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. 2025 Feb;21(2):e14412.
doi: 10.1002/alz.14412. Epub 2024 Dec 28.

Longitudinal synaptic loss versus tau Braak staging in amnestic mild cognitive impairment

Greet Vanderlinden  1   2 , Michel Koole  1   2 , Laura Michiels  2   3   4   5 , Robin Lemmens  2   3   4   5 , Mathieu Vandenbulcke  2   6   7 , Koen Van Laere  1   2   8
Affiliations

Longitudinal synaptic loss versus tau Braak staging in amnestic mild cognitive impairment

Greet Vanderlinden et al. Alzheimers Dement. 2025 Feb.

Abstract

Introduction: The longitudinal progression of synaptic loss in Alzheimer's disease (AD) and how it is affected by tau pathology remains poorly understood.

Methods: Thirty patients with amnestic mild cognitive impairment (aMCI) and 26 healthy controls underwent cognitive evaluations and tau, synaptic vesicle protein 2A (SV2A), and amyloid positron emission tomography. Twenty-one aMCI underwent 2-year follow-up (FU) investigations.

Results: Tau levels in aMCI increased longitudinally in Braak regions III through VI but not in Braak regions I and II. SV2A decreased longitudinally in all Braak regions in aMCI. Baseline tau was negatively associated with longitudinal SV2A loss in early Braak regions and with SV2A at FU across regions. Baseline tau and longitudinal change in SV2A were associated with longitudinal cognitive decline.

Discussion: Tau accumulation reaches a plateau in early Braak regions already in the aMCI stage of AD. In early Braak regions, the association between baseline tau and longitudinal SV2A loss might reflect synaptic dysfunction caused by tau pathology.

Highlights: Tau accumulation reached a plateau in early Braak regions in amnestic mild cognitive impairment (aMCI) patients. aMCI patients show widespread longitudinal decrease in synaptic vesicle protein 2A (SV2A) over 2 years. Baseline tau was predictive for longitudinal SV2A loss. The tau-SV2A relation showed individual variability and was negative across patients. Baseline tau and longitudinal SV2A change were associated with change in cognition.

Keywords: Alzheimer's disease; cognition; positron emission tomography; synaptic density; synaptic vesicle protein 2A; tau.

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Conflict of interest statement

K.V.L. performed this study as senior investigator of FWO Flanders. K.V.L. is an advisory board member of Cerveau‐Lantheus and has received fees through KU Leuven for consultancy activities for GE Healthcare. K.V.L. and M.K. have performed contract research through KU Leuven for Merck, Janssen Pharmaceuticals, UCB, Syndesi, Eikonizo, GE Healthcare, Cerevel, BMS, and Curasen. No other potential conflicts of interest relevant to this article exist. Author disclosures are available in the supporting information.

Figures

FIGURE 1
FIGURE 1
Baseline and longitudinal changes in tau and SV2A PET. Dot plots indicating baseline differences between HC and aMCI patients as well as longitudinal changes in aMCI for both tau (18F‐MK‐6240) and SV2A (11C‐UCB‐J). Effect sizes and uncorrected p values are indicated. Black circles indicate HC SUVR, red circles indicate aMCI SUVR at baseline, blue circles indicate aMCI SUVR at 2‐year follow‐up. aMCI, amnestic mild cognitive impairment; HC, healthy control; PET, positron emission tomography; SUVR, standardized uptake value ratio; SV2A, synaptic vesicle protein 2A.
FIGURE 2
FIGURE 2
Voxel‐based baseline and longitudinal changes in tau and SV2A PET. Surface renderings indicating (A) baseline differences between HC and aMCI in 18F‐MK‐6240 SUVR and (B) 11C‐UCB‐J SUVR; (C) longitudinal changes in the aMCI group for 18F‐MK‐6240 SUVR and (D) for 11C‐UCB‐J SUVR; and (E) differences between aMCI at follow‐up and HC at baseline for 18F‐MK‐6240 SUVR and (F) for 11C‐UCB‐J SUVR. Color bars indicate SPM t values. aMCI, amnestic mild cognitive impairment; HC, healthy control; PET, positron emission tomography; SPM, statistical parametric mapping; SUVR, standardized uptake value ratio; SV2A, synaptic vesicle protein 2A.
FIGURE 3
FIGURE 3
Association between baseline tau in Braak I and baseline SV2A in Braak II across all study subjects. aMCI patients are indicated in red, healthy controls are indicated in black. aMCI, amnestic mild cognitive impairment; HC, healthy control; SV2A, synaptic vesicle protein 2A.
FIGURE 4
FIGURE 4
Association between baseline tau and SV2A at FU across Braak regions in function of amyloid and cognition. (A) Individual regression slopes from linear regressions between baseline tau and SV2A levels at FU across the six Braak regions unilaterally (= 12 regions). The group average association is shown in red. The individual regression slopes as shown in (A) were not significantly associated with (B) baseline amyloid Centiloid values, (C), baseline RAVLT scores, or (D) baseline MMSE scores. CL, Centiloid; FU, follow‐up; MMSE, Mini‐Mental State Examination; RAVLT, Rey Auditory Verbal Learning Test; SUVR, standardized uptake value ratio; SV2A, synaptic vesicle protein 2A.
FIGURE 5
FIGURE 5
Association of longitudinal change in SV2A PET with longitudinal cognitive decline. Bar plots indicate longitudinal relative differences in SV2A SUVR between (A) those whose MMSE score decreased (black) and those whose score remained stable (gray) and (B) those whose RCPM score decreased (black) and those whose score remained stable (gray). Group median values and uncorrected p values from Mann–Whitney U test are indicated. MMSE, Mini‐Mental State Examination; PET, positron emission tomography; RCPM, Raven's Coloured Progressive Matrices; SUVR, standardized uptake value ratio; SV2A, synaptic vesicle protein 2A.
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