The Correlations of Plasma Liver-Type Fatty Acid-Binding Protein with Amyloid-β and Tau Levels in Patients with Alzheimer’s Disease

Abstract

Background:

The dysregulation of lipid metabolism plays an important role in the pathogenesis of Alzheimer’s disease (AD). Liver-type fatty acid-binding protein (L-FABP, also known as FABP1) is critical for fatty acid transport and may be involved in AD.

Objective:

To investigate whether the FABP1 level is altered in patients with AD, and its associations with levels of amyloid-β (Aβ) and tau in the plasma and cerebrospinal fluid (CSF).

Methods:

A cross-sectional study was conducted in a Chinese cohort consisting of 39 cognitively normal controls and 47 patients with AD. The levels of FABP1 in plasma, and Aβ and tau in CSF, were measured by enzyme-linked immunosorbent assay (ELISA). A single-molecule array (SIMOA) was used to detect plasma Aβ levels.

Results:

The level of plasma FABP1 was significantly elevated in the AD group (p = 0.0109). Further analysis showed a positive correlation of FABP1 with CSF total tau (t-tau) and phosphorylated tau (p-tau) levels. Besides, plasma FABP1/Aβ₄₂ (AUC = 0.6794, p = 0.0071) and FABP1/t-tau (AUC = 0.7168, p = 0.0011) showed fair diagnostic efficacy for AD. When combined with other common AD biomarkers including plasma Aβ₄₂, Aβ₄₀, and t-tau, both FABP1/Aβ₄₂ and FABP1/t-tau showed better diagnostic efficacy than using these biomarkers alone. Among all AUC analyses, the combination of plasma FABP1/t-tau and Aβ₄₂ had the highest diagnostic value (AUC = 0.8075, p < 0.0001).

Conclusion:

These findings indicate that FABP1 may play a role in AD pathogenesis and be worthy of further investigation in the future.

Keywords

Alzheimer’s disease amyloid-β liver-type fatty acid-binding protein tau

INTRODUCTION

Alzheimer’s disease (AD) is the most common form of dementia among the elderly [1]. Senile plaques containing amyloid-β protein (Aβ) and neurofibrillary tangles consisting of hyperphosphorylated tau in the brain are two pathological hallmarks of AD [2]. However, the pathogenesis of this complex disease remains to be fully clarified. Up till now, cumulative epidemiological and experimental evidence has shown that the dysregulation of lipid metabolism is involved in AD [3, 4]. It was further validated by the findings that several genes participating in lipid metabolisms, such as APOE, CLU, and PICALM, are associated with the risk of AD [5, 6].

Fatty acid-binding protein (FABP) is a protein superfamily that can modulate lipid trafficking, signaling, and metabolisms [7]. A recent study suggested that brain-specific FABP (B-FABP) is elevated in the serum of patients with AD [8]. Another research showed that heart-type FABP (H-FABP) is decreased in the brains of patients with AD [9]. Furthermore, cerebrospinal fluid (CSF) H-FABP levels are significantly associated with atrophy of the AD-vulnerable brain regions [10]. All these evidence implicated a potential role for FABP in AD pathogenesis. However, as another important member of the FABP superfamily, the role of liver-type FABP (L-FABP, also known as FABP1) in AD is not well understood. A previous study once revealed a link between FABP1 and APOE ɛ4, the most acknowledged AD-risk allele [11], and the present study was conducted to explore the alterations of FABP1 in AD patients.

MATERIALS AND METHODS

Study population

Patients with AD were recruited from Army Medical Center (Daping Hospital) from December 2018 to May 2020. Age- and gender-matched controls with normal cognition were recruited from the hospital at the same time. Subjects were excluded if they have: 1) a family history of dementia; 2) diseases or conditions that may affect FABP1 levels, including dyslipidemia, hematologic system diseases (e.g., bleeding disorders, etc), abnormal liver function (abnormal levels of alanine aminotransferase, aspartate aminotransferase, albumin, or bilirubin), and abnormal renal function (abnormal blood creatinine, urea nitrogen); 3) recent treatments that affect FABP1 levels (e.g., blood transfusion, statins use); 4) severe cardiac or pulmonary diseases, or any type of tumor, infectious and rheumatic diseases; 5) a concomitant neurologic disorder that could potentially affect the cognitive function or other types of dementia; 6) mental illness (e.g., schizophrenia); 7) an allergy to the ¹¹C-Pittsburgh compound.

Clinical assessment and sampling

All subjects performed clinical assessments following a previously used protocol [12]. In brief, the demographic data and medical history (such as hypertension, coronary heart disease, and diabetes mellitus) were collected and the cognitive function was assessed based on a neuropsychological battery by trained and experienced neurologists. Mini-Mental State Examination (MMSE) and Activities of Daily Living Scale (ADL) were administered to evaluate the overall cognitive. The subjects who were abnormal in MMSE assessments were further administered with neuropsychological tests including Clinical Dementia Rating (CDR), administered for detecting extensive cognitive dysfunction; and Hachinski Ischemic Score (HIS) for assessing significant vascular diseases. The clinical diagnosis of AD was made according to the criteria of the National Institute of Neurological and Communicative Diseases and Stroke/AD and Related Disorders Association (NINCDS-ADRDA) following the protocols we previously used [13]. Besides, patients enrolled in this study received the Pittsburgh compound B-positron emission tomography (PiB-PET) examination, and all enrolled subjects in the AD group are amyloid (+) AD dementia patients. The cognitively normal (CN) controls consisted of subjects who had no history or signs of neurologic disorders. Fasting blood was collected between 7:00 and 9:00 am to avoid the potential influence of circadian rhythm. The blood samples were centrifuged within an hour of collection, and EDTA plasma was aliquoted in 0.5 mL polypropylene tubes and stored at – 80°C until used. The CSF samples were collected by lumbar puncture and then centrifuged at 2000 g at 4°C for 10 min, and the aliquots were then immediately frozen and stored at – 80°C until use. This study was approved by the Institutional Review Board of Daping Hospital and informed consents were obtained from all participants or their legal representatives.

APOE genotyping

APOE genotypes (rs429358 and rs7412) were determined by the restriction fragment length polymorphism (RFLP) method. The PCR reactions were performed with 1μL DNA sample, 1×GCI buffer (TaKaRa, Japan), 2.0 mM Mg2+ (TaKaRa, Japan), 0.2 mM dNTP (Generay Biotech, China), 1 U HotStarTaq polymerase (Qiagen, Germany), 2μM multiple PCR primers (Sangon, China), and ddH₂O in a total volume of 10μL. The cycling program was the same as described previously [14]. The digestion of endonuclease was performed with AflIII or HaeII (New England Biolabs, USA) for rs429358 or rs7412 respectively. Then the products were analyzed with an ABI3130XL sequencer (Applied Biosystems, USA).

Measurements of FABP1, Aβ, and tau levels

The level of FABP1 in plasma was detected using human FABP1 ELISA kits (Jiangsu Jingmei Biotechnology Co., Ltd., Yancheng, China). Plasma levels of Aβ₄₂ and Aβ₄₀ were measured using the commercially available single-molecule array (SIMOA) Human Neurology 3-Plex A assay kit (Quanterix, United States) on board of the automated SIMOA HD-1 analyzer (Quanterix, United States). CSF levels of Aβ₄₀, Aβ₄₂, total tau (t-tau), and phosphorylated tau-181 (p-tau) were measured using the human Aβ and tau enzyme-linked immunosorbent assay (ELISA) kits (Innotest, United States).

Statistical analysis

Continuous variables were described as median/mean, and the categorical data were summarized as absolute frequencies. Differences in the frequencies of gender and APOE ɛ carriers were assessed by the chi-square test. Differences in other demographic characteristics and FABP1 levels between the groups were assessed with two-tailed independent t-tests. Spearman correlation analyses were used to examine the correlations between FABP1 levels and Aβ or tau levels. The data are expressed as the mean±standard deviation (SD). The diagnostic accuracy of FABP1 was determined via the receiver operating characteristic (ROC) curve analysis utilizing a nonparametric approach. All hypothesis testing was two-sided, and p < 0.05 was defined as statistically significant. The statistical analyses were performed with SPSS version 20.0 (SPSS Inc., United States)

RESULTS

Characteristics of the study population

The characteristics of the subjects were shown in Table 1. The study consisted of 47 AD patients and 39 age- and gender-matched CN controls. There were no significant differences in age, sex, education level, or comorbidity (hypertension, diabetes mellitus, and cardiovascular disease) between the two groups. As expected, the AD group had a higher percentage of APOE #x025B;4 carriers (p < 0.0001). The median MMSE score of the AD group was significantly lower than those of the CN group (p < 0.0001).

Table 1

Characteristics of the participants in the AD and CN groups

Characteristics	CN group (n = 39)	AD group (n = 47)	p
Age, mean (SD), y	67.79 (7.29)	67.85 (10.55)	0.9776
Female, N (%)	18 (46.15)	25 (53.19)	0.6651
Education level, mean (SD), y	9.33 (4.45)	9.68 (4.00)	0.7041
MMSE score, mean (SD)	26.41 (2.17)	14.96 (6.47)	< 0.0001
APOE ɛ 4 carriers, N (%)	5 (12.82)	27 (57.45)	< 0.0001
Hypertension (%)	8 (21.23)	11 (23.40)	0.7991
Diabetes (%)	6 (15.38)	9 (19.15)	0.7780
Stroke history (%)	4 (10.26)	5 (10.64)	> 0.9999
Coronary artery disease (%)	8 (20.51)	10 (21.28)	> 0.9999

Results are shown as mean (SD) or number (%). AD, Alzheimer’s disease; CN, cognitively normal; y, years; MMSE, Mini-Mental State Examination; APOE, apolipoprotein E; N, number; SD, standard deviations.

Plasma FABP1 levels in different groups

As shown in Fig. 1, the plasma FABP1 levels in the AD group were significantly higher than that in the CN group (229.8±131.7 pg/ml versus 166.9±78.10 pg/ml, p = 0.0109). In sub-group analysis, there was no difference in plasma FABP1 levels between APOE ɛ4 non-carriers and carriers in patients with AD (232.0±131.0 pg/ml versus 215.6±137.2 pg/ml, p = 0.6844).

Fig. 1

Comparison of the plasma FABP1 levels between different groups. Comparison of the plasma FABP1 levels between the CN controls and AD patients (A) and FABP1 levels between APOE ɛ4 carries and non-carries in AD group (B). AD, Alzheimer’s disease; CN, cognitively normal; APOE, apolipoprotein E.

Correlation of plasma FABP1 levels with Aβ and tau levels

FABP1 levels had no correlation with plasma Aβ₄₂ levels (p = 0.9159) and Aβ₄₀ levels (p = 0.8278) in AD patients. There was no correlation of FABP1 levels with plasma Aβ₄₂ levels (p = 0.7426) and Aβ₄₀ levels (p = 0.2562) in CN group (Fig. 2A, B). In total subjects, FABP1 levels had no correlation with plasma Aβ₄₀ (p = 0.2888), or Aβ₄₂ levels (p = 0.3968) (Fig. 2C, D). There was no correlation of FABP1 levels with age and MMSE scores in AD group (data not shown).

Fig. 2

The correlation analyses of plasma FABP1 and Aβ. Correlations of FABP1 levels with plasma Aβ₄₀ levels (A) and Aβ₄₂ levels (B) in AD patients and CN controls. Correlations of FABP1 levels with plasma Aβ₄₀ levels (C) and Aβ₄₂ levels (D) in total study subjects. AD, Alzheimer’s disease; CN, cognitively normal.

FABP1 levels in AD patients had no correlation with CSF Aβ₄₀ (p = 0.6959), or Aβ₄₂ levels (p = 0.2429) (Fig. 3A, B), but had positive correlations with CSF t-tau levels (R² = 0.2977, p = 0.0288) and p-tau levels (R² =0.3958, p = 0.0090) (Fig. 3C, D). Moreover, based on the finding that ratios of tau and Aβ₄₂ (t-tau/Aβ₄₂ and p-tau/Aβ₄₂) may have a closer correlation with the PiB-PET cortical standard uptake ratio (SUVR), and better reflect Aβ deposition in the brain [15, 16], we analyzed the correlation between these ratios and FABP1, yet with negative findings.

Fig. 3

Correlations of plasma FABP1 levels with CSF AD biomarkers. Correlations between plasma FABP1 levels with CSF Aβ₄₀ levels (A), Aβ₄₂ levels (B), t-tau levels (C), and p-tau levels (D) in AD patients and CN controls. AD, Alzheimer’s disease; CN, cognitively normal.

The diagnostic efficacy of plasma FABP1 levels for AD

Receiver operating characteristic (ROC) analysis was conducted to determine the diagnostic efficacy of FABP1 in distinguishing the AD group from the CN group. However, the diagnostic value of FABP1 was very limited, and the area under the curve (AUC) was low (0.6371, p = 0.0297, 95% CI = 0.5203– 0.7539) (Fig. 4A). Based on a previous finding that H-FABP/Aβ₄₂ may be a predictor for AD dementia conversion [17], we investigated whether plasma FABP1/Aβ₄₂ and FABP1/t-tau was more helpful in diagnosing AD. The results of ROC analysis showed that the AUC of plasma FABP1/Aβ₄₂ and FABP1/t-tau in AD versus CN group was 0.6794 (p = 0.0071, 95% CI = 0.5586– 0.8002) and 0.7168 (p = 0.0011, 95% CI = 0.6031– 0.8304) which is higher than using FABP1 only (Fig. 4A). The AUC of other known plasma AD biomarkers were 0.7539 (p = 0.0001), 0.6618 (p = 0.0139), and 0.7401 (p = 0.0003) for t-tau, Aβ₄₀, and Aβ₄₂, respectively (Fig. 4B). The AUC values were all elevated when combining each of these plasma biomarkers with FABP1/Aβ₄₂ (AUC: FABP1/Aβ₄₂ & Aβ₄₂, 0.7583, p = 0.0001; FABP1/Aβ₄₂ & Aβ₄₀, 0.7134, p = 0.0013; FABP1/Aβ₄₂ & t-tau, 0.7756, p < 0.0001) (Fig. 4C), and with FABP1/t-tau (AUC: FABP1/t-tau & Aβ₄₂, 0.8075, p < 0.0001; FABP1/ t-tau & Aβ₄₀, 0.7486, p = 0.0002; FABP1/ t-tau & t-tau, 0.7729, p < 0.0001) (Fig. 4D). Among all AUC analyses, the combination of plasma FABP1/t-tau and Aβ₄₂ had the highest diagnostic value (AUC = 0.8075, p < 0.0001)∥

Fig. 4

The diagnostic potential of plasma FABP1 levels for AD. A) Diagnostic values of plasma FABP1, FABP1/Aβ42, and FABP1/t-tau to distinguish AD from CN controls. B) The ROC curve of common plasma AD biomarkers. C) The ROC curve of plasma FABP1/Aβ₄₂ in combination with other plasma AD biomarkers. D) The ROC curve of plasma FABP1/t-tau in combination with other plasma AD biomarkers. AD, Alzheimer’s disease; CN, cognitively normal; ROC, Receiver Operating Characteristic.

DISCUSSION

To our knowledge, the present study firstly demonstrated that plasma FABP1 levels are altered in AD patients compared with CN controls, and revealed the correlation between FABP1 and AD biomarkers in humans. In AD patients, the plasma level of FABP1 was positively correlated with CSF levels of t-tau and p-tau but did not correlate with plasma and CSF levels of Aβ₄₀ or Aβ₄₂. The results also showed that plasma FABP1/t-tau and FABP1/Aβ₄₂ had a potential diagnostic value for AD either applied alone or in combination with other plasma AD biomarkers.

In recent years, increasing evidence suggests a relationship between AD and dyslipidemia. Although much attention has been paid to the link between APOE, cholesterol metabolism, and AD pathogenesis, cumulative evidence suggests that other lipids, such as fatty acids, are also involved in AD [3]. A previous clinical study demonstrated that patients with very mild AD or mild cognitive impairment could benefit from omega-3 fatty acid supplementation, implying the neuroprotective effect of omega-3 fatty acid [18]. Fatty acid homeostasis is reported to be disturbed in APOE ɛ4 carriers compared to the non-carriers [19], indicating that APOE ɛ4 may lead to a high risk of AD via a fatty acid-dependent approach. In addition, another research link neurogenesis impairments and AD-associated cognitive decline to brain abnormal fatty acid metabolism, and propose a critical role of fatty acid in regulating homeostasis [20]. However, the underlying mechanism that fatty acids participate in AD pathogenesis is not fully understood.

FABPs are small intracellular cytoplasmic proteins involved in the binding, transport, and metabolism of long-chain free fatty acids, which have been implicated in diabetes, obesity, and dyslipidemia [21, 22], and may also contribute to neurological disorders [23, 24]. FABPs can bind and regulate polyunsaturated fatty acid, including arachidonic acid and docosahexaenoic acid, which have been regarded as a protective factor against AD [25]. In addition, alternations in membrane lipid composition of the aging brain that are mediated by FABPs could be related to decreased membrane fluidity and result in neurotoxicity in neurodegenerative diseases [26].

As for FABP1, it may participate in AD progression in several ways. A recent study suggests that elevated FABP1 blocked the beneficial effect of exercise via inhibiting autophagy flux in a Non-alcoholic fatty liver disease mouse model [27]. FABP1-induced defective autophagy may be implicated in AD pathogenesis, and this helps to partially explain our finding that plasma FABP1 level is increased in the AD group. Another study found that increased FABP1 induced apoptosis and inhibited the proliferation and migration in vitro, implying the detrimental effect of FABP1 on cell viability [28]. The present study showed that plasma FABP1 is positively correlated with CSF t-tau and p-tau, and may affect neuronal loss in the brain, especially in the presence of over-produced Aβ. Cognitive impairment in AD may be also attributed to enhanced FABP1-induced cytotoxic effect to some extent. Furthermore, several studies suggested the potential of FABP1 in circulating blood as a biomarker for hepatic damage and indicated that elevated blood FABP1 levels were a prognostic factor for survival in chronic liver disease [29, 30], a condition closely related to AD [31]. The above evidence provides some clues to how FABP1 participates in AD. However, the causal relationship between FABP1 and AD could not be drawn in this cross-sectional study, despite the strength that all AD patients enrolled in this study were amyloid (+). Prospective studies with larger sample sizes or Mendelian randomization methods are needed to clarify this.

Recent research indicated the potential value of FABP as a diagnostic biomarker in neurodegenerative diseases. Serum B-FABP is reported elevated in patients with dementia-related diseases [8]. Furthermore, H-FABP was elevated in the CSF of Creutzfeldt-Jakob Disease and Lewy body dementia patients compared to patients with AD [9]. Another study demonstrated that the ratio of serum H-FABP to CSF tau protein represents a candidate marker for the differential diagnosis between AD and Lewy body dementia [32]. The ratios of different biomarkers as novel diagnostic indicators have been widely used in AD. These potential indicators are but are not limited to CSF Aβ₄₂/Aβ₄₀, CSF t-tau/p-tau, and CSF p-tau/Aβ₄₂. The current study used a similar approach to generate new indicators which have proven to be diagnostic promising. We firstly provide the evidence that plasma FABP1/t-tau and FABP1/Aβ₄₂ may be a potential biomarker for distinguishing AD patients from CN, but it seems to be inapplicable when using FABP1 alone. Although CSF biomarkers already have high sensitivity and specificity in the diagnosis of AD, studies on novel blood biomarkers of AD are still attractive due to their convenience and non-invasiveness in clinical practice. The current study revealed that the combination of FABP1/t-tau, or FABP1/Aβ₄₂ with other common blood biomarkers, including Aβ₄₂, Aβ₄₀, or t-tau, shows better diagnostic efficacy than each blood biomarker alone in the diagnosis of AD. Further studies are encouraged to validate the diagnostic value of FABP1/t-tau and FABP1/Aβ₄₂ at different stages of AD. Of note, one of the limitations of the present study is that subjects enrolled in the CN group may unavoidably include some preclinical AD. However, because all AD dementia patients are amyloid positive who represent the late biological stage of AD, the conclusions would not be affected, even if some preclinical AD patients in the CN group represent the very early stage of AD.

In conclusion, the plasma levels of FABP1 are elevated in AD patients and correlated with CSF t-tau and p-tau levels. The AD diagnostic value of common plasma biomarkers is better when combined with FABP1/Aβ₄₂ or FABP1/t-tau. Future studies are warranted to reveal the role of FABP1 in the pathogenesis of AD.

Footnotes

ACKNOWLEDGMENTS

This work was supported by the National Natural Science Foundation of China (grant no. 81870860).

Authors’ disclosures available online .

References

Selkoe

(2001) Alzheimer’s disease: Genes, proteins, and therapy. Physiol Rev 81, 741–766.

Ittner

, Gotz

(2011) Amyloid-beta and tau–a toxic pas de deux in Alzheimer’s disease. Nat Rev Neurosci 12, 65–72.

Mallick

, Basak

, Duttaroy

(2021) Fatty acids and evolving roles of their proteins in neurological, cardiovascular disorders and cancers. Prog Lipid Res 83, 101116.

Hamilton

, Dufresne

, Joppe

, Petryszyn

, Aumont

, Calon

, Barnabe-Heider

, Furtos

, Parent

, Chaurand

, Fernandes

(2015) Aberrant lipid metabolism in the forebrain niche suppresses adult neural stem cell proliferation in an animal model of Alzheimer’s disease. Cell Stem Cell 17, 397–411.

Kunkle

, Grenier-Boley

, Sims

, Bis

, Damotte

, Naj

, Boland

, Vronskaya

, van der Lee

, Amlie-Wolf

et al,. (2019) Genetic meta-analysis of diagnosed Alzheimer’s disease identifies new risk loci and implicates Abeta, tau, immunity and lipid processing. Nat Genet 51, 414–430.

Sims

, Hill

, Williams

(2020) The multiplex model of the genetics of Alzheimer’s disease. Nat Neurosci 23, 311–322.

Hotamisligil

, Bernlohr

(2015) Metabolic functions of FABPs–mechanisms and therapeutic implications. Nat Rev Endocrinol 11, 592–605.

Teunissen

, Veerhuis

, De Vente

, Verhey

, Vreeling

, van Boxtel

, Glatz

, Pelsers

(2011) Brain-specific fatty acid-binding protein is elevated in serum of patients with dementia-related diseases. Eur J Neurol 18, 865–871.

Steinacker

, Mollenhauer

, Bibl

, Cepek

, Esselmann

, Brechlin

, Lewczuk

, Poser

, Kretzschmar

, Wiltfang

, Trenkwalder

, Otto

(2004) Heart fatty acid binding protein as a potential diagnostic marker for neurodegenerative diseases. Neurosci Lett 370, 36–39.

10.

Desikan

, Thompson

, Holland

, Hess

, Brewer

, Zetterberg

, Blennow

, Andreassen

, McEvoy

, Hyman

, Dale

Alzheimer’s Disease Neuroimaging Initiative (2013) Heart fatty acid binding protein and Abeta-associated Alzheimer’s neurodegeneration. Mol Neurodegener 8, 39.

11.

Conway

, Larouche

, Alata

, Vandal

, Calon

, Plourde

(2014) Apolipoprotein E isoforms disrupt long-chain fatty acid distribution in the plasma, the liver and the adipose tissue of mice. Prostaglandins Leukot Essent Fatty Acids 91, 261–267.

12.

Wang

, Zhou

, Li

, Zhang

, Deng

, Tang

, Gao

, Li

, Lian

, Chen

(2006) Leisure activity and risk of cognitive impairment: The Chongqing aging study. Neurology 66, 911–913.

13.

McKhann

, Knopman

, Chertkow

, Hyman

, Jack

, Jr. , Kawas

, Klunk

, Koroshetz

, Manly

, Mayeux

, Mohs

, Morris

, Rossor

, Scheltens

, Carrillo

, Thies

, Weintraub

, Phelps

(2011) The diagnosis of dementia due to Alzheimer’s disease: Recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement 7, 263–269.

14.

Zeng

, Zou

, Zhou

, Li

, Wang

, Cao

, Yi

, Wang

, Liang

, Wang

, Zhang

, Tan

, Peng

, Zhang

, Gao

, Xu

, Wen

, Lian

, Zhou

, Wang

(2013) The relationship between single nucleotide polymorphisms of the NTRK2 gene and sporadic Alzheimer’s disease in the Chinese Han population. Neurosci Lett 550, 55–59.

15.

Hansson

, Seibyl

, Stomrud

, Zetterberg

, Trojanowski

, Bittner

, Lifke

, Corradini

, Eichenlaub

, Batrla

, Buck

, Zink

, Rabe

, Blennow

, Shaw

, Swedish

Fsg

Alzheimer’s Disease Neuroimaging Initiative (2018) CSF biomarkers of Alzheimer’s disease concord with amyloid-beta PET and predict clinical progression: A study of fully automated immunoassays in BioFINDER and ADNI cohorts. Alzheimers Dement 14, 1470–1481.

16.

Schindler

, Gray

, Gordon

, Xiong

, Batrla-Utermann

, Quan

, Wahl

, Benzinger

TLS

, Holtzman

, Morris

, Fagan

(2018) Cerebrospinal fluid biomarkers measured by Elecsys assays compared to amyloid imaging. Alzheimers Dement 14, 1460–1469.

17.

Harari

, Cruchaga

, Kauwe

, Ainscough

, Bales

, Pickering

, Bertelsen

, Fagan

, Holtzman

, Morris

, Goate

, Alzheimer’s Disease Neuroimaging Initiative (2014) Phosphorylated tau-Abeta42 ratio as a continuous trait for biomarker discovery for early-stage Alzheimer’s disease in multiplex immunoassay panels of cerebrospinal fluid. Biol Psychiatry 75, 723–731.

18.

Hooijmans

, Pasker-de Jong

, de Vries

, Ritskes-Hoitinga

(2012) The effects of long-term omega-3 fatty acid supplementation on cognition and Alzheimer’s pathology in animal models of Alzheimer’s disease: A systematic review and meta-analysis. J Alzheimers Dis 28, 191–209.

19.

Chouinard-Watkins

, Plourde

(2014) Fatty acid metabolism in carriers of apolipoprotein E epsilon 4 allele: Is it contributing to higher risk of cognitive decline and coronary heart disease? Nutrients 6, 4452–4471.

20.

Hamilton

, Fernandes

KJL

(2018) Neural stem cells and adult brain fatty acid metabolism: Lessons from the 3xTg model of Alzheimer’s disease. Biol Cell 110, 6–25.

21.

Nemecz

, Schroeder

(1991) Selective binding of cholesterol by recombinant fatty acid binding proteins. J Biol Chem 266, 17180–17186.

22.

Martin

, Atshaves

, McIntosh

, Mackie

, Kier

, Schroeder

(2006) Liver fatty acid binding protein gene ablation potentiates hepatic cholesterol accumulation in cholesterol-fed female mice.. Am J Physiol Gastrointest Liver Physiol 290, G36–48.

23.

Matsumata

, Inada

, Osumi

(2016) Fatty acid binding proteins and the nervous system: Their impact on mental conditions. Neurosci Res 102, 47–55.

24.

Cheng

, Jia

, Kawahata

, Fukunaga

(2021) Impact of fatty acid-binding proteins in alpha-synuclein-induced mitochondrial injury in synucleinopathy. Biomedicines 9, 560.

25.

Tomata

, Larsson

, Hagg

(2020) Polyunsaturated fatty acids and risk of Alzheimer’s disease: A Mendelian randomization study. Eur J Nutr 59, 1763–1766.

26.

Yang

, Askarova

, Lee

(2010) Membrane biophysics and mechanics in Alzheimer’s disease. Mol Neurobiol 41, 138–148.

27.

, Liu

, Xi

, Chen

, Tian

, Xie

, Chen

, Wang

, Yang

, Yu

, Zhou

, Gao

(2019) Long-term exercise prevents hepatic steatosis: A novel role of FABP1 in regulation of autophagy-lysosomal machinery. FASEB J 33, 11870–11883.

28.

Lin

, Wu

, Zheng

, Zhang

, Chen

, Zhan

, An

(2021) Mechanistic investigation on the regulation of FABP1 by the IL-6/miR-603 signaling in the pathogenesis of hepatocellular carcinoma. Biomed Res Int 2021, 8579658.

29.

Eguchi

, Iwasa

(2021) The role of elevated liver-type fatty acid-binding proteins in liver diseases. Pharm Res 38, 89–95.

30.

Eguchi

, Hasegawa

, Iwasa

, Tamai

, Ohata

, Oikawa

, Sugaya

, Takei

(2019) Serum liver-type fatty acid-binding protein is a possible prognostic factor in human chronic liver diseases from chronic hepatitis to liver cirrhosis and hepatocellular carcinoma. Hepatol Commun 3, 825–837.

31.

Bassendine

, Taylor-Robinson

, Fertleman

, Khan

, Neely

(2020) Is Alzheimer’s disease a liver disease of the brain? J Alzheimers Dis 75, 1–14.

32.

Mollenhauer

, Steinacker

, Bahn

, Bibl

, Brechlin

, Schlossmacher

, Locascio

, Wiltfang

, Kretzschmar

, Poser

, Trenkwalder

, Otto

(2007) Serum heart-type fatty acid-binding protein and cerebrospinal fluid tau: Marker candidates for dementia with Lewy bodies. Neurodegener Dis 4, 366–375.