr21, 672–687.
27.
National Health and Medical Research Council (2001) Australian Alcohol Guidelines, Health Risks and Benefits. https://www.nhmrc.gov.au/guidelines-publications/ds9.
28.
WinbladB, PalmerK, KivipeltoM, JelicV, FratiglioniL, WahlundL-O, Nordberga, BäckmanL, AlbertM, AlmkvistO, AraiH, BasunH, BlennowK, de LeonM, DeCarliC, ErkinjunttiT, GiacobiniE, GraffC, HardyJ, JackC, JormA, RitchieK, van DuijnC, VisserP, PetersenRC (2004) Mild cognitive impairment–beyond controversies, towards a consensus: Report of the International Working Group on Mild Cognitive Impairment. J Intern Med256, 240–246.
29.
McKhannGM, DrachmanD, FolsteinM, KatzmanR, PriceD, StadlanEM (1984) Clinical diagnosis of Alzheimer’s disease: Report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer’s Disease. Neurology34, 939–944.
30.
PorterT, BurnhamSC, DoréV, SavageG, BourgeatP, BegemannK, MilicicL, AmesD, BushAI, MaruffP, MastersCL, RoweCC, Rainey-SmithS, MartinsRN, GrothD, VerdileG, VillemagneVL, LawsSM (2018) KIBRA is associated with accelerated cognitive decline and hippocampal atrophy in APOE ɛ4-positive cognitively normal adults with high Aβ-amyloid burden. Sci Rep8, 1–9.
31.
ZigmondAS, SnaithRP (1983) The hospital anxiety and depression scale. Acta Psychiatr Scand67, 361–370.
32.
CrookTH, FeherEP, LarrabeeGJ (1992) Assessment of memory complaint in age-associated memory impairment: The MAC-Q. Int Psychogeriatrics4, 165–176.
33.
RoweCC, EllisKA, RimajovaM, BourgeatP, PikeKE, JonesG, FrippJ, Tochon-DanguyH, MorandeauL, O’KeefeG, PriceR, RanigaP, RobinsP, AcostaO, LenzoN, SzoekeC, SalvadoO, HeadR, MartinsR, MastersCL, AmesD, VillemagneVL (2010) Amyloid imaging results from the Australian Imaging, Biomarkers and Lifestyle (AIBL) study of aging. Neurobiol Aging31, 1275–1283.
TonelliM, WiebeN, StrausS, FortinM, GuthrieB, JamesMT, KlarenbachSW, Tam-ThamH, LewanczukR, MannsBJ, QuanH, RonksleyPE, SargiousP, HemmelgarnB; Alberta Kidney Disease Network (2017) Multimorbidity, dementia and health care in older people: A population-based cohort study. CMAJ Open5, E623–E631.
36.
CummingG (2009) Inference by eye: Reading the overlap of independent confidence intervals. Stat Med28, 205–220.
37.
PetersenRC, WisteHJ, WeigandSD, RoccaWA, RobertsRO, MielkeMM, LoweVJ, KnopmanDS, PankratzVS, MachuldaMM, GedaYE, JackCR (2016) Association of elevated amyloid levels with cognition and biomarkers in cognitively normal people from the community. JAMA Neurol73, 85.
38.
LimYY, KalinowskiP, PietrzakRH, LawsSM, BurnhamSC, AmesD, VillemagneVL, FowlerCJ, Rainey-SmithSR, MartinsRN, RoweCC, MastersCL, MaruffPT (2018) Association of β-amyloid and apolipoprotein E ɛ4 with memory decline in preclinical Alzheimer disease. JAMA Neurol3052, 1–7.
BiesselsGJ, StaekenborgS, BrunnerE, BrayneC, ScheltensP (2006) Risk of dementia in diabetes mellitus: A systematic review. Lancet Neurol5, 64–74.
41.
PattersonBW, ElbertDL, MawuenyegaKG, KastenT, OvodV, MaS, XiongC, ChottR, YarasheskiK, SigurdsonW, ZhangL, GoateA, BenzingerT, MorrisJC, HoltzmanD, BatemanRJ (2015) Age and amyloid effects on human central nervous system amyloid-beta kinetics. Ann Neurol78, 439–453.
42.
RazN, RodrigueKM (2006) Differential aging of the brain: Patterns, cognitive correlates and modifiers. Neurosci Biobehav Rev30, 730–748.
43.
ChételatG, OssenkoppeleR, VillemagneVL, PerrotinA, LandeauB, MézengeF, JagustWJ, DoreV, MillerBL, EgretS, SeeleyWW, Van Der FlierWM, La JoieR, AmesD, Van BerckelBNM, ScheltensP, BarkhofF, RoweCC, MastersCL, De La SayetteV, BouwmanF, RabinoviciGD (2016) Atrophy, hypometabolism and clinical trajectories in patients with amyloid-negative Alzheimer’s disease. Brain139, 2528–2539.
44.
HarringtonKD, LimYY, AmesD, HassenstabJ, Rainey-SmithS, RobertsonJ, SalvadoO, MastersCL, MaruffP, AIBL Research Group (2017) Using robust normative data to investigate the neuropsychology of cognitive aging., Arch Clin Neuropsychol32, 142–154.
45.
EdmondsEC, Delano-WoodL, GalaskoDR, SalmonDP, BondiMW (2015) Subtle cognitive decline and biomarker staging in preclinical Alzheimer’s disease. J Alzheimers Dis47, 231–242.
46.
ToledoJB, WeinerMW, WolkDA, DaX, ChenK, ArnoldSE, JagustW, JackC, ReimanEM, DavatzikosC, ShawLM, TrojanowskiJQ (2014) Neuronal injury biomarkers and prognosis in ADNI subjects with normal cognition. Acta Neuropathol Commun2, 26.
