Research investigates roles of neurotrophic factors on cognition in Alzheimer's patients carrying APOE ε4

By Pooja Toshniwal PahariaReviewed by Benedette Cuffari, M.Sc.Mar 1 2023

In a recent study under review at the Alzheimer's Research & Therapy journal and currently posted to the Research Square* preprint server, researchers investigate the role of neurotrophic factors (NFs) on the cognitive performance of Alzheimer’s disease (AD) patients carrying the apolipoprotein E (APOE) ε4 gene.

Study: Role of nerve growth factor on cognitive impairment in Alzheimer's disease patients carrying apolipoprotein E ε4. Image Credit: Atthapon Raksthaput / Shutterstock.com 

*Important notice: Research Square publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.

Background

The APOE ε4 gene is a strong known risk factor for the spontaneous development of AD. In fact, several studies have reported an earlier onset, faster cognitive decay, and worse cognition-related outcomes among APOE ε4 carriers than non-carriers.

APOE ε4 reportedly mediates synaptic dysfunctions and aggravates cognitive decline by promoting neuropathological protein deposition and inducing neurological inflammation among AD patients. However, the impact of APOE ε4 levels on cranial neurotrophy is unclear.  

Abnormal NF levels have been correlated with the neuropathological progression of cognitive decay among AD patients. Nevertheless, data on the correlations between NF levels in cerebrospinal fluid (CSF) with APOE ε4 levels and different cognitive domain functions are limited.

About the study

In the present cross-sectional study, researchers investigate the associations between APOE ε4 levels, NF levels in CSF, and cognition among AD patients.

Individuals were recruited for the study from the Center for Cognitive Neurology at the Tiantan Hospital and Capital Medical University of Beijing. A total of 173 AD patients were divided into APOE ε4 carrier and non-carrier groups.

AD was diagnosed using the National Institute of Aging and Alzheimer’s Association (NIA-AA) diagnosis criteria. Blood and CSF samples were obtained from the patients, and APOE single nucleotide variants (SNVs) rs7412C/T and rs429358 C/T, as well as APOE ε2, ε3, and ε4 alleles were genotyped using quantitative real-time polymerase chain reaction.

The levels of NFs, such as the nerve growth factor (NGF), brain-derived NF (BDNF), and glial cell-derived NF (GDNF), in CSF were measured using enzyme-linked immunosorbent assays (ELISA).

The team excluded individuals suffering from diseases that could contribute to altered cognition, such as frontotemporal dementia, Lewy body dementia, progressive-type aphasia, cortico-basal degeneration, multiple sclerosis, Parkinson’s disease, and epilepsy. In addition, individuals with systematic disorders of high severity, chronic-type wasting diseases, active infections, autoimmune disorders, hematological disorders, and malignancies, those with a recent history of traumatic brain injuries and major surgeries, and those on steroids were excluded.

Demographic data on age, sex, body mass index (BMI), age at disease onset, educational status, alcohol intake, and smoking habits were obtained. In addition, data were obtained on medical diseases such as diabetes mellitus, hyperlipidemia, atrial fibrillation, hypertension, and myocardial infarction.

Overall cognition was measured using the Montreal cognitive assessment (MoCA) and mini-mental state examination (MMSE) scales. Visual delayed-type memory was assessed using the rey-osterreithm complex figure test (RCFT)-delayed-type recall, whereas verbal memory was assessed through the auditory verbal learning test (AVLT).

Language ability was assessed using the Boston naming test (BNT) and verbal fluency test (VFT), whereas attention was assessed using the trail-making test (TMT)-A, Stroop colour-word Test (SCWT) parts A and B, and symbol digit modalities test (SDMT). Executive functions were assessed using TMT-B and SCWT-C.

Results

In total, 173 patients were recruited into the study, 32% of whom carried APOE ε4, and 62% were women. The average age of the study cohort was 66 years and the median duration of disease was 24 years among APOE ε4 carriers.

Several domains and global cognitive functions were impaired with lowered CSF NGF levels among APOE ε4 carriers. NGF levels also correlated with several domains and global cognitive functions, with NGF-mediated associations observed between APOE ε4 and language and attention/executive function.

APOE ε4 was related to lower scores of MoCA, AVLT N1-3, AVLT N1-5, AVLT N6, AVLT N7, and AFT, with β values of -2.3, -2.4, -4.2, -1.0, -2.6, and -2.1, respectively. Comparatively, APOE ε4 carriers showed greater TMT-A duration with a β value of 0.5.

NGF expression among APOE ε4+/- individuals was markedly lower as compared to the levels among APOE ε4-/- individuals and was the least among APOE ε4+/+ individuals. APOE ε4 was related to lower CSF NGF levels after adjusting for sex, age, age at disease onset, duration of disease, educational status, and BMI values (β -2.0).

NGF expression showed significant and positive associations with MMSE scores, RCFT-delayed scores, AFT, and VFT-alternating fluency, with β values of 0.3, 0.5, 0.4, and 0.3, respectively.

NGF expression correlated significantly but negatively with TMT-A duration with a β value of -0.1. Furthermore, NGF expression positively correlated with SCWT-B scores with a β value of 0.7, thus reflecting attention/executive functions.

Concerning memory, NGF expression showed significant and positive associations with AVLT N1-3, AVLT N4, AVLT N1-5, and RCFT-delayed scores, with β values of 0.5, 0.2, 0.6, and 1.3, respectively.

In regard to language, NGF expression showed a significant positive association with VFT-alternating fluency scores with a β value of 0.4. NGF CSF expression significantly regulated the associations of APOE ε4 with AFT and AFT TMT-A duration, with β values of -0.5 and 0.2, respectively.

Conclusions

Among AD patients, APOE ε4 levels appear to relate to cognitive decline, with APOE ε4 carriers having lower NGF levels in CSF than APOE ε4 non-carriers. Lower NGF levels correlated with cognitive impairments and NGF-mediated APOE ε4-associated cognitive decay.

*Important notice: Research Square publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.