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[Preprint]. 2025 May 2:2025.05.01.25326668.
doi: 10.1101/2025.05.01.25326668.

Use of preclinical Alzheimer's disease trajectories for clinical trial design

Rebecca E Langhough  1   2 , Derek L Norton  3 , Karly A Cody  2   4 , Lianlian Du  1   2   5 , Erin M Jonaitis  1   2 , Rachael Wilson  2 , Ramiro Eduardo Rea Reyes  2 , Bruce P Hermann  1   6 , Henrik Zetterberg  2   7   8   9   9   10 , Sterling C Johnson  1   2
Affiliations

Use of preclinical Alzheimer's disease trajectories for clinical trial design

Rebecca E Langhough et al. medRxiv. .

Abstract

Introduction: This study uses longitudinal amyloid biomarker and cognitive data to generate sample size estimates for two-armed, pre-clinical amyloid clearance clinical trials.

Methods: PET PiB DVR ranges defined three amyloid groups (positive, "A+"; sub threshold/low positive, "subA+"; and negative, "A-") in cognitively unimpaired Wisconsin Registry for Alzheimer's Prevention participants. Amyloid group trajectories estimated from mixed effects models informed per-treatment-arm sample size estimates to detect plausible treatment effects over 3-year (biomarker) or 6-year (cognition) study windows (80% power).

Results: To detect ≥60% slowing in PiB accumulation, ≤40 may be needed per arm for both SubA+ and A+; to detect the same effect sizes in plasma p-tau217 trajectories, ~50-1700 are needed, depending on assay and amyloid subgroup. Among cognitive outcomes, Digit Symbol Substitution and a 5-test Preclinical Alzheimer's Cognitive Composite consistently required fewest (<2000) per arm.

Discussion: Early intervention study planning will benefit from selection of outcomes that are most sensitive to AD biomarker-related preclinical change.

Keywords: Alzheimer’s disease; biomarkers; clinical trial design; preclinical; preclinical intervention.

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Conflict of interest statement

Conflict of Interest Statement/Disclosures Authors REL, DLN, KAC, LD, EMJ, RW, RERR, BH have nothing to disclose. HZ has served at scientific advisory boards and/or as a consultant for Abbvie, Acumen, Alector, Alzinova, ALZpath, Amylyx, Annexon, Apellis, Artery Therapeutics, AZTherapies, Cognito Therapeutics, CogRx, Denali, Eisai, Enigma, LabCorp, Merry Life, Nervgen, Novo Nordisk, Optoceutics, Passage Bio, Pinteon Therapeutics, Prothena, Quanterix, Red Abbey Labs, reMYND, Roche, Samumed, Siemens Healthineers, Triplet Therapeutics, and Wave, has given lectures sponsored by Alzecure, BioArctic, Biogen, Cellectricon, Fujirebio, Lilly, Novo Nordisk, Roche, and WebMD, and is a co-founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program (outside submitted work). SCJ serves as an advisor to Enigma Biomedical and ALZpath.

Figures

Figure 1:
Figure 1:. Illustration of partitioning of participant visits for slope estimates
In panel A (top), partitioning of PiB DVR data is shown for three participants. The participant at the top left transitioned from A− to A+ between PiB visits 2 and 3, which were 2.5 and 7 years post baseline PiB scan, respectively. The first two visits met criteria for slope estimates in the A- group while the second two visits contributed to the slope estimates for the subA+ group. In the top middle panel, the participant had two visits each that contributed to slope estimates in the subA+ and A+ groups. In the panel at the top right, the participant’s first two visits contributed to slope estimates for the A+ range, while the third visit was not included because it was beyond the trial design window of 3 years for PiB. Panel B (bottom) shows partitioning of cognitive visit data based on the imputed/modeled PiB DVR at each cognitive visit for the same participants to estimate slopes for a six-year cognitive follow-up window. Abbreviations: A- = amyloid negative group (CL<~13); subA+ = sub-threshold to low positive group (CL ~13–23); and A+ = overtly A+ group (CL >~23); DVR=Distribution Volume Ratio; PiB= Pittsburgh Compound B.
Figure 2:
Figure 2:. Estimated 3-year regression slopes with 95% CI’s of biomarkers by amyloid group
The top row depicts estimated slopes by amyloid group for PiB DVR (left), Lilly MSD plasma pTau217 pg/mL (middle), and Quanterix ALZpath plasma pTau217 pg/mL (right). The bottom row shows the same data using standardized slope estimates to facilitate visual comparisons of effect sizes across biomarkers. Slopes that differ significantly from zero are in orange while those not differing from zero are in green. Abbreviations: A- = amyloid negative group (CL<~13); subA+ = sub-threshold to low positive group (CL ~13–23); and A+ = overtly A+ group (CL >~23); CL=Centiloid; DVR=Distribution Volume Ratio; Lilly MSD= Lilly Meso Scale Discovery; PiB= Pittsburgh Compound B; pTau217= phosphorylated tau protein at amino acid 217.
Figure 3:
Figure 3:. Sample size projections for biomarker outcomes
Sample size projections for biomarker outcomes. Red, green, and blue indicate numbers of participants needed per treatment arm to have 80% power to detect effect sizes of 60–90% reduction in treatment vs control trajectories for PiB DVR, Lilly MSD pTau217, and ALZpath pTau217, respectively. N’s are shown for studies targeting amyloid clearance in the subA+ group (top row: left panel depicts slope attenuation to 0 while right panel depicts slope attenuation to the A- group) and in the A+ group (bottom row: left panel depicts slope attenuation to 0 and right panel shows sample size needed within low A+ and higher A+ subgroups.) Sample size estimates are also listed in Supplementary Table 3. Abbreviations: A- = amyloid negative group (CL<~13); subA+ = sub-threshold to low positive group (CL ~13–23); and A+ = overtly A+ group (CL >~23); CL= Centiloid; DVR=Distribution Volume Ratio; Lilly MSD= Lilly Meso Scale Discovery; PiB= Pittsburgh Compound B; pTau217= phosphorylated tau protein at amino acid 217.
Figure 4:
Figure 4:. Estimated 6-year regression slopes with 95% CI’s of cognitive composite and individual test by amyloid group
Estimated slopes (test change direction) with 95% confidence intervals for cognitive composites (top row) and individual tests (bottom 3 rows), by amyloid group. Green indicates slope did not differ from 0 (p>0.05) while orange indicates slopes that differed from 0. For all but Trails A and B, negative numbers indicate decline. Abbreviations: A- = amyloid negative group (CL<~13); subA+ = sub- threshold to low positive group (CL ~13–23); and A+ = overtly A+ group (CL >~23); CI=Confidence interval; CL=Centiloid; Animals: Semantic fluency with animal naming; AVLT: Rey Auditory Verbal Learning Test; Digit Sym: CFL: Phonemic fluency with letters C, F, and L; CI= Confidence Interval; Digit Sym.=Digit Symbol Substitution Test; PACC: Preclinical Alzheimer’s Cognitive Composite (3 and 5 test versions); PS: Processing Speed composite (inspired by Harvard Aging Brain Study (HABS) composite).
Figure 5:
Figure 5:. Study partner cognitive outcomes
Study partner (aka “informant”) reports of functioning (top row: average slopes and confidence intervals based on raw scores; bottom row: standardized slope scale to facilitate visual comparison of effect sizes across outcomes). CDR-SB/QDRS-SB is a sum of boxes score comprised of the CDR-SB when it is available or the sum of boxes on similar QDRS items when the CDR is not available (see Berman et al, 2017). Abbreviations: A- = amyloid negative group (CL<~13); subA+ = sub-threshold to low positive group (CL ~13–23); and A+ = overtly A+ group (CL >~23); CL=Centiloid; CDR=Clinical Dementia Rating; CI= Confidence Interval; SB=Sum of Boxes; SD=Standard deviation; QDRS=Quick Dementia Rating Scale.
Figure 6:
Figure 6:. Sample size estimates for cognitive and study partner outcomes requiring <=2,000 per treatment arm
Top panel: Sample size estimates are shown for the subset of cognitive and study partner outcomes that required <=2,000 per treatment arm to detect a 25% slowing in decline in a subA+ study. When attenuation to the A- slope was factored in, only the Digit Symbol Substitution Task and PACC5 composite were sensitive enough to preclinical decline to require <=2000 per treatment arm. Bottom panel: Sample size estimates are shown for the subset of cognitive and study partner outcomes that required <=2,000 per treatment arm to detect a 25% slowing in decline in each of three A+ trial design options: Solid red line depicts sample sizes needed for 25% slowing in decline for all in the A+ group; Dotted lines with triangles or squares represent sample size estimates for the subsets that are <40 CL or >=40 CL, respectively. Sample size estimates for all cognitive and study partner outcomes and for a range of effect sizes are also listed in Supplementary Table 5. Abbreviations: A- = amyloid negative group (CL<~13); subA+ = sub-threshold to low positive group (CL ~13–23); and A+ = overtly A+ group (CL >~23); CL = Centiloid; DVR=Distribution Volume Ratio; pTau217= phosphorylated tau protein at amino acid 217; AVLT: Rey Auditory Verbal Learning Test; Digit Sym: CFL: Phonemic fluency with letters C, F, and L; CI= Confidence Interval; Digit Sym.=Digit Symbol Substitution Test; Logical Mem=Logical Memory II; PACC: Preclinical Alzheimer’s Cognitive Composite (3 and 5 test versions); PS: Processing Speed composite (inspired by Harvard Aging Brain Study (HABS) composite).
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