Cognitively Normal APOE ε4 Carriers Have Specific Elevation of CSF SNAP-25

doi:10.21203/rs.3.rs-122858/v1

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Cognitively Normal APOE ε4 Carriers Have Specific Elevation of CSF SNAP-25

https://doi.org/10.21203/rs.3.rs-122858/v1

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Background: Cerebrospinal fluid (CSF) synaptosomal-associated protein 25 (SNAP-25) and neurogranin are recently described biomarkers for synaptic integrity that are known to be elevated in the CSF of symptomatic Alzheimer disease (AD). Their relationship with Apolipoprotein E (APOE) ε4 carrier status, the major genetic risk factor for AD, remains unclear.

Methods: In this study, CSF SNAP-25 and neurogranin were compared in cognitively normal APOE ε4 carriers and non-carriers (n=274, mean age 65.0 ± 9.0 years, 39% APOE ε4 carriers, 58% female) enrolled at the Knight Alzheimer Disease Research Center, and in the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database.

Results: SNAP-25, a biomarker of pre-synaptic integrity, was specifically elevated in APOE ε4 carriers versus non-carriers (5.95 ± 1.72 pg/ml, 4.44 ± 1.40 pg/ml, p <0.0001), even after adjusting for age, sex, years of education, and amyloid status (p <0.0001). In contrast, CSF neurogranin, a biomarker of post-synaptic integrity, did not vary by APOE ε4 status. Further, CSF total tau (t-tau), phosphorylated-tau-181 (ptau181), and neurofilament light chain (NfL) also did not vary by APOE ε4 status. Similar results were observed in the ADNI cohort.

Conclusion: Our findings suggest APOE ε4 carriers have both amyloid-related and amyloid-independent presynaptic disruption as reflected by elevated CSF SNAP-25 levels. In contrast, post-synaptic disruption as reflected by elevations in CSF neurogranin is related to amyloid status.

Cellular & Molecular Neuroscience

Neurology

APOE

SNAP-25

neurogranin

synapse

cerebrospinal fluid

biomarker

Apolipoprotein E (APOE) genotype is the major genetic risk factor for Alzheimer disease (AD) and is thought to modify both amyloid- (1–4), and tau-related pathology (5, 6). APOE genotype has also been implicated in a variety of neurodegenerative disorders including α-synucleinopathies such as Parkinson disease and Lewy Body dementia (7, 8), Huntington disease (9), frontotemporal dementia (10), and chronic traumatic encephalopathy (11). The mechanism by which APOE genotype affects these diverse disorders remains unclear. However, multiple studies have highlighted amyloid-independent toxicity through synapse related pathways (8, 12–16).

The APOE ε4 allele has been implicated in both presynaptic and postsynaptic dysfunction. This includes reductions of key presynaptic proteins (14) and disruptions of presynaptic vesicular release and glutamine-to-glutamate production (17). Postsynaptic effects include disruptions of reelin-mediated long-term potentiation and plasticity (18) and reductions in dendritic spine density and complexity (12, 15, 19) that may be further amplified in the presence of amyloid plaques (20). However, the relationship between APOE genotype and pre- or post-synaptic dysfunction in cognitively normal older adults remains unclear.

Two recent cerebrospinal fluid (CSF) biomarkers have emerged for assessing synaptic integrity in humans: synaptosomal-associated protein 25 (SNAP-25) and neurogranin (Ng). SNAP-25 is a component of the presynaptic SNARE complex, which is essential for vesicular trafficking (21). Ng is expressed in post-synaptic dendritic spines (22). Both CSF SNAP-25 (23, 24), and Ng concentrations (25–31) are elevated in individuals with AD dementia.

In this study, we compared levels of CSF SNAP-25 and Ng in cognitively normal individuals as a function of APOE ε4 status. We adjusted for the effects of age, sex, years of education and amyloid status. Additionally, we evaluated levels of CSF total tau (t-tau), tau phosphorylated at position 181 (ptau181), and neurofilament light chain (NfL). Finally, we replicated our major finding in an independent cohort.

2.1 Participants

The primary cohort consisted of participants enrolled at the Knight Alzheimer Disease Research Center (Knight ADRC) at Washington University in St Louis. Inclusion criteria were the following: participants who were cognitively normal (Clinical Dementia Rating [CDR®] 0; 32), had APOE genotype data, and had undergone analysis of CSF SNAP-25 and/or Ng. Methods for recruitment and assessment have previously been described (33).

2.2 Genetic Analyses

DNA samples were collected at enrollment and genotyped using either an Illumina 610 or Omniexpress chip, as previously described (34). APOE ε4 carriers were defined by the presence of at least one ε4 allele (ε2/ε4, ε3/ε4, or ε4/ε4) in contrast to APOE ε4 non-carriers (ε2/ε2, ε2/ε3, or ε3/ε3).

2.3 CSF acquisition and processing

Participants underwent CSF collection as previously described (35). Briefly, CSF was collected at 8 AM after overnight fasting in a polypropylene tube via gravity drip using an atraumatic Sprotte 22 gauge spinal needle. Samples were gently inverted and centrifuged at low speed to pellet any cellular debris. CSF was then aliquoted into 500 µl volumes in polypropylene tubes and stored at − 80 °C until the time of assay.

CSF Aβ42, t- tau, and ptau181 were measured with corresponding Elecsys immunoassays on the Roche cobas e601 analyzer (36). Amyloid status was established per previously published cutoffs for CSF ptau181/Aβ42 (36), with individuals with a CSF ptau181/Aβ42 ratio \(\le\) 0.0198 categorized as amyloid-negative and individuals with ptau181/Aβ42 > 0.0198 categorized as amyloid-positive.

CSF SNAP-25 and Ng were measured via the microparticle-based immunoassay, Single Molecule Counting™ Erenna® system (EMD Millipore, Burlington MA) system, with antibodies developed in the laboratory of Dr. Jack Ladenson at Washington University. CSF NfL was measured with an immunoassay kit manufactured by Uman Diagnostics (UmanDiagnostics, Umeå, Sweden).

2.4 PET image acquisition and processing

Amyloid positron emission tomography (PET) images were acquired on a subset of participants per previously described methods (37–40) using either [¹¹C] Pittsburgh Compound B (PiB) or florbetapir (¹⁸F-AV-45). Standard uptake value ratios (SUVR) were calculated for the 30–60 minute post-injection window for PiB and 50–70 minutes for ¹⁸F-AV-45. Raw PET data was then processed using a PET Unified Pipeline (github.com/ysu001/PUP). FreeSurfer 5.3 was employed for region of interest (ROI) segmentation. For each region, a tissue mask was generated based on segmentation, and partial volume correction performed (38). SUVRs, also known as regional target-to-reference intensity ratios, were evaluated for each region using the cerebral cortex as the reference region. The partial volume corrected SUVR derived from cortical regions was used as a summary value for each PET imaging modality. To standardize across PiB and ¹⁸ F-AV-45, SUVRs were converted to centiloids (39, 41).

2.5 Statistical Analyses

Testing between subgroups was compared using unpaired t-tests for continuous variables and chi-square testing for categorical variables. Secondary validation for multiple comparisons was performed by calculating a false discovery rate. Analysis for covariance were implemented using the Matlab function LinearModel.fit between CSF SNAP-25 or Ng and APOE ε4 status, amyloid status, age, gender (female), and years of education.

2.6 Replication Cohort

For replication of the major finding, data were also obtained from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database (adni.loni.usc.edu). The ADNI was launched in 2003 as a public-private partnership, led by Principal Investigator Michael W. Weiner, MD. The primary goal of ADNI has been to test whether serial magnetic resonance imaging (MRI), PET, other biological markers, and clinical and neuropsychological assessment can be combined to measure the progression of mild cognitive impairment (MCI) and early AD. For up-to-date information, see www.adni-info.org.

Inclusion criteria were identical to the primary cohort: participants who were cognitively normal (CDR 0), had available APOE genotype data, and had undergone analysis of CSF SNAP-25 and/or Ng using consistent assay lot number.

3.1 Participant characteristics

The Knight ADRC cohort consisted of 274 participants who met inclusion criteria. The characteristics of the cohort, grouped by either amyloid status based on CSF ptau181/Aβ42 or APOE ε4 carrier status, are shown in Table 1. There was no significant difference in years of education or gender by either amyloid status or APOE ε4 carrier status. Amyloid-positive individuals tended to be older and were more likely to carry an APOE ε4 allele (p < 0.0001). As expected, the individuals categorized as amyloid-positive by CSF ptau181/Aβ42 had significantly higher PET centiloid values. APOE ε4 carriers also had a higher average PET centiloid values (p = 0.0004).

Table 1

Knight Alzheimer Disease Research Center (ADRC) Participant Characteristics
Group	All	Amyloid-	Amyloid+	p
n	274	191	83
Age (years ± SD)	65 ± 9.0	62.3 ± 8.3	71.2 ± 7.4	< 0.0001
Education (years ± SD)	16.0 ± 2.50	16.1 ± 2.41	15.8 ± 2.70	N.S.
Sex (n, % Female)	159, 58%	116, 61%	43, 52%	N.S.
Race (n, %)
Asian	1, < 1%	1, < 1%	0, 0%	N.S.
Black	23, 8%	19, 10%	4, 5%	N.S.
Non-Hispanic White	250, 91%	171, 90%	79, 95%	N.S.
APOE ε4 status^a (n, %)	107, 39%	56, 29%	51, 61%	< 0.0001
PET Centiloid (mean ± SD)	13.3 ± 28.3	-2.14 ± 5.16	46.4 ± 29.4	< 0.0001
CSF Aβ₄₂ (pg/ml)	1330 ± 620	1600 ± 540	730 ± 260	< 0.0001
CSF t-tau (pg/ml)	229 ± 106	188 ± 64.1	321 ± 124	< 0.0001
CSF ptau181 (pg/ml)	21.2 ± 11.8	16.5 ± 5.71	32.1 ± 14.6	< 0.0001
CSF SNAP-25 (pg/ml)	5.03 ± 1.72	4.66 ± 1.56	5.9 ± 1.76	< 0.0001
CSF Ng (pg/ml)	2080 ± 1120	1770 ± 880	2790 ± 1290	< 0.0001
CSF NfL (pg/ml)	1390 ± 690	1230 ± 620	1750 ± 690	< 0.0001

Group	APOE ε4-	APOE ε4+	p
n	167	107
Age (years ± SD)	64.9±8.5	65.2±9.78	N.S.
Education (years ± SD)	16±2.5	16±2.58	N.S.
Sex (n, % Female)	101, 60%	58, 54%	N.S.
Race (n, %)
Asian	1, 1%	0, 0%	N.S.
Black	15, 9%	8, 7%	N.S.
Non-Hispanic White	151, 90%	99, 93%	N.S.
Amyloid status^a (n, %)	32, 19%	51, 48%	<0.0001
PET Centiloid (mean ± SD)^c	7.82±26.0	22.9±30.0	0.0004
CSF Aβ₄₂ (pg/ml)	1460±630	1130±550	<0.0001
CSF t-tau (pg/ml)	216±100	249±109	0.01
CSF ptau181 (pg/ml)	19.8±11	23.5±12	0.01
CSF SNAP-25 (pg/ml)	4.44±1.4	5.95±1.72	<0.0001
CSF Ng (pg/ml)	1970±1070	2250±1190	0.04
CSF NfL (pg/ml)	1340±680	1470±690	N.S.

Table 1. Demographic comparison of amyloid-positive and amyloid-negative^agroups, and APOE ε4 carriers and non-carriers. P values reflect between group comparisons using unpaired t-tests for continuous variables and chi-square tests for categorical variables. All participants are CDR 0.

^aAmyloid-negative if CSF ptau181/Aβ₄₂ < 0.0198; Amyloid-positive if CSF ptau181/Aβ₄₂ ≥ 0.0198 (36)

^bAverage across the subset of participants who had PET Centiloid data; all participants underwent CSF testing

Knight ADRC, Knight Alzheimer Disease Research Center at Washington University in St. Louis; APOE, Apolipoprotein E; PET, positron emission tomography; CSF, cerebrospinal fluid; Aβ, Amyloid β; t-tau, total tau; ptau181, tau phosphorylated at 181; Ng, neurogranin; NfL, neurofilament light chain; NS, not significant; CDR, Clinical Dementia Rating Scale

3.2 Differences in CSF biomarkers by amyloid status or APOE ε4 carrier status

Concentrations of CSF biomarkers including Aβ42, t-tau, ptau181, SNAP-25, Ng, and NfL were examined as a function of amyloid status and or APOE ε4 carrier status. All six CSF biomarkers were significantly different between amyloid-positive individuals and amyloid-negative individuals (p < 0.0001). When grouped by APOE ε4 carrier status, significant group differences in Aβ42 (p < 0.0001), t-tau (p = 0.01), and ptau181 (p = 0.01) were observed (Table 1). Significant elevations in SNAP-25 (p < 0.0001) and Ng (p = 0.04) were also observed, although the difference in Ng did not survive after correction for multiple comparisons. Finally, no significant group difference in NfL was observed between APOE ε4 carriers and non-carriers.

3.3 CSF biomarkers in different APOE allele genotypes

CSF SNAP-25 and Ng as a function of APOE genotype were evaluated (Fig. 1). Presence of the APOE ε4 allele was associated with higher CSF SNAP-25 levels (Fig. 1A). In contrast, Ng levels did not vary consistently by APOE genotype (Fig. 1B). Similarly, no consistent relationship was observed between APOE ε4 carrier status and CSF t-tau, ptau181, or NfL (Fig. S1A-C).

3.4 CSF SNAP-25 and Ng by amyloid status

We next determined whether elevations in either CSF SNAP-25 or Ng were present when controlling for amyloid status in our cohort of cognitively normal participants (Fig. 2). Amyloid-positive individuals had higher CSF SNAP-25 levels (p < 0.0001; Fig. 2A). Among amyloid-negative individuals, APOE ε4 carriers had higher SNAP-25 levels (p < 0.0001); among amyloid-positive individuals, APOE ε4 carriers also had higher SNAP-25 levels (p < 0.05; Fig. 2C). In contrast, while amyloid-positive individuals had higher CSF Ng levels (Fig. 2B), there was no difference between APOE ε4 non-carriers or carriers after controlling for amyloid status (Fig. 2D).

3.5 Modeling CSF biomarker as function of amyloid status and APOE ε4 carrier status

All previous group comparisons were between unadjusted values for each CSF biomarker. Linear modeling was next used to examine the relationship between either CSF SNAP-25 or Ng and APOE ε4 carrier status, amyloid status, participant’s age, sex, and years of education (Table 2). Linear modeling revealed that both APOE ε4 carrier status (p < 0.0001) and amyloid status (p = 0.004) were significant determinants of CSF SNAP-25 levels. In contrast, CSF Ng levels were affected by amyloid status (p < 0.0001) and age (p = 0.003), but not by APOE ε4 carrier status.

Table 2

Effects of Amyloid Status and *APOE* ε4 status on CSF SNAP-25 and Ng levels
	SNAP-25				Ng
Overall Model	F-statistic		p		F-statistic		p
Overall Model	17.3		< 0.0001		13.6		< 0.0001
Parameter	Estimate	Standard Error	tStat	p	Estimate	Standard Error		tStat	p
APOE ε4 carrier	1.30	0.20	6.5	< 0.0001	55.70	133		0.42	N.S.
Amyloid Positive	0.69	0.24	2.9	0.004	784	158		4.95	< 0.0001
Age (years)	0.012	0.012	0.98	0.33	23.9	7.87		3.04	0.003
Female Sex	-0.24	0.19	-1.24	0.22	62.2	129		0.48	N.S.
Education (years)	-0.06	0.038	-1.58	0.12	-14.2	25.2		-0.56	N.S.
Intercept	4.89	1.14	4.3	< 0.0001	394	762		0.52	N.S.

Table 2. CSF SNAP-25 and CSF Ng as a function of APOE ε4 carrier status and amyloid status^a, adjusting for age, sex, and years of education. The estimate reflects the pg/ml change in biomarker levels associated with a unit change in the predictor values.

^aAmyloid-negative if CSF ptau181/Aβ₄₂ < 0.0198; Amyloid-positive if CSF ptau181/Aβ₄₂ ≥ 0.0198 (36)

APOE, Apolipoprotein E; CSF, cerebrospinal fluid; Ng, neurogranin; NS, not significant

Identical models for CSF t-tau and ptau181 demonstrated only a clear relationship with amyloid status (p < 0.0001) and age (p < 0.0001) (Table S1). For CSF NfL, only age (p < 0.0001) and female sex (p < 0.0001) were significant determinants; no significant effect of amyloid status or APOE ε4 carrier status was observed (Table S2).

Finally, modeling was repeated using an independent cohort from the ADNI dataset (n = 57, mean age 76 ± 5.3 years, 21% APOE ε4 carriers, 40% female). In contrast to our Knight ADRC dataset, participants were older with a lower percentage of cognitively normal individuals who were APOE ε4 carriers and female participants (Table S3). The relationship between CSF SNAP-25, Ng, APOE ε4 carrier status, amyloid status, age, sex, and years of education was evaluated in the ADNI cohort using the same models as applied to the Knight ADRC cohort (Table 3). As before, CSF SNAP-25 levels were significantly higher in APOE ε4 carriers (p = 0.03). In this smaller cohort, CSF Ng levels were not significantly associated with any of the predictors. In summary, two independently collected datasets both reveal that CSF SNAP-25 levels are higher in cognitively normal APOE ε4 carriers, even after accounting for possible confounds.

Table 3

Effects of Amyloid Status and *APOE* ε4 status on CSF SNAP-25 and Ng levels (ADNI)
	SNAP-25				Ng
Overall Model	F-statistic		p		F-statistic		p
Overall Model	2.39		0.05		1.93		0.105
Parameter	Estimate	Standard Error	tStat	p	Estimate	Standard Error		tStat	p
APOE ε4 carrier	0.99	0.44	2.27	0.03	164.25	312.99		0.52	N.S.
Amyloid Positive	0.17	0.36	0.48	0.64	423.9	258.14		1.64	N.S.
Age (years)	-0.01	0.03	-0.16	0.87	16.26	22.91		0.71	N.S.
Female Sex	0.68	0.38	1.78	0.08	437.14	272.9		1.6	N.S.
Education (years)	0	0.06	-0.07	0.94	7.61	41.88		0.18	N.S.
Intercept	3.61	2.76	1.31	0.2	23.35	1973.57		0.01	N.S.

Table 3. CSF SNAP-25 and CSF Ng as a function of APOE ε4 carrier status and amyloid status^a, accounting for confounds of age, sex, and years of education for the ADNI dataset. The estimate reflects the pg/ml change in biomarker levels associated with a unit change in the predictor values.

^aAmyloid-negative if CSF ptau181/Aβ₄₂ < 0.0198; Amyloid-positive if CSF ptau181/Aβ₄₂ > 0.0198 (36)

APOE, Apolipoprotein E; CSF, cerebrospinal fluid; Ng, neurogranin; N.S., not significant; ADNI, Alzheimer's Disease Neuroimaging Initiative

This study investigated CSF levels of the presynaptic marker SNAP-25 and the post-synaptic marker Ng in cognitively normal, older individuals. Presynaptic SNAP-25, but not post-synaptic Ng, was specifically elevated in the CSF of APOE ε4 carriers even after adjusting for age, sex, years of education, and amyloid status. CSF levels of t-tau, ptau181, and NfL also did not vary by APOE ε4 carrier status. These results are the first to demonstrate a relationship between CSF SNAP-25 elevation and APOE ε4 carrier status in cognitively normal older individuals without biomarker evidence of brain amyloidosis, and extend earlier reports of elevated CSF SNAP-25 levels in APOE ε4 carriers with early symptomatic AD (equivalent to mild cognitive impairment (MCI) due to AD and mild AD dementia (24, 42–46).

Previous work examining CSF SNAP-25 and Ng levels report that levels reach their maximum in individuals with early symptomatic AD, and then decline with progression to AD dementia (42). However, after accounting for APOE ε4 carrier status, differences between the cognitively normal and early symptomatic AD groups were present for Ng but not SNAP-25. This suggests that differences in SNAP-25 were related to APOE ε4 carrier status rather than diagnosis. Wang and colleagues (43) also demonstrated significantly higher levels of CSF SNAP-25 in APOE ε4 carriers compared to non-carriers with MCI, but no significant relationship was observed for participants who were cognitively normal or who had dementia due to AD. Both studies relied on the ADNI dataset, which includes a sizeable number of participants with MCI or AD dementia, but comparatively fewer cognitively normal elderly participants. Cognitively normal APOE ε4 carriers are particularly under-represented in the ADNI cohort, but are well represented in the Knight ADRC cohort, explaining why our current findings were not previously observed. More recently, Galasko and colleagues (45) reported elevations in CSF SNAP-25 and Ng in AD dementia compared to cognitively normal individuals, but did not specifically evaluate the effect of APOE genotype in cognitively normal individuals. Finally, Tible and colleagues (46) also reported CSF SNAP-25 and Ng elevations in APOE ε4 carriers with AD and non-AD dementia, but again, the effects of APOE genotype in cognitively normal individuals were not evaluated.

A number of studies have demonstrated that APOE ε4 is associated with synaptic dysfunction. Neuropathologic analyses of human brain from normal APOE ε4 carriers demonstrate decreased protein levels of synaptic markers (13). APOE ε4 targeted replacement (TR) mice exhibit progressive loss of dendritic arbors and lower levels of excitatory synaptic activity (15, 47). APOE ε4 has been shown to interfere with endosome recycling and glutamate receptor function via effects on Reelin signaling (48). Isogenic iPSC-derived human neurons expressing APOE ε4 exhibit early synaptic maturation and reduced expression of a number of genes, most of which are associated with synaptic function (49). Thus, most of the previously described mechanisms have been restricted to the postsynaptic compartment.

The mechanism(s) underlying possible presynaptic dysfunction in cognitively normal APOE ε4 carriers remains unclear. In animal models, the APOE ε4 allele has been associated with decreased presynaptic protein levels in response to environmental factors (50). Subsequent studies using transgenic mice expressing human APOE (ApoE4-TR, ApoE3-TR, and ApoE2-TR) reveal disruptions in vesicular release of several neurotransmitters (17, 51). ApoE4-TR mice demonstrated impaired glutaminase activity resulting in a net decrease in glutamate present in the nerve terminals not observed in ApoE2-TR or ApoE3-TR mice (17). More recent work reveals inhibition of hippocampal ACh release from cholinergic nerve terminals in ApoE4-TR mice in a choline acetyltransferase-independent manner (51). Human studies are more limited, with reports of decreased presynaptic protein levels in APOE ε4 carriers (14).

There are several limitations of this study. It remains unclear whether in vivo APOE ε4 mediated disruptions in presynaptic glutamate or acetylcholine are associated with increases in interstitial or CSF SNAP-25 levels. Furthermore, the specific pathological change reflected by elevated CSF SNAP-25 levels in cognitively normal, amyloid-negative APOE ε4 carriers remains unclear. It is possible that changes in SNAP-25 levels in APOE ε4 carriers are not specific to the presynaptic compartment and instead reflect global synaptic dysfunction or loss that is not reflected in the levels of other CSF synaptic markers. This uncertainty further extends to the neuro-anatomical localization for elevated SNAP-25 levels. It remains unclear whether elevations in SNAP-25 reflect a localized or more cortically distributed phenomena. Additional studies are needed to better characterize the source of CSF SNAP-25 and associated neuro-pathologic and neuro-anatomic changes at the synaptic level in cognitively normal, amyloid-negative APOE ε4 carriers.

This study also duplicates a significant association of age and sex with CSF NfL levels (52). No clear association between NfL and APOE ε4 or amyloid status was observed in our study, also as previously reported (53). Previous studies exploring NfL in healthy adults reported no change in association of CSF NfL with risk of early symptomatic AD after adjustment for APOE status (54). Further NfL elevations observed in dementia associated with Parkinson’s disease (55) support NfL as a sensitive global marker of cumulative neural injury due to multiple etiologies rather than a highly specific marker of AD-related pathology.

Increased CSF SNAP-25 levels in cognitively normal APOE ε4 carriers, even those without brain amyloidosis, suggest that APOE ε4 may be associated with presynaptic dysfunction unrelated to amyloid. This difference is not seen with Ng, a post-synaptic marker, or another marker of neuronal injury, NfL. Differences in the longitudinal change of SNAP-25 in relation to APOE ε4 status remains unknown. It is also unclear if APOE ε4 carriers under 50 years old also have significant elevations in CSF SNAP-25. Further studies are needed to further discern the mechanism by which APOE ε4 modulates SNAP-25 levels and pre-synaptic dysfunction.

Aβ = amyloid-β

AD = Alzheimer’s disease

ADNI = Alzheimer’s Disease Neuroimaging Initiative

APOE = Apolipoprotein E

CDR = clinical dementia rating

CSF = cerebrospinal fluid

Knight ADRC = Knight Alzheimer Disease Research Center

MCI = mild cognitive impairment (early symptomatic AD)

NfL = neurofilament light chain

Ng = neurogranin

NS = not significant

PiB = Pittsburgh compound B

ptau181 = tau phosphorylated at 181

ROI = region of interest

SNAP-25 = synaptosomal-associated protein 25

SUVR = standardized uptake value ratio

t-tau = total tau

TR = targeted replacement (transgenic)

7.1 Ethics Approval and Consent to Participate

This study was approved by the Washington University Institutional Review Board and each participant provided signed informed consent.

7.2 Consent for Publication (individual person’s data)

Not applicable

7.3 Availability of data and materials

Data are available to qualified investigators upon request to the Knight ADRC (https://knightadrc.wustl.edu/Research/ResourceRequest.htm) and ADNI (http://adni.loni.usc.edu/data-samples/access-data/).

7.4 Competing Interests

AMF is a member of the scientific advisory boards for Roche Diagnostics, Genentech and AbbVie and also consults for Araclon/Grifols, DiademRes, DiamiR and Otsuka Pharmaceuticals. All remaining authors report no conflict of interest.

7.5 Funding

This project was funded by National Institute on Aging (NIA) grants R03AG050921 (SES, PI) and K23AG053426 (SES, PI). Data from the Knight ADRC cohort was funded by NIA grants P50 AG05681 (JCM, PI), P01 AG03991 (JCM, PI), and P01 AG026276 (JCM, PI).

In addition, data collection and sharing for this project was funded by the Alzheimer's Disease Neuroimaging Initiative (ADNI) (National Institutes of Health Grant U01 AG024904) and DOD ADNI (Department of Defense award number W81XWH-12-2-0012). ADNI is funded by the National Institute on Aging, the National Institute of Biomedical Imaging and Bioengineering, and through generous contributions from the following: AbbVie, Alzheimer’s Association; Alzheimer’s Drug Discovery Foundation; Araclon Biotech; BioClinica, Inc.; Biogen; Bristol-Myers Squibb Company; CereSpir, Inc.; Cogstate; Eisai Inc.; Elan Pharmaceuticals, Inc.; Eli Lilly and Company; EuroImmun; F. Hoffmann-La Roche Ltd and its affiliated company Genentech, Inc.; Fujirebio; GE Healthcare; IXICO Ltd.; Janssen Alzheimer Immunotherapy Research & Development, LLC.; Johnson & Johnson Pharmaceutical Research & Development LLC.; Lumosity; Lundbeck; Merck & Co., Inc.; Meso Scale Diagnostics, LLC.; NeuroRx Research; Neurotrack Technologies; Novartis Pharmaceuticals Corporation; Pfizer Inc.; Piramal Imaging; Servier; Takeda Pharmaceutical Company; and Transition Therapeutics. The Canadian Institutes of Health Research is providing funds to support ADNI clinical sites in Canada. Private sector contributions are facilitated by the Foundation for the National Institutes of Health (www.fnih.org). The grantee organization is the Northern California Institute for Research and Education, and the study is coordinated by the Alzheimer’s Therapeutic Research Institute at the University of Southern California. ADNI data are disseminated by the Laboratory for Neuro Imaging at the University of Southern California.

7.6 Author contributions

O.H.B analyzed the data and wrote the manuscript. J.M.L aided in preparing the manuscript and provided critical manuscript review. R.L.H. ran samples and performed quality-control for assays. E.H. aided in the development, validation, and quality-control of the assays. C.L.S completed preliminary data analyses and ran samples. A.M.F provided critical manuscript review. C.C. provided critical manuscript review. D.M.H provided critical manuscript review. J.C.M. provided participant characterization and provided critical manuscript review. B.M.A. helped prepare the manuscript and provided critical manuscript review. S.E.S performed the initial data analysis, helped prepare the manuscript and provided critical manuscript review. All authors read and approved the final manuscript.

7.7 Acknowledgements

We thank all participants at the Knight Alzheimer Disease Research Center for their role in the sample provision and data collection. This work was also supported by the generous support of Barnes-Jewish Hospital, the Knight Alzheimer Disease Research Center, the Hope Center for Neurological Disorders, the Paula and Rodger O. Riney Fund, the Daniel J. Brennan MD Fund, and the Fred Simmons and Olga Mohan Fund.

Kok E, Haikonen S, Luoto T, Huhtala H, Goebeler S, Haapasalo H, Karhunen PJ. Apolipoprotein E-dependent accumulation of Alzheimer disease-related lesions begins in middle age. Ann Neurol. 2009 Jun;65(6):650-7. doi: 10.1002/ana.21696. PMID: 19557866.
Morris JC, Roe CM, Xiong C, Fagan AM, Goate AM, Holtzman DM, Mintun MA. APOE predicts amyloid-beta but not tau Alzheimer pathology in cognitively normal aging. Ann Neurol. 2010 Jan;67(1):122-31. doi: 10.1002/ana.21843. PMID: 20186853; PMCID: PMC2830375.
Fleisher AS, Chen K, Liu X, Ayutyanont N, Roontiva A, Thiyyagura P, Protas H, Joshi AD, Sabbagh M, Sadowsky CH, Sperling RA, Clark CM, Mintun MA, Pontecorvo MJ, Coleman RE, Doraiswamy PM, Johnson KA, Carpenter AP, Skovronsky DM, Reiman EM. Apolipoprotein E ε4 and age effects on florbetapir positron emission tomography in healthy aging and Alzheimer disease. Neurobiol Aging. 2013 Jan;34(1):1-12. doi: 10.1016/j.neurobiolaging.2012.04.017. Epub 2012 May 24. PMID: 22633529.
Liu CC, Zhao N, Fu Y, Wang N, Linares C, Tsai CW, Bu G. ApoE4 Accelerates Early Seeding of Amyloid Pathology. Neuron. 2017 Dec 6;96(5):1024-1032.e3. doi: 10.1016/j.neuron.2017.11.013. PMID: 29216449; PMCID: PMC5948105.
Shi Y, Yamada K, Liddelow SA, Smith ST, Zhao L, Luo W, Tsai RM, Spina S, Grinberg LT, Rojas JC, Gallardo G, Wang K, Roh J, Robinson G, Finn MB, Jiang H, Sullivan PM, Baufeld C, Wood MW, Sutphen C, McCue L, Xiong C, Del-Aguila JL, Morris JC, Cruchaga C; Alzheimer’s Disease Neuroimaging Initiative, Fagan AM, Miller BL, Boxer AL, Seeley WW, Butovsky O, Barres BA, Paul SM, Holtzman DM. ApoE4 markedly exacerbates tau-mediated neurodegeneration in a mouse model of tauopathy. Nature. 2017 Sep 28;549(7673):523-527. doi: 10.1038/nature24016. Epub 2017 Sep 20. PMID: 28959956; PMCID: PMC5641217.
Shi Y, Manis M, Long J, Wang K, Sullivan PM, Remolina Serrano J, Hoyle R, Holtzman DM. Microglia drive APOE-dependent neurodegeneration in a tauopathy mouse model. J Exp Med. 2019 Nov 4;216(11):2546-2561. doi: 10.1084/jem.20190980. Epub 2019 Oct 10. PMID: 31601677; PMCID: PMC6829593.7 Li et al, 2004
Li YJ, Hauser MA, Scott WK, Martin ER, Booze MW, Qin XJ, Walter JW, Nance MA, Hubble JP, Koller WC, Pahwa R, Stern MB, Hiner BC, Jankovic J, Goetz CG, Small GW, Mastaglia F, Haines JL, Pericak-Vance MA, Vance JM. Apolipoprotein E controls the risk and age at onset of Parkinson disease. Neurology. 2004 Jun 8;62(11):2005-9. doi: 10.1212/01.wnl.0000128089.53030.ac. PMID: 15184605.
Zhao N, Attrebi ON, Ren Y, Qiao W, Sonustun B, Martens YA, Meneses AD, Li F, Shue F, Zheng J, Van Ingelgom AJ, Davis MD, Kurti A, Knight JA, Linares C, Chen Y, Delenclos M, Liu CC, Fryer JD, Asmann YW, McLean PJ, Dickson DW, Ross OA, Bu G. APOE4 exacerbates α-synuclein pathology and related toxicity independent of amyloid. Sci Transl Med. 2020 Feb 5;12(529):eaay1809. doi: 10.1126/scitranslmed.aay1809. PMID: 32024798.
Panegyres PK, Beilby J, Bulsara M, Toufexis K, Wong C. A study of potential interactive genetic factors in Huntington's disease. Eur Neurol. 2006;55(4):189-92. doi: 10.1159/000093867. Epub 2006 Jun 13. PMID: 16772714.
Agosta F, Vossel KA, Miller BL, Migliaccio R, Bonasera SJ, Filippi M, Boxer AL, Karydas A, Possin KL, Gorno-Tempini ML. Apolipoprotein E epsilon4 is associated with disease-specific effects on brain atrophy in Alzheimer's disease and frontotemporal dementia. Proc Natl Acad Sci U S A. 2009 Feb 10;106(6):2018-22. doi: 10.1073/pnas.0812697106. Epub 2009 Jan 22. PMID: 19164761; PMCID: PMC2644156.
McKee AC, Cantu RC, Nowinski CJ, Hedley-Whyte ET, Gavett BE, Budson AE, Santini VE, Lee HS, Kubilus CA, Stern RA. Chronic traumatic encephalopathy in athletes: progressive tauopathy after repetitive head injury. J Neuropathol Exp Neurol. 2009 Jul;68(7):709-35. doi: 10.1097/NEN.0b013e3181a9d503. PMID: 19535999; PMCID: PMC2945234.
Wang C, Wilson WA, Moore SD, Mace BE, Maeda N, Schmechel DE, Sullivan PM. Human apoE4-targeted replacement mice display synaptic deficits in the absence of neuropathology. Neurobiol Dis. 2005 Mar;18(2):390-8. doi: 10.1016/j.nbd.2004.10.013. PMID: 15686968.
Love S, Siew LK, Dawbarn D, Wilcock GK, Ben-Shlomo Y, Allen SJ. Premorbid effects of APOE on synaptic proteins in human temporal neocortex. Neurobiol Aging. 2006 Jun;27(6):797-803. doi: 10.1016/j.neurobiolaging.2005.04.008. Epub 2005 Jun 23. PMID: 15979210.
Tannenberg RK, Scott HL, Tannenberg AE, Dodd PR. Selective loss of synaptic proteins in Alzheimer's disease: evidence for an increased severity with APOE varepsilon4. Neurochem Int. 2006 Dec;49(7):631-9. doi: 10.1016/j.neuint.2006.05.004. Epub 2006 Jun 30. PMID: 16814428.
Dumanis SB, Tesoriero JA, Babus LW, Nguyen MT, Trotter JH, Ladu MJ, Weeber EJ, Turner RS, Xu B, Rebeck GW, Hoe HS. ApoE4 decreases spine density and dendritic complexity in cortical neurons in vivo. J Neurosci. 2009 Dec 2;29(48):15317-22. doi: 10.1523/JNEUROSCI.4026-09.2009. PMID: 19955384; PMCID: PMC2846754.
Nwabuisi-Heath E, Rebeck GW, Ladu MJ, Yu C. ApoE4 delays dendritic spine formation during neuron development and accelerates loss of mature spines in vitro. ASN Neuro. 2014 Jan 13;6(1):e00134. doi: 10.1042/AN20130043. PMID: 24328732; PMCID: PMC3891498.
Dumanis SB, DiBattista AM, Miessau M, Moussa CE, Rebeck GW. APOE genotype affects the pre-synaptic compartment of glutamatergic nerve terminals. J Neurochem. 2013 Jan;124(1):4-14. doi: 10.1111/j.1471-4159.2012.07908.x. Epub 2012 Sep 28. PMID: 22862561; PMCID: PMC3509249.
Weeber EJ, Beffert U, Jones C, Christian JM, Forster E, Sweatt JD, Herz J. Reelin and ApoE receptors cooperate to enhance hippocampal synaptic plasticity and learning. J Biol Chem. 2002 Oct 18;277(42):39944-52. doi: 10.1074/jbc.M205147200. Epub 2002 Aug 7. PMID: 12167620.
Jain S, Yoon SY, Leung L, Knoferle J, Huang Y. Cellular source-specific effects of apolipoprotein (apo) E4 on dendrite arborization and dendritic spine development. PLoS One. 2013;8(3):e59478. doi: 10.1371/journal.pone.0059478. Epub 2013 Mar 19. PMID: 23527202; PMCID: PMC3602301.
Holtzman DM, Bales KR, Tenkova T, Fagan AM, Parsadanian M, Sartorius LJ, Mackey B, Olney J, McKeel D, Wozniak D, Paul SM. Apolipoprotein E isoform-dependent amyloid deposition and neuritic degeneration in a mouse model of Alzheimer's disease. Proc Natl Acad Sci U S A. 2000 Mar 14;97(6):2892-7. doi: 10.1073/pnas.050004797. PMID: 10694577; PMCID: PMC16026.
Shin OH. Exocytosis and synaptic vesicle function. Compr Physiol. 2014 Jan;4(1):149-75. doi: 10.1002/cphy.c130021. PMID: 24692137.
Chang JW, Schumacher E, Coulter PM 2nd, Vinters HV, Watson JB. Dendritic translocation of RC3/neurogranin mRNA in normal aging, Alzheimer disease and fronto-temporal dementia. J Neuropathol Exp Neurol. 1997 Oct;56(10):1105-18. doi: 10.1097/00005072-199710000-00004. PMID: 9329454.
Brinkmalm A, Brinkmalm G, Honer WG, Frölich L, Hausner L, Minthon L, Hansson O, Wallin A, Zetterberg H, Blennow K, Öhrfelt A. SNAP-25 is a promising novel cerebrospinal fluid biomarker for synapse degeneration in Alzheimer's disease. Mol Neurodegener. 2014 Nov 23;9:53. doi: 10.1186/1750-1326-9-53. PMID: 25418885; PMCID: PMC4253625.
Zhang H, Therriault J, Kang MS, Ng KP, Pascoal TA, Rosa-Neto P, Gauthier S; Alzheimer’s Disease Neuroimaging Initiative. Cerebrospinal fluid synaptosomal-associated protein 25 is a key player in synaptic degeneration in mild cognitive impairment and Alzheimer's disease. Alzheimers Res Ther. 2018 Aug 16;10(1):80. doi: 10.1186/s13195-018-0407-6. PMID: 30115118; PMCID: PMC6097333.
Thorsell A, Bjerke M, Gobom J, Brunhage E, Vanmechelen E, Andreasen N, Hansson O, Minthon L, Zetterberg H, Blennow K. Neurogranin in cerebrospinal fluid as a marker of synaptic degeneration in Alzheimer's disease. Brain Res. 2010 Nov 29;1362:13-22. doi: 10.1016/j.brainres.2010.09.073. Epub 2010 Sep 25. PMID: 20875798.
Kvartsberg H, Duits FH, Ingelsson M, Andreasen N, Öhrfelt A, Andersson K, Brinkmalm G, Lannfelt L, Minthon L, Hansson O, Andreasson U, Teunissen CE, Scheltens P, Van der Flier WM, Zetterberg H, Portelius E, Blennow K. Cerebrospinal fluid levels of the synaptic protein neurogranin correlates with cognitive decline in prodromal Alzheimer's disease. Alzheimers Dement. 2015 Oct;11(10):1180-90. doi: 10.1016/j.jalz.2014.10.009. Epub 2014 Dec 19. PMID: 25533203.
Kester MI, Teunissen CE, Crimmins DL, Herries EM, Ladenson JH, Scheltens P, van der Flier WM, Morris JC, Holtzman DM, Fagan AM. Neurogranin as a Cerebrospinal Fluid Biomarker for Synaptic Loss in Symptomatic Alzheimer Disease. JAMA Neurol. 2015 Nov;72(11):1275-80. doi: 10.1001/jamaneurol.2015.1867. PMID: 26366630; PMCID: PMC4694558.
Kvartsberg H, Portelius E, Andreasson U, Brinkmalm G, Hellwig K, Lelental N, Kornhuber J, Hansson O, Minthon L, Spitzer P, Maler JM, Zetterberg H, Blennow K, Lewczuk P. Characterization of the postsynaptic protein neurogranin in paired cerebrospinal fluid and plasma samples from Alzheimer's disease patients and healthy controls. Alzheimers Res Ther. 2015 Jul 1;7(1):40. doi: 10.1186/s13195-015-0124-3. PMID: 26136856; PMCID: PMC4487851.
De Vos A, Jacobs D, Struyfs H, Fransen E, Andersson K, Portelius E, Andreasson U, De Surgeloose D, Hernalsteen D, Sleegers K, Robberecht C, Van Broeckhoven C, Zetterberg H, Blennow K, Engelborghs S, Vanmechelen E. C-terminal neurogranin is increased in cerebrospinal fluid but unchanged in plasma in Alzheimer's disease. Alzheimers Dement. 2015 Dec;11(12):1461-1469. doi: 10.1016/j.jalz.2015.05.012. Epub 2015 Jun 16. PMID: 26092348.
Portelius E, Zetterberg H, Skillbäck T, Törnqvist U, Andreasson U, Trojanowski JQ, Weiner MW, Shaw LM, Mattsson N, Blennow K; Alzheimer’s Disease Neuroimaging Initiative. Cerebrospinal fluid neurogranin: relation to cognition and neurodegeneration in Alzheimer's disease. Brain. 2015 Nov;138(Pt 11):3373-85. doi: 10.1093/brain/awv267. Epub 2015 Sep 15. PMID: 26373605; PMCID: PMC4643642.
Tarawneh R, D'Angelo G, Crimmins D, Herries E, Griest T, Fagan AM, Zipfel GJ, Ladenson JH, Morris JC, Holtzman DM. Diagnostic and Prognostic Utility of the Synaptic Marker Neurogranin in Alzheimer Disease. JAMA Neurol. 2016 May 1;73(5):561-71. doi: 10.1001/jamaneurol.2016.0086. PMID: 27018940; PMCID: PMC4861689.
Morris JC. The Clinical Dementia Rating (CDR): current version and scoring rules. Neurology. 1993 Nov;43(11):2412-4. doi: 10.1212/wnl.43.11.2412-a. PMID: 8232972.
Morris JC, Schindler SE, McCue LM, Moulder KL, Benzinger TLS, Cruchaga C, Fagan AM, Grant E, Gordon BA, Holtzman DM, Xiong C. Assessment of Racial Disparities in Biomarkers for Alzheimer Disease. JAMA Neurol. 2019 Mar 1;76(3):264-273. doi: 10.1001/jamaneurol.2018.4249. PMID: 30615028; PMCID: PMC6439726.
Cruchaga C, Kauwe JS, Harari O, Jin SC, Cai Y, Karch CM, Benitez BA, Jeng AT, Skorupa T, Carrell D, Bertelsen S, Bailey M, McKean D, Shulman JM, De Jager PL, Chibnik L, Bennett DA, Arnold SE, Harold D, Sims R, Gerrish A, Williams J, Van Deerlin VM, Lee VM, Shaw LM, Trojanowski JQ, Haines JL, Mayeux R, Pericak-Vance MA, Farrer LA, Schellenberg GD, Peskind ER, Galasko D, Fagan AM, Holtzman DM, Morris JC; GERAD Consortium; Alzheimer’s Disease Neuroimaging Initiative (ADNI); Alzheimer Disease Genetic Consortium (ADGC), Goate AM. GWAS of cerebrospinal fluid tau levels identifies risk variants for Alzheimer's disease. Neuron. 2013 Apr 24;78(2):256-68. doi: 10.1016/j.neuron.2013.02.026. Epub 2013 Apr 4. PMID: 23562540; PMCID: PMC3664945.
Fagan AM, Mintun MA, Mach RH, Lee SY, Dence CS, Shah AR, LaRossa GN, Spinner ML, Klunk WE, Mathis CA, DeKosky ST, Morris JC, Holtzman DM. Inverse relation between in vivo amyloid imaging load and cerebrospinal fluid Abeta42 in humans. Ann Neurol. 2006 Mar;59(3):512-9. doi: 10.1002/ana.20730. PMID: 16372280.
Schindler SE, Gray JD, Gordon BA, Xiong C, Batrla-Utermann R, Quan M, Wahl S, Benzinger TLS, Holtzman DM, Morris JC, Fagan AM. Cerebrospinal fluid biomarkers measured by Elecsys assays compared to amyloid imaging. Alzheimers Dement. 2018 Nov;14(11):1460-1469. doi: 10.1016/j.jalz.2018.01.013. Epub 2018 Mar 2. PMID: 29501462; PMCID: PMC6119652.
Mintun MA, Larossa GN, Sheline YI, Dence CS, Lee SY, Mach RH, Klunk WE, Mathis CA, DeKosky ST, Morris JC. [11C]PIB in a nondemented population: potential antecedent marker of Alzheimer disease. Neurology. 2006 Aug 8;67(3):446-52. doi: 10.1212/01.wnl.0000228230.26044.a4. PMID: 16894106.
Su Y, Blazey TM, Snyder AZ, et al. Partial volume correction in quantitative amyloid imaging. Neuroimage. 2015;107:55-64. doi:10.1016/j.neuroimage.2014.11.058
Su Y, Flores S, Hornbeck RC, Speidel B, Vlassenko AG, Gordon BA, Koeppe RA, Klunk WE, Xiong C, Morris JC, Benzinger TLS. Utilizing the Centiloid scale in cross-sectional and longitudinal PiB PET studies. Neuroimage Clin. 2018 Apr 25;19:406-416. doi: 10.1016/j.nicl.2018.04.022. PMID: 30035025; PMCID: PMC6051499.
Su Y, Flores S, Wang G, Hornbeck RC, Speidel B, Joseph-Mathurin N, Vlassenko AG, Gordon BA, Koeppe RA, Klunk WE, Jack CR Jr, Farlow MR, Salloway S, Snider BJ, Berman SB, Roberson ED, Brosch J, Jimenez-Velazques I, van Dyck CH, Galasko D, Yuan SH, Jayadev S, Honig LS, Gauthier S, Hsiung GR, Masellis M, Brooks WS, Fulham M, Clarnette R, Masters CL, Wallon D, Hannequin D, Dubois B, Pariente J, Sanchez-Valle R, Mummery C, Ringman JM, Bottlaender M, Klein G, Milosavljevic-Ristic S, McDade E, Xiong C, Morris JC, Bateman RJ, Benzinger TLS. Comparison of Pittsburgh compound B and florbetapir in cross-sectional and longitudinal studies. Alzheimers Dement (Amst). 2019 Feb 22;11:180-190. doi: 10.1016/j.dadm.2018.12.008. PMID: 30847382; PMCID: PMC6389727.
Klunk WE, Engler H, Nordberg A, Wang Y, Blomqvist G, Holt DP, Bergström M, Savitcheva I, Huang GF, Estrada S, Ausén B, Debnath ML, Barletta J, Price JC, Sandell J, Lopresti BJ, Wall A, Koivisto P, Antoni G, Mathis CA, Långström B. Imaging brain amyloid in Alzheimer's disease with Pittsburgh Compound-B. Ann Neurol. 2004 Mar;55(3):306-19. doi: 10.1002/ana.20009. PMID: 14991808.
Sutphen CL, McCue L, Herries EM, Xiong C, Ladenson JH, Holtzman DM, Fagan AM; ADNI. Longitudinal decreases in multiple cerebrospinal fluid biomarkers of neuronal injury in symptomatic late onset Alzheimer's disease. Alzheimers Dement. 2018 Jul;14(7):869-879. doi: 10.1016/j.jalz.2018.01.012. Epub 2018 Mar 23. PMID: 29580670; PMCID: PMC6110083.
Wang S, Zhang J, Pan T; for Alzheimer’s Disease Neuroimaging Initiative. APOE ε4 is associated with higher levels of CSF SNAP-25 in prodromal Alzheimer's disease. Neurosci Lett. 2018 Oct 15;685:109-113. doi: 10.1016/j.neulet.2018.08.029. Epub 2018 Aug 23. PMID: 30144541.
Wang Q, Zhou W, Zhang J; Alzheimer’s Disease Neuroimaging Initiative. Levels of Cortisol in CSF Are Associated With SNAP-25 and Tau Pathology but Not Amyloid-β. Front Aging Neurosci. 2018 Nov 20;10:383. doi: 10.3389/fnagi.2018.00383. PMID: 30524269; PMCID: PMC6256241.
Galasko D, Xiao M, Xu D, Smirnov D, Salmon DP, Dewit N, Vanbrabant J, Jacobs D, Vanderstichele H, Vanmechelen E; Alzheimer's Disease Neuroimaging Initiative (ADNI), Worley P. Synaptic biomarkers in CSF aid in diagnosis, correlate with cognition and predict progression in MCI and Alzheimer's disease. Alzheimers Dement (N Y). 2019 Dec 9;5:871-882. doi: 10.1016/j.trci.2019.11.002. PMID: 31853477; PMCID: PMC6911971.
Tible M, Sandelius Å, Höglund K, Brinkmalm A, Cognat E, Dumurgier J, Zetterberg H, Hugon J, Paquet C, Blennow K. Dissection of synaptic pathways through the CSF biomarkers for predicting Alzheimer disease. Neurology. 2020 Aug 25;95(8):e953-e961. doi: 10.1212/WNL.0000000000010131. Epub 2020 Jun 25. PMID: 32586895.
Klein RC, Mace BE, Moore SD, Sullivan PM. Progressive loss of synaptic integrity in human apolipoprotein E4 targeted replacement mice and attenuation by apolipoprotein E2. Neuroscience. 2010 Dec 29;171(4):1265-72. doi: 10.1016/j.neuroscience.2010.10.027. Epub 2010 Oct 15. PMID: 20951774; PMCID: PMC2991419.
Chen Y, Durakoglugil MS, Xian X, Herz J. ApoE4 reduces glutamate receptor function and synaptic plasticity by selectively impairing ApoE receptor recycling. Proc Natl Acad Sci U S A. 2010 Jun 29;107(26):12011-6. doi: 10.1073/pnas.0914984107. Epub 2010 Jun 14. PMID: 20547867; PMCID: PMC2900641.
Lin YT, Seo J, Gao F, Feldman HM, Wen HL, Penney J, Cam HP, Gjoneska E, Raja WK, Cheng J, Rueda R, Kritskiy O, Abdurrob F, Peng Z, Milo B, Yu CJ, Elmsaouri S, Dey D, Ko T, Yankner BA, Tsai LH. APOE4 Causes Widespread Molecular and Cellular Alterations Associated with Alzheimer's Disease Phenotypes in Human iPSC-Derived Brain Cell Types. Neuron. 2018 Jun 27;98(6):1141-1154.e7. doi: 10.1016/j.neuron.2018.05.008. Epub 2018 May 31. Erratum in: Neuron. 2018 Jun 27;98 (6):1294. PMID: 29861287; PMCID: PMC6023751.
Levi O, Jongen-Relo AL, Feldon J, Roses AD, Michaelson DM. ApoE4 impairs hippocampal plasticity isoform-specifically and blocks the environmental stimulation of synaptogenesis and memory. Neurobiol Dis. 2003 Aug;13(3):273-82. doi: 10.1016/s0969-9961(03)00045-7. PMID: 12901842.
Dolejší E, Liraz O, Rudajev V, Zimčík P, Doležal V, Michaelson DM. Apolipoprotein E4 reduces evoked hippocampal acetylcholine release in adult mice. J Neurochem. 2016 Feb;136(3):503-9. doi: 10.1111/jnc.13417. Epub 2015 Nov 19. PMID: 26526158; PMCID: PMC4738402.
Khalil M, Pirpamer L, Hofer E, Voortman MM, Barro C, Leppert D, Benkert P, Ropele S, Enzinger C, Fazekas F, Schmidt R, Kuhle J. Serum neurofilament light levels in normal aging and their association with morphologic brain changes. Nat Commun. 2020 Feb 10;11(1):812. doi: 10.1038/s41467-020-14612-6. PMID: 32041951; PMCID: PMC7010701.
Bos I, Vos S, Verhey F, Scheltens P, Teunissen C, Engelborghs S, Sleegers K, Frisoni G, Blin O, Richardson JC, Bordet R, Tsolaki M, Popp J, Peyratout G, Martinez-Lage P, Tainta M, Lleó A, Johannsen P, Freund-Levi Y, Frölich L, Vandenberghe R, Westwood S, Dobricic V, Barkhof F, Legido-Quigley C, Bertram L, Lovestone S, Streffer J, Andreasson U, Blennow K, Zetterberg H, Visser PJ. Cerebrospinal fluid biomarkers of neurodegeneration, synaptic integrity, and astroglial activation across the clinical Alzheimer's disease spectrum. Alzheimers Dement. 2019 May;15(5):644-654. doi: 10.1016/j.jalz.2019.01.004. Epub 2019 Mar 8. PMID: 30853464.
Kern S, Syrjanen JA, Blennow K, Zetterberg H, Skoog I, Waern M, Hagen CE, van Harten AC, Knopman DS, Jack CR Jr, Petersen RC, Mielke MM. Association of Cerebrospinal Fluid Neurofilament Light Protein With Risk of Mild Cognitive Impairment Among Individuals Without Cognitive Impairment. JAMA Neurol. 2019 Feb 1;76(2):187-193. doi: 10.1001/jamaneurol.2018.3459. PMID: 30419087; PMCID: PMC6439969.
Lin YS, Lee WJ, Wang SJ, Fuh JL. Levels of plasma neurofilament light chain and cognitive function in patients with Alzheimer or Parkinson disease. Sci Rep. 2018 Nov 26;8(1):17368. doi: 10.1038/s41598-018-35766-w. PMID: 30478269; PMCID: PMC6255914.

SNAPFigSupp1.pdf
Supplemental Figure 1. CSF t-tau, ptau181, and NfL by APOE genotype. Levels of CSF t-tau (A) ptau181 (B), and NfL (C) as a function of APOE genotype. No clear relationship between APOE genotype and either of the three CSF biomarkers is observed. CSF, cerebrospinal fluid; t-tau, total tau; ptau181, tau phosphorylated at 181; NfL, neurofilament light chain; APOE, Apolipoprotein E *, p < 0.05
SNAPFigSupp1.pdf
Supplemental Figure 1. CSF t-tau, ptau181, and NfL by APOE genotype. Levels of CSF t-tau (A) ptau181 (B), and NfL (C) as a function of APOE genotype. No clear relationship between APOE genotype and either of the three CSF biomarkers is observed. CSF, cerebrospinal fluid; t-tau, total tau; ptau181, tau phosphorylated at 181; NfL, neurofilament light chain; APOE, Apolipoprotein E *, p < 0.05
SupplementalTables.docx
SupplementalTables.docx

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Cognitively Normal APOE ε4 Carriers Have Specific Elevation of CSF SNAP-25

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Abstract

Figures

1. Background

2. Materials And Methods

2.1 Participants

2.2 Genetic Analyses

2.3 CSF acquisition and processing

2.4 PET image acquisition and processing

2.5 Statistical Analyses

2.6 Replication Cohort

3. Results

3.1 Participant characteristics

3.2 Differences in CSF biomarkers by amyloid status or APOE ε4 carrier status

3.3 CSF biomarkers in different APOE allele genotypes

3.4 CSF SNAP-25 and Ng by amyloid status

3.5 Modeling CSF biomarker as function of amyloid status and APOE ε4 carrier status

4. Discussion

5. Conclusions

6. Abbreviations

7. Declarations

8. References

Supplementary Files

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