Temporal Dynamics and Biological Variability of Alzheimer Biomarkers
Authors: Yun Jihwan , Shin Daeun , Lee Eun Hye , Kim Jun Pyo , Ham Hongki , Gu Yuna , Chun Min Young , Kang Sung Hoon , Kim Hee Jin , Na Duk L. , Kim Chi-Hun , Kim Ko Woon , Kim Si Eun , Kim Yeshin , Kim Jaeho , Jung Na-Yeon , Kim Yeo Jin , Cho Soo Hyun , Zetterberg Henrik , Blennow Kaj , Gonzalez-Ortiz Fernando , Ashton Nicholas J. , Therriault Joseph , Rahmouni Nesrine , Rosa-Neto Pedro , Weiner Michael W. , Seo Sang Won , Jang Hyemin ,   ADNI, TRIAD, and K-ROAD study groups, Kim Youngsoo , Han Sun-Ho , Seong JoonKyung , Choi Jun-Kyu , Lee Eek-Sung , Lee Tak-Kyeong , Chin Juhee , Kim Chi-Hun , Kim Hee Jin , Bok Haesook , Kim Hang-Rai , Kim Seung Joo , Na Seunghee , Kim Geon Ha , Lee Jin San , Cho Hanna , Kim Byeong C. , Lee Dong Young , Moon So Young , Byun Min Soo , Jung Giijung , Yi Dahyun , Lee Han Na , Jang Jae-Won , Jeong Jee Hyang , Jung Young Hee , Kim Jong Hun , Kim Youngju , Cheon Bo Kyoung , Seo Jinkyu , Noh Young , Yang Hyunjung , Ha Youngji , Shin Hae-Eun , Kang Kyunghun , Eom SungHui , Shin Ki Young , Kim Yeongshin , Jang Jisung , Yoon Changsik , Lee Do kyung , Ham Hongki , Park Yu Hyun , Kim Soo-Jong , Byun Byunghyun , Choi Yejoo , Lee Na Kyung , Won Hong-Hee , Cho Minyoung , Jung Sang-Hyuk , Lee Dong Hyun , Kim Beomsu , Aisen Paul , Petersen Ronald , Jack, Jr. Clifford R. , Jagust William , Trojanowki John Q. , Toga Arthur W. , Beckett Laurel , Green Robert C. , Saykin Andrew J. , Morris John , Shaw Leslie M. , Khachaturian Zaven , Sorensen Greg , Carrillo Maria , Kuller Lew , Raichle Marc , Paul Steven , Davies Peter , Fillit Howard , Hefti Franz , Holtzman David , Mesulam M. Marcel , Potter William , Snyder Peter , Logovinsky Veronika , Montine Tom , Jimenez Gustavo , Donohue Michael , Gessert Devon , Harless Kelly , Salazar Jennifer , Cabrera Yuliana , Walter Sarah , Hergesheimer Lindsey , Harvey Danielle , Bernstein Matthew , Fox Nick , Thompson Paul , Schuff Norbert , DeCarli Charles , Borowski Bret , Gunter Jeff , Senjem Matt , Vemuri Prashanthi , Jones David , Kantarchi Kejal , Ward Chad , Koeppe Robert A. , Foster Norm , Reiman Eric M. , Chen Kewei , Mathis Chet , Landau Susan , Morris John C. , Cairns Nigel J. , Franklin Erin , Taylor-Reinwald Lisa , Lee Virginia , Korecka Magdalena , Figurski Michal , Crawford Karen , Neu Scott , Foroud Tatiana M. , Potkin Steven , Shen Li , Faber Kelley , Kim Sungeun , Nho Kwangsik , Thal Lean , Buckholtz Neil , Albert Marilyn , Frank Richard , Hsiao John , Tissot Cecile , Bezgin Gleb , Servaes Stijn , Stevenson Jenna , Gauthier Serge , Vitali Paolo 
Published: February 2025

ImportanceUnderstanding the characteristics of discordance between plasma biomarkers and positron emission tomography (PET) results in Alzheimer disease (AD) is crucial for accurate interpretation of the findings.ObjectiveTo compare (1) medical comorbidities affecting plasma biomarker concentrations, (2) imaging and clinical features, and (3) cognitive changes between plasma biomarker and PET discordant and concordant cases.Design, Setting, and ParticipantsThis multicenter cohort study, conducted between 2016 and 2023, included individuals with unimpaired cognition, mild cognitive impairment, or Alzheimer-type dementia, who had both amyloid β (Aβ) PET imaging and plasma biomarkers. A subset of participants also underwent tau PET imaging.ExposuresParticipants were categorized into 4 groups based on their plasma and PET biomarker results: plasma−/PET−, plasma+/PET−, plasma−/PET+, and plasma+/PET+.Main Outcomes and MeasuresClinical characteristics were compared between the 4 groups, focusing on the discordant groups.ResultsA total of 2611 participants (mean [SD] age was 71.2 [8.7] years; 1656 female [63.4%]), of whom 124 additionally underwent tau PET, were included. Among the plasma biomarkers, phosphorylated tau (p-tau) 217 exhibited the highest concordance rate with Aβ (2326 of 2571 [90.5%]) and tau (100 of 120 [83.3%]) PET. The p-tau217+/Aβ PET− group was older (mean [SD] age, 75.8 [7.2] years vs 70.0 [8.8] years; P &amp;lt; .001) with a higher prevalence of hypertension (56 of 152 [36.8%] vs 266 of 1073 [25.0%]), diabetes (40 of 152 [26.3%] vs 156 of 1059 [14.7%]), and chronic kidney disease (17 of 152 [11.2%] vs 21 of 1073 [2.0%]) compared with the p-tau217−/Aβ PET− group (P &amp;lt; .001 for all). Body mass index was higher in p-tau217−/Aβ PET+ than in p-tau217+/Aβ PET+ (mean [SD], 24.1 [2.8] vs 23.1 [3.1], respectively; P = .001; calculated as weight in kilograms divided by height in meters squared). The p-tau217+/Aβ PET− group had lower hippocampal volume (mean [SD], 2555.4 [576.9] vs 2979.1 [545.8]; P &amp;lt; .001) and worse clinical trajectory compared with p-tau217−/Aβ PET− (β = −0.53; P &amp;lt; .001). In contrast, tau PET discordant cases did not show significant differences in medical comorbidities or clinical outcomes compared with the p-tau217−/tau PET− group. Only the p-tau 217+/tau PET+ group demonstrated faster cognitive deterioration compared with the p-tau 217−/tau PET− group (β = −1.66; P &amp;lt; .001).Conclusions and RelevanceResults of this cohort study suggest that the mechanisms underlying the discordance between plasma biomarkers and PET findings may be multifaceted, underscoring the need to consider the temporal dynamics and biological variability of plasma biomarkers.