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. 2024 Jan 23;102(2):e207978.
doi: 10.1212/WNL.0000000000207978. Epub 2023 Dec 26.

Cognitive and Functional Change Over Time in Cognitively Healthy Individuals According to Alzheimer Disease Biomarker-Defined Subgroups

Mark A Dubbelman  1 , Heleen M A Hendriksen  1 , John E Harrison  1 , Everard G B Vijverberg  1 , Niels D Prins  1 , Lior A Kroeze  1 , Lois Ottenhoff  1 , Mardou M S S A Van Leeuwenstijn  1 , Inge M W Verberk  1 , Charlotte E Teunissen  1 , Elsmarieke M van de Giessen  1 , Argonde C Van Harten  1 , Wiesje M Van Der Flier  1 , Sietske A M Sikkes  1
Affiliations

Cognitive and Functional Change Over Time in Cognitively Healthy Individuals According to Alzheimer Disease Biomarker-Defined Subgroups

Mark A Dubbelman et al. Neurology. .

Abstract

Background and objectives: It is unclear to what extent cognitive outcome measures are sensitive to capture decline in Alzheimer disease (AD) prevention trials. We aimed to analyze the sensitivity to changes over time of a range of neuropsychological tests in several cognitively unimpaired, biomarker-defined patient groups.

Methods: Cognitively unimpaired individuals from the Amsterdam Dementia Cohort and the SCIENCe project with available AD biomarkers, obtained from CSF, PET scans, and plasma at baseline, were followed over time (4.5 ± 3.1 years, range 0.6-18.9 years). Based on common inclusion criteria for clinical trials, we defined groups (amyloid, phosphorylated tau [p-tau], APOE ε4). Linear mixed models, adjusted for age, sex, and education, were used to estimate change over time in neuropsychological tests, a functional outcome, and 2 cognitive composite measures. Standardized regression coefficients of time in years (βtime) were reported as outcome of interest. We analyzed change over time with full follow-up, as well as with follow-up limited to 1.5 and 3 years.

Results: We included 387 individuals (aged 61.7 ± 8.6 years; 44% female) in the following (partly overlapping) biomarker groups: APOE ε4 carriers (n = 212), amyloid-positive individuals (n = 109), amyloid-positive APOE ε4 carriers (n = 66), CSF p-tau-positive individuals (n = 127), plasma p-tau-positive individuals (n = 71), and amyloid and CSF p-tau-positive individuals (n = 50), or in a control group (normal biomarkers; n = 65). An executive functioning task showed most decline in all biomarker groups (βtime range -0.30 to -0.71), followed by delayed word list recognition (βtime range -0.18 to -0.50). Functional decline (βtime range -0.17 to -0.63) was observed in all, except the CSF and plasma tau-positive groups. Both composites showed comparable amounts of change (βtime range -0.12 to -0.62) in all groups, except plasma p-tau-positive individuals. When limiting original follow-up duration, many effects disappeared or even flipped direction.

Discussion: In conclusion, functional, composite, and neuropsychological outcome measures across all cognitive domains detect changes over time in various biomarker-defined groups, with changes being most evident among individuals with more AD pathology. AD prevention trials should use sufficiently long follow-up duration and/or more sensitive outcome measures to optimally capture subtle cognitive changes over time.

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Conflict of interest statement

M.A. Dubbelman reports no disclosures relevant to the manuscript. H.M.A. Hendriksen is appointed at the EU-FINGERS project, which is an EU Joint Programme–Neurodegenerative Disease Research (JPND) project. The project is supported through the following funding organizations under the guidance of JPND (www.jpnd.eu): Finland, Academy of Finland; Germany, Federal Ministry of Education and Research; Spain, National Institute of Health Carlos III; Luxemburg, National Research Fund; Hungary, National Research, Development and Innovation Office; The Netherlands, Netherlands Organisation for Health Research and Development; and Sweden, Swedish Research Council. J.E. Harrison is an employee of Scottish Brain Sciences. He reports receipt of personal fees in the past 2 years from Actinogen, Alto Pharma, AlzeCure, ADvantage, Astra Zeneca, Athira Therapeutics, Axoltis, Axon Neuroscience, Axovant, Bial Biotech, Biogen Idec, Boehringer Ingelheim, Brands2life, Cerecin, Cognition Therapeutics, Compass Pathways, Corlieve, Curasen, EcoR1, EIP Pharma, EQT Life, GfHEU, Heptares, ImPACT, Ki Elements, LSP Operations, Lundbeck, Lysosome Therapeutics, Neurotrack, the NHS, Novartis, Novo Nordisk, Nutricia, Prothena, Recognify, reMYND, Roche, Rodin Therapeutics, Signant, Stoke Therapeutics, Syndesi Therapeutics, Takeda, Vivoryon Therapeutics, and Winterlight Labs. Additionally, he holds stock options in Neurotrack Inc. and is a joint holder of patents with My Cognition Ltd. E.G.B. Vijverberg reports no disclosures relevant to the manuscript. N.D. Prins performed consultancy work for Aribio, Amylyx, Eli-Lilly, and Janssen. He is co‐PI of a study with Fuji Film Toyama Chemical. N.D. Prins received a speaker fee from Biogen. N.D. Prins served on the DSMB of Abbvie's M15‐566 trial. N.D. Prins is CEO and co‐owner of Brain Research Center, the Netherlands. L.A. Kroeze reports no disclosures relevant to the manuscript. L. Ottenhoff reports no disclosures relevant to the manuscript. M.S.S.A.Van Leeuwenstijn reports no disclosures relevant to the manuscript. I.M.W. Verberk reports no disclosures relevant to the manuscript; Research of C.E. Teunissen is supported by the European Commission (Marie Curie International Training Network, grant agreement no 860197 [MIRIADE]), Innovative Medicines Initiatives 3TR (Horizon 2020, grant no. 831434) EPND (IMI 2 Joint Undertaking [JU], grant no. 101034344) and JPND (bPRIDE), National MS Society (Progressive MS alliance), Alzheimer Association, Health Holland, the Dutch Research Council (ZonMW), Alzheimer Drug Discovery Foundation, The Selfridges Group Foundation, Alzheimer Netherlands. C.E. Teunissen is recipient of ABOARD, which is a public-private partnership receiving funding from ZonMW (#73305095007) and Health∼Holland, Topsector Life Sciences & Health (PPP-allowance; #LSHM20106). C.E. Teunissen is recipient of TAP-dementia, a ZonMw funded project (#10510032120003) in the context of the Dutch National Dementia Strategy. C.E. Teunissen has a collaboration contract with ADx Neurosciences, Quanterix, and Eli Lilly, performed contract research or received grants from AC-Immune, Axon Neurosciences, BioConnect, Bioorchestra, Brainstorm Therapeutics, Celgene, EIP Pharma, Eisai, Fujirebio, Grifols, Instant Nano Biosensors, Merck, Novo Nordisk, PeopleBio, Roche, Siemens, Toyama, and Vivoryon. She is editor of Alzheimer Research and Therapy and serves on editorial boards of Medidact Neurologie/Springer and Neurology: Neuroimmunology & Neuroinflammation. She had speaker contracts for Roche, Grifols, and Novo Nordisk. All funds were paid to her institution. E.M. van de Giessen reports no disclosures relevant to the manuscript. Research of A.C. Van Harten is funded by Stichting Alzheimer Nederland, the Alzheimer's Drug Discovery Foundation (ADDF), Stichting Steun Alzheimercentrum Amsterdam, and ZonMW. She has been a speaker for Roche Diagnostics. All proceeds were paid to her institution. W.M. Van Der Flier is recipient of ABOARD (A Personalized Medicine Approach for Alzheimer's Disease); a public-private partnership receiving funding from ZonMW (#73305095007); and Health∼Holland, Topsector Life Sciences & Health (PPP-allowance #LSHM20106). More than 30 partners participate in ABOARD. Research programs of W.M. Van Der Flier have been funded by ZonMW, NWO, EU-FP7, EU-JPND, Alzheimer Nederland, Hersenstichting CardioVascular Onderzoek Nederland, Health∼Holland, Topsector Life Sciences & Health, stichting Dioraphte, Gieskes-Strijbis fonds, stichting Equilibrio, Edwin Bouw fonds, Pasman stichting, stichting Alzheimer & Neuropsychiatrie Foundation, Philips, Biogen MA Inc., Novartis-NL, Life-MI, AVID, Roche BV, Fujifilm, and Combinostics. W.M. Van Der Flier has performed contract research for Biogen MA Inc., and Boehringer Ingelheim. W.M. Van Der Flier has been an invited speaker at Boehringer Ingelheim, Biogen MA Inc., Danone, Eisai, WebMD Neurology (Medscape), NovoNordisk, Springer Healthcare, European Brain Council. W.M. Van Der Flier is consultant to Oxford Health Policy Forum CIC, Roche, and Biogen MA Inc. W.M. Van Der Flier participated in advisory boards of Biogen MA Inc., Roche, and Eli Lilly. All funding is paid to her institution. W.M. Van Der Flier is member of the steering committee of PAVE and Think Brain Health. W.M. Van Der Flier was associate editor at Alzheimer, Research & Therapy in 2020/2021. W.M. Van Der Flier is associate editor at Brain. S.A.M. Sikkes received grant support from Health Holland (LSHM19051, LSHM20084, LSHM22026-SGF), and Zon-MW (#7330502051 and #73305095008). S.A.M. Sikkes provided consultancy services for Biogen, Boehringer and Toyama. S.A.M. Sikkes is the developer of the Amsterdam IADL Questionnaire, and received license fees from Green Valley, VtV Therapeutics, Alzheon, Vivoryon and Roche. All funding was paid to her institution. Go to Neurology.org/N for full disclosures.

Figures

Figure 1
Figure 1. Venn Diagram Showing the Biomarker and Control Groups
p-tau = phosphorylated tau.
Figure 2
Figure 2. Change Over Time on All Tests, Across All Biomarker Groups
Standardized coefficients, adjusted for age, sex, and education, are visualized as triangles. The magnitude of the coefficient is reflected by the triangle's size. Upward-pointing triangles represent an improvement in performance; downward-pointing triangles represent a decrease in performance. When no triangle is displayed, there was no change over time (i.e., the 95% CI included change in both directions). Full data are shown in eTable 1. A-IADL-Q = Amsterdam Instrumental Activities of Daily Living Questionnaire; AVLT = Auditory Verbal Learning Test; BNT = Boston Naming Test; CFC = Cognitive-Functional Composite; DS = digit span; LDST = Letter Digit Substitution Test; MMSE = Mini-Mental State Examination; PACC5 = Preclinical Alzheimer's Cognitive Composite; p-tau = phosphorylated tau; RBMT = Rivermead Behavioral Memory Test.
Figure 3
Figure 3. Change Over Time on All Tests, Across All Biomarker Groups, With Follow-Up Duration Limited to 156 Weeks (A) and 78 Weeks (B)
Standardized coefficients, adjusted for age, sex, and education, are visualized as triangles. The magnitude of the coefficient is reflected by the triangle's size. Upward-pointing triangles represent an improvement in performance; downward-pointing triangles represent a decrease in performance. When no triangle is displayed, there was no change over time (i.e., the 95% CI included change in both directions). Full data are shown in eTable 1. A-IADL-Q = Amsterdam Instrumental Activities of Daily Living Questionnaire; AVLT = Auditory Verbal Learning Test; BNT = Boston Naming Test; CFC = Cognitive-Functional Composite; DS = digit span; LDST = Letter Digit Substitution Test; MMSE = Mini-Mental State Examination; PACC5 = Preclinical Alzheimer's Cognitive Composite; p-tau = phosphorylated tau; RBMT = Rivermead Behavioral Memory Test.
See this image and copyright information in PMC

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