The NIA-AA Research Framework on Alzheimer’s disease (AD) proposes a transitional stage (stage 2) characterized by subtle cognitive decline, subjective cognitive decline (SCD) and mild neurobehavioral symptoms (NPS).
Objective:
To identify participant clusters based on stage 2 features and assess their association with amyloid positivity in cognitively unimpaired individuals.
Methods:
We included baseline data of N = 338 cognitively unimpaired participants from the DELCODE cohort with data on cerebrospinal fluid biomarkers for AD. Classification into the AD continuum (i.e., amyloid positivity, A+) was based on Aβ42/40 status. Neuropsychological test data were used to assess subtle objective cognitive dysfunction (OBJ), the subjective cognitive decline interview (SCD-I) was used to detect SCD, and the Neuropsychiatric Inventory Questionnaire (NPI-Q) was used to assess NPS. A two-step cluster analysis was carried out and differences in AD biomarkers between clusters were analyzed.
Results:
We identified three distinct participant clusters based on presented symptoms. The highest rate of A+ participants (47.6%) was found in a cluster characterized by both OBJ and SCD. A cluster of participants that presented with SCD and NPS (A+:26.6%) and a cluster of participants with overall few symptoms (A+:19.7%) showed amyloid positivity in a range that was not higher than the expected A+ rate for the age group. Across the full sample, participants with a combination of SCD and OBJ in the memory domain showed a lower Aβ42/ptau181 ratio compared to those with neither SCD nor OBJ.
Conclusions:
The cluster characterized by participants with OBJ and concomitant SCD was enriched for amyloid pathology.
DuboisB, HampelH, FeldmanHH, ScheltensP, AisenP, AndrieuS, BakardjianH, BenaliH, BertramL, BlennowK, BroichK, CavedoE, CrutchS, DartiguesJ-F, DuyckaertsC, EpelbaumS, FrisoniGB, GauthierS, GenthonR, GouwAA, HabertM-O, HoltzmanDM, KivipeltoM, ListaS, MolinuevoJ-L, O’BryantSE, RabinoviciGD, RoweC, SallowayS, SchneiderLS, SperlingR, TeichmannM, CarrilloMC, CummingsJ, JackCR, Proceedings of the Meeting of the International Working Group (IWG) and the American Alzheimer’s Association on “The Preclinical State of AD”; July 23, 2015; Washington DC, USA (2016) Preclinical Alzheimer’s disease: Definition, natural history, and diagnostic criteria. Alzheimers Dement12, 292–323.
ReisbergB, ShulmanMB, TorossianC, LengL, ZhuW (2010) Outcome over seven years of healthy adults with and without subjective cognitive impairment. Alzheimers Dement6, 11–24.
JessenF, WieseB, BachmannC, Eifflaender-GorferS, HallerF, KölschH, LuckT, MöschE, Van Den BusscheH, WagnerM, WollnyA, ZimmermannT, PentzekM, Riedel-HellerSG, RombergHP, WeyererS, KaduszkiewiczH, MaierW, BickelH (2010) Prediction of dementia by subjective memory impairment effects of severity and temporal association with cognitive impairment. Arch Gen Psychiatry67, 414–422.
van HartenAC, MielkeMM, Swenson-DravisDM, HagenCE, EdwardsKK, RobertsRO, GedaYE, KnopmanDS, PetersenRC (2018) Subjective cognitive decline and risk of MCI: The Mayo Clinic Study of Aging. Neurology91, e300–e312.
10.
PikeKE, CavuotoMG, LiL, WrightBJ, KinsellaGJ (2022) Subjective cognitive decline: Level of risk for future dementia and mild cognitive impairment, a meta-analysis of longitudinal studies. Neuropsychol Rev32, 703–735.
11.
AmariglioRE, BeckerJA, CarmasinJ, WadsworthLP, LoriusN, SullivanC, MayeJE, GidicsinC, PepinLC, SperlingRA, JohnsonKA, RentzDM (2012) Subjective cognitive complaints and amyloid burden in cognitively normal older individuals. Neuropsychologia50, 2880–2886.
12.
SchwarzC, LangeC, BensonGS, HornN, WurdackK, LukasM, BuchertR, WirthM, FlöelA (2021) Severity of subjective cognitive complaints and worries in older adults are associated with cerebral amyloid-β load. Front Aging Neurosci13, 675583.
13.
MiebachL, WolfsgruberS, PolcherA, PetersO, MenneF, LutherK, IncesoyE, PrillerJ, SpruthE, AltensteinS, BuergerK, CatakC, JanowitzD, PerneczkyR, UtechtJ, LaskeC, BuchmannM, SchneiderA, FliessbachK, KalbhenP, HenekaMT, BrosseronF, SpottkeA, RoyN, TeipelSJ, KilimannI, WiltfangJ, BartelsC, DüzelE, DobischL, MetzgerC, MeiberthD, RamirezA, JessenF, WagnerM (2019) Which features of subjective cognitive decline are related to amyloid pathology? Findings from the DELCODE study. Alzheimers Res Ther11, 66.
14.
JessenF, AmariglioRE, BuckleyRF, van der FlierWM, HanY, MolinuevoJL, RabinL, RentzDM, Rodriguez-GomezO, SaykinAJ, SikkesSAM, SmartCM, WolfsgruberS, WagnerM (2020) The characterisation of subjective cognitive decline. Lancet Neurol19, 271–278.
BarnesDE, AlexopoulosGS, LopezOL, WilliamsonJD, YaffeK (2006) Depressive symptoms, vascular disease, and mild cognitive impairment: Findings from the cardiovascular health study. Arch Gen Psychiatry63, 273–280.
17.
GedaYE, RobertsRO, MielkeMM, KnopmanDS, ChristiansonTJH, PankratzVS, BoeveBF, SochorO, TangalosEG, PetersenRC, RoccaWA (2014) Baseline neuropsychiatric symptoms and the risk of incident mild cognitive impairment: A population-based study. Am J Psychiatry171, 572–81.
18.
BanksSJ, RamanR, HeF, SalmonDP, FerrisS, AisenP, CummingsJ (2014) The Alzheimer’s disease cooperative study prevention instrument project: Longitudinal outcome of behavioral measures as predictors of cognitive decline. Dement Geriatr Cogn Dis Extra4, 509–516.
19.
MastersMC, MorrisJC, RoeCM (2015) Noncognitive symptoms of early Alzheimer disease: A longitudinal analysis. Neurology84, 617–22.
20.
TaraganoFE, AllegriRF, HeiseckeSL, MartelliMI, FeldmanML, SánchezV, GarcíaVA, TufroG, CastroDM, LeguizamónPP, GuelarV, RuotoloE, ZegarraC, DillonC (2018) Risk of conversion to dementia in a mild behavioral impairment group compared to a psychiatric group and to a mild cognitive impairment group. J Alzheimers Dis62, 227–238.
21.
IsmailZ, SmithEE, GedaY, SultzerD, BrodatyH, SmithG, Agüera-OrtizL, SweetR, MillerD, LyketsosCG, ISTAART Neuropsychiatric Symptoms Professional Interest Area (2016) Neuropsychiatric symptoms as early manifestations of emergent dementia: Provisional diagnostic criteria for mild behavioral impairment. Alzheimers Dement12, 195–202.
22.
JessenF, SpottkeA, BoeckerH, BrosseronF, BuergerK, CatakC, FliessbachK, FrankeC, FuentesM, HenekaMT, JanowitzD, KilimannI, LaskeC, MenneF, NestorP, PetersO, PrillerJ, ProssV, RamirezA, SchneiderA, SpeckO, SpruthEJ, TeipelS, VukovichR, WesterteicherC, WiltfangJ, WolfsgruberS, WagnerM, DüzelE (2018) Design and first baseline data of the DZNE multicenter observational study on predementia Alzheimer’s disease (DELCODE). Alzheimers Res Ther10, 15.
FolsteinMF, FolsteinSE, McHughPR (1975) “Mini-mental state”: A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res12, 189–198.
25.
MohsRC, KnopmanD, PetersenRC, FerrisSH, ErnestoC, GrundmanM, SanoM, BieliauskasL, GeldmacherD, ClarkC, ThalLJ (1997) Development of cognitive instruments for use in clinical trials of antidementia drugs: Additions to the Alzheimer’s disease assessment scale that broaden its scope. Alzheimer Dis Assoc Disord11, S1321–S13-21.
26.
GroberE, Ocepek-WeliksonK, TeresiJA (2009) The Free and Cued Selective Reminding Test: Evidence of psychometric adequacy. Psychol Sci Q51, 266–282.
27.
Petermann F, Lepach AC (2012) Wechsler memory scale. Dtsch Übersetzung und Adapt der WMS-IV von Davis Wechsler Frankfurt a M Pearson Assess Inf GmbH.
SmithA (1973) Symbol digit modalities test (SDMT) Manual (Revised), Los Angeles: Western Psychological Services.
30.
ReitanRM (1958) Validity of the Trail Making Test as an indicator of organic brain damage. Percept Mot Skills8, 271–276.
31.
RouleauI, SalmonDP, ButtersN, KennedyC, McGuireK (1992) Quantitative and qualitative analyses of clock drawings in Alzheimer’s and Huntington’s disease. Brain Cogn18, 70–87.
32.
ThalmannB, MonschAU, SchneitterM, BernasconiF, AebiC, Camachova-DavetZ, StaehelinHB (2000) The cerad neuropsychological assessment battery (Cerad-NAB)— A minimal data set as a common tool for German-speaking Europe. Neurobiol Aging21, 30.
KauferDI, CummingsJL, KetchelP, SmithV, MacMillanA, ShelleyT, LopezOL, DeKoskyST (2000) Validation of the NPI-Q, a brief clinical form of the Neuropsychiatric Inventory. J Neuropsychiatry Clin Neurosci12, 233–239.
37.
GelbardR, GoldmanO, SpieglerI (2007) Investigating diversity of clustering methods: An empirical comparison. Data Knowl Eng63, 155–166.
38.
SarstedtM, MooiE (2014) A Concise Guide to Market ResearchSpringer Berlin Heidelberg, Heidelberg, Berlin, Heidelberg.
39.
TomczakM, TomczakE (2014) The need to report effect size estimates revisited. An overview of some recommended measures of effect size. Trends Sport Sci1, 19–25.
40.
YaffeK, PetersenRC, LindquistK, KramerJ, MillerB (2006) Subtype of mild cognitive impairment and progression to dementia and death. Dement Geriatr Cogn Disord22, 312–319.
41.
JansenWJ, JanssenO, TijmsBM, VosSJB, OssenkoppeleR, VisserPJ, AarslandD, AlcoleaD, AltomareD, von ArnimC, et al. (2022) Prevalence estimates of amyloid abnormality across the Alzheimer disease clinical spectrum. JAMA Neurol79, 228–243.
42.
TimmersT, OssenkoppeleR, VerfaillieSCJ, van der WeijdenCWJ, SlotRER, WesselmanLMP, WindhorstAD, WoltersEE, YaqubM, PrinsND, LammertsmaAA, ScheltensP, van der FlierWM, van BerckelBNM (2019) Amyloid PET and cognitive decline in cognitively normal individuals: The SCIENCe project. Neurobiol Aging79, 50–58.
43.
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, 85–92.
44.
BurhanullahMH, TschanzJAT, PetersME, LeoutsakosJM, MatyiJ, LyketsosCG, NowrangiMA, RosenbergPB (2020) Neuropsychiatric symptoms as risk factors for cognitive decline in clinically normal older adults: The Cache County Study. Am J Geriatr Psychiatry28, 64–71.
45.
FermanTJ, SmithGE, KantarciK, BoeveBF, PankratzVS, DicksonDW, Graff-RadfordNR, WszolekZ, Van GerpenJ, UittiR, PedrazaO, MurrayME, AakreJ, ParisiJ, KnopmanDS, PetersenRC (2013) Nonamnestic mild cognitive impairment progresses to dementia with Lewy bodies. Neurology81, 2032–2038.
46.
JungwirthS, ZehetmayerS, HinterbergerM, TraglKH, FischerP (2012) The validity of amnestic MCI and non-amnestic MCI at age 75 in the prediction of Alzheimer’s dementia and vascular dementia. Int Psychogeriatr24, 959–966.
ZlatarZZ, MunizM, GalaskoD, SalmonDP (2018) Subjective cognitive decline correlates with depression symptoms and not with concurrent objective cognition in a clinic-based sample of older adults. J Gerontol B Psychol Sci Soc Sci73, 1198–1202.
49.
HillNL, MogleJ, WionR, MunozE, DePasqualeN, YevchakAM, ParisiJM (2016) Subjective cognitive impairment and affective symptoms: A systematic review. Gerontologist56, e109–e127.
50.
BuckleyR, SalingMM, AmesD, RoweCC, LautenschlagerNT, MacAulaySL, MartinsRN, MastersCL, O’MearaT, SavageG, SzoekeC, VillemagneVL, EllisKA (2013) Factors affecting subjective memory complaints in the AIBL aging study: Biomarkers, memory, affect, and age. Int Psychogeriatr25, 1307–1315.
51.
RileyKP, JichaGA, DavisD, AbnerEL, CooperGE, StilesN, SmithCD, KryscioRJ, NelsonPT, Van EldikLJ, SchmittFA (2011) Prediction of preclinical Alzheimer’s disease: Longitudinal rates of change in cognition. J Alzheimers Dis25, 707–717.
52.
MonsellSE, MockC, HassenstabJ, RoeCM, CairnsNJ, MorrisJC, KukullW (2014) Neuropsychological changes in asymptomatic persons with Alzheimer disease neuropathology. Neurology83, 434–440.
53.
AmievaH, Jacqmin-GaddaH, OrgogozoJM, Le CarretN, HelmerC, LetenneurL, Barberger-GateauP, FabrigouleC, DartiguesJF (2005) The 9 year cognitive decline before dementia of the Alzheimer type: A prospective population-based study. Brain128, 1093–1101.
54.
PappK V, BuckleyR, MorminoE, MaruffP, VillemagneVL, MastersCL, JohnsonKA, RentzDM, SperlingRA, AmariglioRE (2019) Clinical meaningfulness of subtle cognitive decline on longitudinal testing in preclinical AD. Alzheimers Dement16, 552–560.
55.
PudumjeeSB, LundtES, AlbertsonSM, MachuldaMM, KremersWK, JackCR, KnopmanDS, PetersenRC, MielkeMM, StrickerNH, BondiM (2021) A comparison of cross-sectional and longitudinal methods of defining objective subtle cognitive decline in preclinical Alzheimer’s disease based on cogstate one card learning accuracy performance. J Alzheimers Dis83, 861–877.
56.
AldenEC, LundtES, TwohyEL, ChristiansonTJ, KremersWK, MachuldaMM, JackCR, KnopmanDS, MielkeMM, PetersenRC, StrickerNH (2022) Mayo normative studies: A conditional normative model for longitudinal change on the Auditory Verbal Learning Test and preliminary validation in preclinical Alzheimer’s disease. Alzheimers Dement (Amst)14, e12325.
57.
EdmondsEC, Delano-WoodL, GalaskoDR, SalmonDP, BondiMW (2015) Subtle cognitive decline and biomarker staging in preclinical Alzheimer’s disease. J Alzheimers Dis47, 231–242.
58.
StrickerNH, LundtES, AlbertsonSM, MacHuldaMM, PudumjeeSB, KremersWK, JackCR, KnopmanDS, PetersenRC, MielkeMM (2020) Diagnostic and prognostic accuracy of the Cogstate Brief Battery and Auditory Verbal Learning Test in preclinical Alzheimer’s disease and incident mild cognitive impairment: Implications for defining subtle objective cognitive impairment. J Alzheimers Dis76, 261–274.
59.
PalmerBW, BooneKB, LesserIM, WohlMA (1998) Base rates of “impaired” neuropsychological test performance among healthy older adults. Arch Clin Neuropsychol13, 503–511.
60.
JessenF, KleineidamL, WolfsgruberS, BickelH, BrettschneiderC, FuchsA, KaduszkiewiczH, KönigHH, MallonT, MamoneS, PabstA, PentzekM, RoehrS, WeegD, JochenW, WeyererS, WieseB, MaierW, SchererM, Riedel-HellerS, WagnerM (2020) Prediction of dementia of Alzheimer type by different types of subjective cognitive decline. Alzheimers Dement16, 1745–1749.
61.
KiselicaAM (2021) Empirically defining the preclinical stages of the Alzheimer’s continuum in the Alzheimer’s Disease Neuroimaging Initiative. Psychogeriatrics21, 491–502.
