SV2A PET shows hippocampal synaptic loss in cognitively unimpaired APOE ε4/ε4 homozygotes

Anniina Snellman; Jouni Tuisku; Mikko Koivumäki; Saara Wahlroos; Richard Aarnio; Johan Rajander; Mira Karrasch; Laura L Ekblad; Juha O Rinne

doi:10.1002/alz.14327

SV2A PET shows hippocampal synaptic loss in cognitively unimpaired APOE ε4/ε4 homozygotes

Anniina Snellman, Jouni Tuisku, Mikko Koivumäki, Saara Wahlroos, Richard Aarnio, Johan Rajander, Mira Karrasch, Laura L Ekblad, Juha O Rinne

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Abstract

INTRODUCTION: We investigated hippocampal synaptic density using synaptic vesicle 2A positron emission tomography (PET), and its association with amyloid beta (Aβ) and cognitive performance in healthy apolipoprotein E (APOE) ε4 carriers.

METHODS: Synaptic density was assessed in 46 individuals (APOE ε4/ε4 n = 14; APOE ε3/ε4 n = 16; APOE ε3/ε3 n = 16) with [11C]UCB-J-PET standardized uptake value ratios (SUVRs), by using the centrum semiovale as a reference region. Differences in hippocampal [11C]UCB-J SUVRs were analyzed with analysis of variance (ANOVA) and linear models. Associations among [11C]UCB-J SUVR, Aβ, hippocampal volume, and cognitive variables were analyzed with Spearman correlation.

RESULTS: Hippocampal synaptic density was different among the APOE groups (PANOVA = 0.016): APOE ε4/ε4 carriers had lower [11C]UCB-J SUVRs compared to APOE ε3/ε3 (p = 0.013). Hippocampal synaptic density did not correlate with Consortium to Establish a Registry for Alzheimer's Disease (CERAD) total score (rho = -0.052, p = 0.74), Alzheimer's Prevention Initiative Preclinical Cognitive Composite (APCC) score (rho = 0.17, p = 0.28), or [11C]PiB uptake (rho = -0.10, p = 0.50).

DISCUSSION: Hippocampal synaptic loss emerges early in the AD continuum and is measurable in vivo in cognitively unimpaired high-risk individuals.

HIGHLIGHTS: Synaptic density was studied in vivo in healthy older adults using [11C]UCB-J positron emission tomography. Apolipoprotein E (APOE) ε4/ε4 carriers had lower hippocampal synaptic density compared to APOE ε3/ε3. Synaptic density was not associated with cognitive performance in this population. Hippocampal synaptic alterations occur before clinical symptoms in APOE ε4/ε4 carriers.

Original language	English
Pages (from-to)	8802-8813
Number of pages	12
Journal	Alzheimer's and Dementia
Volume	20
Issue number	12
Early online date	30 Oct 2024
DOIs	https://doi.org/10.1002/alz.14327
Publication status	Published - 30 Oct 2024
MoE publication type	A1 Journal article-refereed

Funding

All participants of the ASIC\u2010E4 study are warmly acknowledged for their commitment to the study during the COVID\u201019 pandemic. The authors would also like to acknowledge the core staff of Turku PET Centre for all their assistance during the study. A.S. reports funding from the Finnish Governmental Research Funding (VTR) for Turku University Hospital for the ASIC\u2010E4 study. A.S. received additional personal grants from the Research Council of Finland (grant number 341059), the Emil Aaltonen Foundation, the Paulo Foundation, and the Orion Research Foundation sr directly related to this study. L.L.E. was financially supported by the Paulo Foundation, the Emil Aaltonen Foundation, and Finnish Governmental Research Funding (VTR). J.O.R. received funding from the Sigrid Juselius Foundation and the Finnish Governmental Research Funding (VTR) for Turku University Hospital.

Keywords

Alzheimer's disease
[c-11]ucb-j
Amyloid beta
apolipoprotein E
Biomarker
Cognition
Hippocampus
Positron emission tomography
Preclinical
Synaptic density
synaptic vesicle 2A

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10.1002/alz.14327Licence: CC BY-NC-ND

Alzheimer s Dementia - 2024 - Snellman - SV2A PET shows hippocampal synaptic loss in cognitively unimpaired APOE 4 4Final published version, 2.48 MBLicence: CC BY-NC-ND

https://urn.fi/URN:NBN:fi-fe20241206100093

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title = "SV2A PET shows hippocampal synaptic loss in cognitively unimpaired APOE ε4/ε4 homozygotes",

abstract = "INTRODUCTION: We investigated hippocampal synaptic density using synaptic vesicle 2A positron emission tomography (PET), and its association with amyloid beta (Aβ) and cognitive performance in healthy apolipoprotein E (APOE) ε4 carriers.METHODS: Synaptic density was assessed in 46 individuals (APOE ε4/ε4 n = 14; APOE ε3/ε4 n = 16; APOE ε3/ε3 n = 16) with [11C]UCB-J-PET standardized uptake value ratios (SUVRs), by using the centrum semiovale as a reference region. Differences in hippocampal [11C]UCB-J SUVRs were analyzed with analysis of variance (ANOVA) and linear models. Associations among [11C]UCB-J SUVR, Aβ, hippocampal volume, and cognitive variables were analyzed with Spearman correlation.RESULTS: Hippocampal synaptic density was different among the APOE groups (PANOVA = 0.016): APOE ε4/ε4 carriers had lower [11C]UCB-J SUVRs compared to APOE ε3/ε3 (p = 0.013). Hippocampal synaptic density did not correlate with Consortium to Establish a Registry for Alzheimer's Disease (CERAD) total score (rho = -0.052, p = 0.74), Alzheimer's Prevention Initiative Preclinical Cognitive Composite (APCC) score (rho = 0.17, p = 0.28), or [11C]PiB uptake (rho = -0.10, p = 0.50).DISCUSSION: Hippocampal synaptic loss emerges early in the AD continuum and is measurable in vivo in cognitively unimpaired high-risk individuals.HIGHLIGHTS: Synaptic density was studied in vivo in healthy older adults using [11C]UCB-J positron emission tomography. Apolipoprotein E (APOE) ε4/ε4 carriers had lower hippocampal synaptic density compared to APOE ε3/ε3. Synaptic density was not associated with cognitive performance in this population. Hippocampal synaptic alterations occur before clinical symptoms in APOE ε4/ε4 carriers.",

keywords = "Alzheimer's disease, [c-11]ucb-j, Amyloid beta, apolipoprotein E, Biomarker, Cognition, Hippocampus, Positron emission tomography, Preclinical, Synaptic density, synaptic vesicle 2A",

author = "Anniina Snellman and Jouni Tuisku and Mikko Koivum{\"a}ki and Saara Wahlroos and Richard Aarnio and Johan Rajander and Mira Karrasch and Ekblad, \{Laura L\} and Rinne, \{Juha O\}",

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T1 - SV2A PET shows hippocampal synaptic loss in cognitively unimpaired APOE ε4/ε4 homozygotes

AU - Snellman, Anniina

AU - Tuisku, Jouni

AU - Koivumäki, Mikko

AU - Wahlroos, Saara

AU - Aarnio, Richard

AU - Rajander, Johan

AU - Karrasch, Mira

AU - Ekblad, Laura L

AU - Rinne, Juha O

PY - 2024/10/30

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N2 - INTRODUCTION: We investigated hippocampal synaptic density using synaptic vesicle 2A positron emission tomography (PET), and its association with amyloid beta (Aβ) and cognitive performance in healthy apolipoprotein E (APOE) ε4 carriers.METHODS: Synaptic density was assessed in 46 individuals (APOE ε4/ε4 n = 14; APOE ε3/ε4 n = 16; APOE ε3/ε3 n = 16) with [11C]UCB-J-PET standardized uptake value ratios (SUVRs), by using the centrum semiovale as a reference region. Differences in hippocampal [11C]UCB-J SUVRs were analyzed with analysis of variance (ANOVA) and linear models. Associations among [11C]UCB-J SUVR, Aβ, hippocampal volume, and cognitive variables were analyzed with Spearman correlation.RESULTS: Hippocampal synaptic density was different among the APOE groups (PANOVA = 0.016): APOE ε4/ε4 carriers had lower [11C]UCB-J SUVRs compared to APOE ε3/ε3 (p = 0.013). Hippocampal synaptic density did not correlate with Consortium to Establish a Registry for Alzheimer's Disease (CERAD) total score (rho = -0.052, p = 0.74), Alzheimer's Prevention Initiative Preclinical Cognitive Composite (APCC) score (rho = 0.17, p = 0.28), or [11C]PiB uptake (rho = -0.10, p = 0.50).DISCUSSION: Hippocampal synaptic loss emerges early in the AD continuum and is measurable in vivo in cognitively unimpaired high-risk individuals.HIGHLIGHTS: Synaptic density was studied in vivo in healthy older adults using [11C]UCB-J positron emission tomography. Apolipoprotein E (APOE) ε4/ε4 carriers had lower hippocampal synaptic density compared to APOE ε3/ε3. Synaptic density was not associated with cognitive performance in this population. Hippocampal synaptic alterations occur before clinical symptoms in APOE ε4/ε4 carriers.

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KW - [c-11]ucb-j

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KW - Hippocampus

KW - Positron emission tomography

KW - Preclinical

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JO - Alzheimer's and Dementia

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SV2A PET shows hippocampal synaptic loss in cognitively unimpaired APOE ε4/ε4 homozygotes

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