Plasma Phosphorylated Tau at Threonine 181 and Neuropsychiatric Symptoms in Preclinical and Prodromal Alzheimer Disease

Maryam Ghahremani; Meng Wang; Hung-Yu Chen; Henrik Zetterberg; Eric Smith; Zahinoor Ismail; Alzheimer's Disease Neuroimaging Initiative*

doi:10.1212/WNL.0000000000201517

Plasma Phosphorylated Tau at Threonine 181 and Neuropsychiatric Symptoms in Preclinical and Prodromal Alzheimer Disease

Neurology. 2023 Feb 14;100(7):e683-e693. doi: 10.1212/WNL.0000000000201517. Epub 2022 Nov 2.

Authors

Maryam Ghahremani¹, Meng Wang¹, Hung-Yu Chen¹, Henrik Zetterberg¹, Eric Smith¹, Zahinoor Ismail²; Alzheimer's Disease Neuroimaging Initiative*

Affiliations

¹ From the Department of Psychiatry (M.G., H.-Y.C., Z.I.), Hotchkiss Brain Institute (M.G., M.W., H.-Y.C., E.S., Z.I.), Department of Clinical Neurosciences (M.W., E.S., Z.I.), Cumming School of Medicine, and Department of Community Health Sciences (M.W., E.S., Z.I.), University of Calgary, Alberta, Canada; Department of Psychiatry and Neurochemistry (H.Z.), Institute of Neuroscience and Physiology, the Sahlgrenska Academy at the University of Gothenburg; Clinical Neurochemistry Laboratory (H.Z.), Sahlgrenska University Hospital, Mölndal, Sweden; Department of Neurodegenerative Disease (H.Z.), UCL Institute of Neurology, Queen Square; UK Dementia Research Institute at UCL (H.Z.); Hong Kong Center for Neurodegenerative Diseases (H.Z.), China; Mathison Centre for Mental Health Research & Education (Z.I.), University of Calgary, Alberta, Canada; and College of Medicine and Health (Z.I.), University of Exeter, United Kingdom.
² From the Department of Psychiatry (M.G., H.-Y.C., Z.I.), Hotchkiss Brain Institute (M.G., M.W., H.-Y.C., E.S., Z.I.), Department of Clinical Neurosciences (M.W., E.S., Z.I.), Cumming School of Medicine, and Department of Community Health Sciences (M.W., E.S., Z.I.), University of Calgary, Alberta, Canada; Department of Psychiatry and Neurochemistry (H.Z.), Institute of Neuroscience and Physiology, the Sahlgrenska Academy at the University of Gothenburg; Clinical Neurochemistry Laboratory (H.Z.), Sahlgrenska University Hospital, Mölndal, Sweden; Department of Neurodegenerative Disease (H.Z.), UCL Institute of Neurology, Queen Square; UK Dementia Research Institute at UCL (H.Z.); Hong Kong Center for Neurodegenerative Diseases (H.Z.), China; Mathison Centre for Mental Health Research & Education (Z.I.), University of Calgary, Alberta, Canada; and College of Medicine and Health (Z.I.), University of Exeter, United Kingdom. ismailz@ucalgary.ca.

Abstract

Background and objectives: Plasma phosphorylated tau at threonine 181 (p-tau181), a well-validated marker of Alzheimer disease (AD) pathologic change, could be a more efficient way to diagnose AD than invasive or expensive biomarkers requiring CSF or PET. In some individuals, neuropsychiatric symptoms (NPS) are the earliest manifestation of AD, observed in advance of clear cognitive decline. However, the few studies assessing AD biomarkers in association with NPS have often had imprecision in capturing behavioral symptoms that represent sequelae of neurodegenerative disease. Thus, the mild behavioral impairment (MBI) construct was developed, framing NPS in a way to improve the precision of risk estimates for disease. MBI core criteria stipulate that NPS emerge de novo in later life and persist for at least 6 months. Here, cross-sectionally and longitudinally, we investigated associations of MBI with p-tau181, neuropsychological test performance, and incident AD.

Methods: Cognitively unimpaired and mild cognitive impairment (MCI) Alzheimer's Disease Neuroimaging Initiative participants were selected. MBI status was derived from the Neuropsychiatric Inventory (NPI) using a published algorithm. NPI total scores at baseline and year 1 visits were used to operationalize MBI (score >0 at both visits), NPS not meeting the MBI criteria (NPS-not-MBI, score >0 at only 1 visit), and no NPS (score = 0 at both visits). Linear regressions were fitted for cross-sectional analyses; multilevel linear mixed-effects and Cox proportional hazards models were implemented to examine the longitudinal associations of MBI with changes in p-tau181 and cognition and incident dementia.

Results: The sample included 571 participants (age 72.2 years, 46.8% female, 64.8% MCI). Cross-sectionally (β = 8.1%, 95% CI 1.4%-15.2%, p = 0.02), MBI was associated with higher plasma p-tau181 levels compared with no NPS; NPS-not-MBI was not. Longitudinally, MBI was associated with higher p-tau181 (β = 0.014%, 95% CI 0.003-0.026, p = 0.02), in addition to a decline in memory and executive function. Survival analyses demonstrated a 3.92-fold greater dementia incidence in MBI, with no significant differences between NPS-not-MBI and no NPS.

Discussion: These findings extend the evidence base that MBI is associated with elevated risk of cognitive decline and dementia and a sequela of emerging Alzheimer-related proteinopathies. MBI offers a substantial improvement over current approaches that explore behavior as a proxy marker for Alzheimer-related proteinopathies, with both clinical and AD trial enrichment implications.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Aged
Alzheimer Disease* / diagnosis
Amyloid beta-Peptides
Biomarkers
Cognitive Dysfunction* / epidemiology
Cross-Sectional Studies
Disease Progression
Female
Humans
Male
Neurodegenerative Diseases*
Neuropsychological Tests
tau Proteins

Substances

tau Proteins
Biomarkers
Amyloid beta-Peptides

Grants and funding

U01 AG024904/AG/NIA NIH HHS/United States