Cognitive Improvement After Multi-Domain Lifestyle Interventions in an APOE ɛ4 Homozygous Carrier with Mild Cognitive Impairment: A Case Report and Literature Review

Abstract

Alzheimer’s disease (AD) is a degenerative disease of the central nervous system with insidious onset and chronic progression. The pathogenesis of AD is complex, which is currently considered to be the result of the interaction between genetic and environmental factors. The APOE ɛ4 is the strongest genetic risk factor for sporadic AD and a risk factor for progression from mild cognitive impairment (MCI) to AD. So far, no effective drugs have been found for the progression of MCI. However, the effects of nonpharmacological interventions such as nutrition, cognitive, and physical exercises on early AD have received increasing attention. We followed up cognitive assessment scales, Aβ-PET and MRI examination of a patient with MCI for 4 years, who carried APOE ɛ4 homozygous with a clear family history. After 4 years of multi-domain lifestyle interventions including nutrition, socialization, and physical exercises, the patient’s cognitive function, especially memory function, improved significantly. Intracerebral amyloid deposition was decreased, and hippocampal atrophy improved. Based on this case, this study reviewed and discussed the interaction of APOE ɛ4 with the environment in AD research in recent years, as well as the impact and mechanisms of non-pharmaceutical multi-domain lifestyle interventions on MCI or early AD. Both the literature review and this case showed that multi-domain lifestyle interventions may reduce the risk of disease progression by reducing Aβ deposition in the brain and other different pathologic mechanisms, which offers promise in brain amyloid-positivity or APOE ɛ4 carriers.

Keywords

Alzheimer’s disease diet genetic risk effect mild cognitive impairment nutrition physical activities social contacts

INTRODUCTION

Alzheimer’s disease (AD) is a degenerative disease of the central nervous system with insidious onset and chronic progression. It is the most common type of senile dementia. The pathogenesis of AD is complex, which is currently considered to be the result of the interaction of genetic and environmental factors. Apolipoprotein (APOE) is one of the genes closely associated with sporadic AD. There are three major alleles ɛ2, ɛ3, and ɛ4, encoding three APOE isomers E2, E3, and E4. So, there are six different APOE phenotypes in the population: three homozygous (E2/2, E3/3, E4/4) and three heterozygous (E3/2, E4/2, E4/3). APOE polymorphism was closely related to AD occurrence [1]. The APOE ɛ4 is the strongest genetic risk factor for sporadic AD, and the APOE ɛ2 is the strongest genetic protection factor [2]. A common hypothesis is that APOE ɛ4 carriers are more susceptible to the harmful effects of environmental risk factors. In addition, studies have found that APOE ɛ4 genotype is also a risk factor of progression from mild cognitive impairment (MCI) to AD [3].

It is generally believed that AD has a long preclinical or asymptomatic period. MCI is an intermediate state between normal cognition and clinical dementia, with a high risk of progression to AD, and is considered as the prodromal stage of AD [4]. Early detection and intervention of MCI is of great significance for delaying the transformation of MCI to AD and reducing the incidence of AD. So far, no effective drugs have been found for the progression of MCI. In this context, the effect of nonpharmacological interventions such as nutrition, social contacts, and physical activities on early AD has received increasing attention [5].

We followed up cognitive assessment scales, Aβ-PET, and MRI examination of a patient with MCI for 4 years, who carried APOE ɛ4 homozygous with a clear family history. After 4 years of multi-domain lifestyle interventions including nutrition, socialization, and physical exercises, the patient’s cognitive function, especially memory function, improved significantly. Decreased amyloid deposition in the brain and improved hippocampal atrophy were also observed. Based on this case, this study reviewed and discussed the interaction of APOE ɛ4 with the environment in AD research in recent years, as well as the impact and mechanisms of non-pharmaceutical multi-domain lifestyle interventions on MCI or early AD.

CASE DESCRIPTION

Clinical manifestations

The patient was a 58-year-old female in 2021 who provided written informed consent to participate in this study. She was admitted to the cognitive clinic in December 2017. The patient’s Chief Complaint was a decrease in memory, concentration and reading abilities at that time. The patient graduated from university. She used to have a good memory. She easily remembered complicated work reports and the names of new friends. The patient has strong reading ability and clear working thinking. As a general manager, she was able to manage more than 400 people with ease. The patient began to experience memory loss a year ago. She often forgot planned events and the names of acquaintances. Her concentration and reading skill also declined significantly. She was too fidgety to read some slightly longer emails or documents (more than 2000 words). Another thing that annoyed her was that she had gotten lost many times. Once she drove the wrong way to an appointment, and another time she could not find the exit in the community parking lot. The patient was extrovert and gentle. There was no significant change in her emotional character and personality. The patient’s appetite, weight, sleep, defecation, and urination were normal. Her family and work assistants confirmed the reliability of the above symptoms.

The patient was healthy in the past, denied the history of major organ diseases, denied the history of “hypertension, diabetes, coronary heart disease”, denied the history of trauma, surgery and blood transfusion, and had an unknown history of vaccination. The patient was not addicted to alcohol or tobacco. She denied taking any drugs and nutrients to improve memory or cognition.

After active intervention and follow-up for 4 years, the above-mentioned related symptoms have not appeared at present. The patient had no previous similar problems in life or work. Her memory and concentration improved significantly. Now she likes to read books and can read more words. The assistant or her family rated her performed positively and said her cognitive impairment had improved significantly.

Cognitive assessment scales

The one-to-one neuropsychological assessment were conducted by professional neuropsychological evaluators. The patient had received three follow-up tests in December 2017, December 2018 and April 2021, which included cognitive screening scales, memory, language, executive function, and attention scales. The scales were as follows:

Cognitive screening scales: Mini-Mental State Examination (MMSE) [6], Montreal cognitive assessment-basic (MOCA-B) [7].

Memory assessment scales: Auditory verbal learning test (AVLT) [8] delay recall and recognition, Rey-Osterrich complex figure test (Rey-O) [9] copy and delay recall.

Language assessment scales: Animal fluency test (AFT) [10] and Boston naming test (BNT) [11].

Executive function assessment scales: Shape trails test-A (STT-A) and Shape trails test-B (STT-B) [12].

Attention assessment scales: Symbol digit modalities test (SDMT) [13].

In 2017, the cognitive scale scores of the patient showed impaired memory function, mainly manifested in AVLT-Delay 4 points, AVLT-Recog 22 points, Rey-O-copy 31 points, and Rey-O-Delay 10 points, which were consistent with her clinical manifestations, and she was diagnosed as amnestic mild cognitive impairment (aMCI). After 4 years of follow-up with the cognitive scales, the patient showed significant improvement in cognitive function, especially memory function according to AVLT (Table 1).

Table 1

Comparison of cognitive assessment scales for 3 times during 4 years

Scales	Dec 2017	Dec 2018	Apr 2021
MMSE	28	30	28
MOCA-B	27	30	30
AVLT-delay	4	12	11
AVLT-recog	22	24	24
Rey-O-copy	31	/	/
Rey-O-delay	10	/	/
AFT	21	16	18
BNT	27	26	26
STT-A	/	45	31
STT-B	/	81	81
SDMT	/	56	44

Cognitive screening scales: Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment-basic (MOCA-B). Memory assessment scales: Auditory Verbal Learning Test (AVLT) delay recall and recognition. Rey-Osterrich complex figure test (Rey-O) copy and delay recall. Language assessment scales: Animal fluency test (AFT) and Boston Naming Test (BNT). Executive function assessment scales: Shape Trails Test-A (STT-A) and Shape Trails Test-B (STT-B). Attention assessment scales: Symbol Digit Modalities Test (SDMT).

In addition, the patient was tested with the depression symptom questionnaire (score 0 / total 84), Hamilton depression (score 0 / total 17), anxiety (score 0 / total 14) scales, and Neuropsychiatric Inventory-Questionnaire (score 2 / total 36) at her first visit. According to the above scales and performance, the patient’s depression, anxiety and other mental and behavioral problems were excluded.

The APOE genotype and family history

APOE genotype was detected by the amplification refractory mutation system (ARMS)-polymerase chain reaction (PCR) assay in December 2017. Genomic DNA for APOE genotype was extracted from peripheral blood mononuclear cells with the Genomic DNA Purification System (Promega, Madison, WI, USA). Briefly, the PCR method and primers were conducted according to the research report [14]. The result showed homozygous mutation at site 112 of APOE gene, but no mutation at site 158. The patient is an APOE ɛ4/ɛ4 carrier. The patient’s mother began to experience progressive memory loss at age of 72 and was diagnosed with AD.

Multi-domain lifestyle interventions

Diet and nutrition: The patient adhered to a bland diet. The patient planned meals with reference to a Healthy Mediterranean-Style Eating Pattern at the 2,000-calorie level. She consumed 2½ cup(c)-equivalents(eq) vegetables, 2½ c-eq fruit, 6 ounce(oz)-eq grains, 2 c-eq dairy, 6½ oz-eq proteins food, and 27 grams(g) oil per day. She paid attention to eating lots of red and orange vegetables (5½ c-eq/week) such as tomatoes, carrots, tomato juice, sweet potatoes, etc., and starchy vegetables (5 c-eq/week) such as potatoes, corn, green peas, cassava, etc., with limited additions such as salt, butter, or creamy sauces. The patient’s bland diet included whole grains and restricted intake of refined grains and products made with refined grains. When selecting protein foods, unsalted nuts and seeds she would choose, and meats and poultry would be consumed in lean forms. She took proper supplements after 2017, including coconut oil, kinadol, cellular phosphocholine, souvenaid (docosahexaenoic acid (DHA), eicosapentaenoic acid (EPA), uridine monophosphate, choline; Vitamins B12, B6, C, E and folic acid, phospholipids, and selenium), spirulina, and fish oil.

Social contacts: The patient liked to read and express. She liked to tell her friends what she is reading. In her spare time, she usually played poker and mahjong and traveled with friends. She insisted on learning cucurbit flute and had reached the level of playing simple songs. She had been learning English for more than three years. Every month, she had no less than 15 one-on-one classes with her foreign teacher. Before each class, she spent nearly 2 hours preparing for smooth communicate with the foreign teacher. She managed a team of over 400 people who were motivated and performed well.

Physical activities: For 4 years, the patient arranged plans according to her physical condition, and performed at least 150 minutes of moderate-intensity training and appropriate muscle-strengthening activities per week. The schedule included doing yoga in the morning and jogging or walking in the evening. She used a pedometer to ensure no less than 10,000 steps every day while self-monitoring physical activities.

The patient was followed up by telephone every six months and face-to-face annually. At the regular follow-up visits, the physician would assess the patient’s adherence to the multi-domain lifestyle interventions, provide feedback to the patient, answer any questions the patient and family may have, and address issues related to following a bland diet and the proper supplements, social connectivity, or physical training.

¹⁸F-AV45 PET examination

The patient underwent ¹⁸F-AV45PET examination twice in PET Center of Huashan Hospital affiliated to Fudan University in December 2017 and April 2021 to observe the deposition of amyloid protein in the brain. After resting for 15 min in a quiet state, patients were intravenously injected ¹⁸F-AV45 (5.55 mbp/kg). After resting for 50 min, brain PET/CT imaging was performed for 10 s low-dose head CT scan and 20 min PET scan in 3D mode (Biograph 64 PET/CT instrument of Siemens, Germany). PET image reconstruction adopted filtering back projection method to fuse reconstructed PET and CT images. SPM12 software was used for image preprocessing. MRI T1 image was six-parameter fused with ¹⁸F-AV45 PET image. T1 image was transformed into standard space by unified segmentation algorithm to realize the spatial standardization of PET image. Definition of gray matter cortical Region of Interest (ROI) was based on AAL (Automated Anatomical localization) Brain Map, containing only the voxels that are partitioned into gray matter in the tissue probability map. There were 12 ROIs and standardized uptake value ratio (SUVR) of Aβ plaque deposition in each ROI was calculated using the cerebellar gray matter region as the reference area.

The results of ¹⁸F-AV45 PET in December 2017: The radioactivity distribution in cerebral cortex was slightly increased. It was particularly evident in the following areas: bilateral frontal lobe (SUVR = 1.40), parietal lobe (SUVR = 1.40), temporal lobe (SUVR = 1.40), and posterior cingulate gyrus (SUVR = 1.10). The distribution of radioactivity in white matter, brainstem, and occipital lobe, and radioactive elution in cerebellar cortex were normal (SUV = 0.84). The visual analysis results of PET images were amyloid deposition in bilateral frontal lobe, parietal lobe, temporal lobe, and posterior cingulate cortex.

The results of ¹⁸F-AV45 PET in April 2021: The radioactivity distribution in cerebral cortex was no significant increased, bilateral frontal lobe (SUV = 1.20), parietal lobe (SUV = 1.08), temporal lobe (SUV = 1.09), and posterior cingulate gyrus (SUV = 1.23). The distribution of radioactivity in white matter, brainstem and occipital lobe, and radioactive elution in cerebellar cortex (SUV = 0.90) were normal. The visual analysis results of PET images showed no abnormal deposition of amyloid in the cerebral cortex.

The comparison results of the above two ¹⁸F-AV45 PET images: The overall SUVR value of cerebral cortex decreased by 4% in 2021 compared with 2017. SUVR value in each brain region was compared between 2021 and 2017, and the different proportions of decrease were found as follows: Caudate nucleus (12.77%), insular lobe (7.56%), anterior cingulate gyrus (6.34%), frontal lobe (6.12%), parietal lobe (5.71%), temporal lobe (3.13%), globus pallidus (3.02%), putamen (2.84%), precuneus (2.70%), posterior cingulate gyrus (2.08%), occipital lobe (1.99%), and thalamus (0.35%) (Fig. 1).

Fig. 1

Comparison of ¹⁸F-AV45 PET between December 2017 and April 2021. A) Images of ¹⁸F-AV45 PET in December 2017 and April 2021. Coronal section (a,d); Median sagittal section (b,e); Transverse section (c,f). B) Comparison of SUVR values in different brain regions. C) Percentage of SUVR declines in different brain regions. Definition of gray matter cortical region of interest (ROI) was based on AAL (Automated Anatomical localization) Brain Map. There are 12 ROIs and Total cerebral cortex.

MRI examination

MRI scanning was performed with a 3.0T high-field superconducting MRI instrument (Skyra 3.0T, Siemens, Germany). Rapid T1 estimation used tagged magnetization-prepared gradient-echo MR imaging. The patient underwent brain MRI in December 2017 and April 2021, and the results were as follows: there was no visible difference about scattered ischemic foci in bilateral frontal and parietal lobes, and slight deep white matter lesions (Fazekas grade I) in both MRI. In 2017, she had a grade 1 hippocampal atrophy rating, according to the MTA. Surprisingly, the brain MRI in 2021 revealed that her hippocampal atrophy had a grade 0 rating, according to the MTA (Fig. 2). Her MRI of 2021 shows a fuller hippocampus than that of 2017. After four years of lifestyle interventions, her hippocampus atrophy was significantly improved.

Fig. 2

MTA grading of hippocampus in brain MRI of December 2017 and April 2021. Grade 1 hippocampal atrophy rating in January 2017 and a grade 0 rating in April 2021, according to the MTA.

DISCUSSION

APOE ɛ4 allele is the strongest genetic risk factor for sporadic AD. Homozygous APOE ɛ4 carriers typically develop earlier onset than heterozygous carriers, highlighting the dose effect of ɛ4 allele on AD. One ɛ4 allele increases the risk of AD by approximately 2 to 6 times, while the presence of two ɛ4 alleles increase the risk by 7.2 to 21.8 times [15, 16]. In the case, the patient was homozygous for APOE ɛ4, with a clear family genetic history, and her mother was an AD patient. She was 54 years old when she began to experience significant declines in cognitive function and memory. She often forgot planned events and the names of acquaintances. Her reading ability also declined markedly. In addition, the patient lost her way while driving, indicating a decrease in her spatial orientation. Combined with her neuropsychological scales, she was diagnosed with aMCI. This case suggested that APOE ɛ4 homozygous carriers have significantly earlier onset of disease. Without effective interventions, the disease progresses and eventually develops into AD.

PET imaging revealed pathological deposition of Aβ protein in the brain, indicating that APOE ɛ4 is closely related to AD pathology. Compared with APOE ɛ3 homozygous carriers, APOE ɛ4 carriers had more Aβ deposition in the cerebral cortex and more severe intracerebral amyloid vascular lesions in the brain, while APOE ɛ2 carriers had lower Aβ deposition in the cerebral cortex [17, 18]. The relationship between APOE ɛ4 allele and AD pathophysiology involves multiple mechanisms. The underlying mechanisms of Aβ metabolism driven by APOE isoforms, including Aβ production, aggregation, and clearance, remain controversial. In vitro and in vivo studies have shown that APOE interacts with Aβ to promote its aggregation and deposition in insoluble fibrous deposits. Compared with APOE2 and APOE3, APOE4 promoted the incorporation of Aβ peptides into Aβ oligomers, fibrils, and fibers, inhibited Aβ clearance from the brain, prolonged its half-life in interstitial tissues, and inhibited its enzymatic degradation. Furthermore, both APOE and Aβ competed for the same receptor, low-density lipoprotein-related protein 1 (LRP1), which is involved in the clearance of Aβ by neurons, astrocytes, endothelial cells, vascular smooth muscle cells, and pericytes [1, 19]. In addition to the mechanisms described above, our understanding of APOE pathogenesis has extended to other non-amyloid pathogenesis mechanisms, including tau phosphorylation and neurofibrillary, microglia, and astrocyte responses, as well as responses to the blood-brain barrier and neuronal [2 , 21]. These mechanisms may increase the susceptibility of APOE ɛ4 carriers to neuropathological changes and subsequent cognitive decline.

However, it is important to note that APOE ɛ4 carriers do not necessarily become AD patients. The risk associated with APOE ɛ4 varies by age and race. There are other risk factors that may play important roles in the development of disease. The main factor contributing to AD susceptibility in APOE ɛ4 carriers is their interaction with environmental factors, which means that APOE ɛ4 carriers are more susceptible to the deleterious effects of environmental risk factors [22 –24]. One of the main concerns of AD prevention strategies is whether genetically susceptible individuals can benefit from preventive lifestyle interventions, so this case has positive practical implications. At four years of follow-up, the APOE ɛ4 allele did not appear to prevent the benefit of the intervention. In fact, several studies suggested that multi-domain lifestyle interventions might be more protective in individuals susceptible to neurodegeneration disease or cognitive impairment (e.g., brain amyloid-positive or APOE ɛ4 carriers) [25]. Multi-domain lifestyle interventions can significantly delay AD progression before the onset of significant clinical symptoms. Clinical trials in recent years have shown promising results from non-pharmacological approaches in multi-domains, including dietary nutrition, social contacts, cognitive training, and physical exercises. A randomized controlled trial (RCT) study demonstrated that omega-3 fatty acids combined with aerobic exercise and cognitive stimulation could prevent atrophy and cognitive decline in brain regions associated with MCI [5]. A 2-year randomized clinical trial involving six medical centers in Finland, the Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER), showed beneficial clinical effects of early lifestyle interventions in APOE ɛ4 carriers. The intervention group added four interventions to the control group: nutritional interventions, cognitive exercises, physical exercises, and a vascular risk factor management program. Within-group analyses of APOE ɛ4 (–) and APOE ɛ4 (+) were performed. The results showed significant improvement in NTB (Neuropsychological Test Battery) scores and complex memory tests in APOE ɛ4 carriers after the interventions [3]. This suggested that in addition to genes, environmental factors may also influence cognitive resilience in APOE ɛ4 carriers. We may be able to modify environmental factors to delay cognitive decline in these high-risk individuals. Multi-domain lifestyle interventions simultaneously target multiple modifiable risk factors and cover multiple mechanisms [26].

Nutrition is an important lifestyle factor that can modify the risk of future cognitive impairment and dementia. The studies included single nutrients, multi-nutrients and dietary patterns. There appeared to be more evidence that multi-nutrient supplementation can delay cognitive decline compared to single-nutrients supplements. In Soininen’s 2020 randomized, double-blind, placebo-controlled clinical trial of LipiDiDiet in 311 patients with prodromal AD, the intervention group was given Fortasyn Connect (Souvenaid) nutritional supplement, a multicomponent nutritional supplement: docosahexaenoic acid (DHA), eicosapentaenoic acid (EPA), uridine monophosphate, choline, vitamins B12, B6, C, E, folic acid, phospholipids, and selenium. The primary endpoint of prodromal AD was not statistically different between the two groups after two years of intervention [27]. However, after 3 years, reductions in clinical markers, such as memory, cognition, and brain atrophy, were observed in the intervention group [28]. These nutrients were selected for their established biological and neuroprotective properties to combine to form a nutrient mixture. Compared with a single nutrient, the intervention effect can be significantly improved. The multi-nutrient combination improves neuronal membrane composition, increase synaptic formation, cholinergic neurotransmission, cerebral blood flow and perfusion, and is beneficial for maintaining neural integrity, restoring hippocampal neurogenesis, and reducing amyloidosis. Therefore, it enhances cognition through various pathological processes associated with AD in vivo. The researchers concluded that early, long-term, and multi-nutrient combinations were key factors in the effectiveness of dietary interventions. This case in our study is consistent with the intervention experience of the LipiDiDiet clinical trial. The patient with MCI stage was treated with the long-term polytrophic combinations for 4 years. Even though she was a homozygous carrier for the APOE ɛ4 gene, nutritional intervention had important benefits. Currently, the evidence for associations between nutrition and cognitive outcomes for healthy dietary patterns, such as the Mediterranean-type diet, is somewhat stronger than for individual nutrients and food groups. The main food groups of the Mediterranean diet include: high consumption of fruits, vegetables, wholegrains, and olive oil; daily consumption of fermented dairy, nuts, seeds, herbs or spices; emphasize plant protein (legumes) and seafood over red meat; a moderate amount of wine; and herbal infusions consumed daily. Findings from most observational studies suggest that higher adherence to the Mediterranean diet is associated with a slower decline in performance on various cognitive test batteries and a reduced risk of dementia, mild cognitive impairment, or progression from mild cognitive impairment to dementia related [25 –29]. Four informative studies on this diet showed exactly protective effects against cognitive decline or dementia: the Washington Heights–Inwood Columbia Aging Project (WHICAP) [30], the Chicago Health and Aging Project (CHAP) [31], the Memory and Aging Project (MAP) [32], and Reasons for Geographic and Racial Differences in Stroke (REGARDS) [33]. Dietary Approaches to Stop Hypertension (DASH), which shares many similar components to the Mediterranean diet, is another dietary pattern associated with cognitive decline. Compared to the Mediterranean diet, DASH places more emphasis on limiting sodium, sugar and saturated fat intake. The results from multiple prospective studies and randomized controlled trials demonstrated the ability of the DASH dietary pattern to improve cognitive performance [34 –36]. A new diet called MIND (Mediterranean–DASH Intervention for Neurodegenerative Delay) combines many elements of the Mediterranean and DASH diets with a unique emphasis on the intake of leafy green vegetables and berries [37]. Higher adherence to the MIND diet was associated with less cognitive decline after a 6-year longitudinal follow-up of older Swedish adults (n = 2223) [38]. Additionally, higher MIND diet scores were also associated with less cognitive decline in a study including US adults (n = 960) [39].

In addition to dietary interventions, maintaining social connection was another factor in patient’s improved cognitive function. The patient enjoy reading, expressing and telling friends about the contents of reading. In her spare time, she usually played poker and mahjong and traveled with friends. She insisted on learning cucurbit flute and had reached the level of playing simple songs. She had been learning English for more than three years. Every month, she had no less than 15 one-on-one lessons with foreign teachers. Before each class, she spent nearly 2 hours preparing for smooth communicate with the foreign teacher. She managed a team of over 400 people who were motivated and perform well. The patient was followed up for 4 years, and cognitive function improved, suggesting that maintaining frequent social interactions in APOE ɛ4 homozygous patients has a positive effect on maintaining work and living abilities. Social contacts have been proved to reduce dementia risk and alleviate cognitive impairment [40 –42]. A longitudinal study using data from China Health and Retirement Longitudinal Study (CHARLS) found a significant link between lack of social contacts and cognitive decline [43]. In another study, researchers recruited patients with possible AD before the COVID-19 pandemic and followed up a year later during the COVID-19 pandemic. The results demonstrated that these patients experienced an accelerated decline in cognitive function due to reduced social contacts and physical activities as the result of the lockdown strategies adopted to effectively limit the COVID-19 epidemic [44]. Zhu et al. used population-based longitudinal data from Gothenburg, Sweden: the H70 Birth Cohort Study and the Prospective Population Study on Women (PPSW) to analyze the association between social networks, APOE ɛ4 allele, and dementia, they affirmed that social networks can positively affect individual mood, increase cognitive reserve, and improve the resilience and compensatory abilities of neuronal networks [45]. Various neurobiological mechanisms have been studied to help explain association of social contacts and dementia risk. One of the hypotheses states that social contact minimizes cardiovascular risk factors in patients, thereby reducing the risk of neurodegenerative diseases. Another more convincing hypothesis is that social contact increases cognitive reserve, and individuals with higher cognitive reserve have less neuropathy and atrophic changes in cognitive deficits [46, 47]. A retrospective cross-sectional study using data from 2,171 participants from the Framingham Study to explore the association between social support and global neuroanatomical measures of the brain in patients with early AD. The results showed that social support was associated with greater cognitive resilience and altered the relationship between lower total brain volume and worse cognitive function [48].

Physical activities are the third meaningful intervention in this case. For 4 years, the patient arranged plan according to her physical condition, with at least 150 minutes of moderate-intensity training and appropriate muscle-strengthening activities per week. The schedule included doing yoga in the morning and jogging or walking in the evening. She used a pedometer to ensure no less than 10,000 steps every day while self-monitoring physical activities. Growing studies support the value of regular physical activity in preventing AD and cognitive decline in patients [49, 50]. Some studies believe that aerobic exercise, resistance training, and tai chi can effectively delay cognitive decline. 45∼60 minutes of moderate-intensity exercise associated with cognitive benefits [51]. Although there was no consensus on the biological mechanisms underlying the benefits of physical activities, some studies suggested that regular physical exercises could control cardiovascular risk factors, increase neurotrophic factors (such as the brain derived neurotrophic factor), modulate immunity, inflammation, and mitochondrial function, improved the antioxidant capacity of the brain [52 –54]. However, other studies have reported that moderate-to-vigorous-intensity aerobic and strength exercises did not reduce cognitive impairment in people with mild-to-moderate dementia [55]. The Dementia and Physical Activity (DAPA) study is a randomized trial using an exercise program to target cognition in people with dementia. The intervention consisted of a supervised portion of a one-hour exercise class, including aerobic and resistance exercise, twice a week for 4 months [56, 57]. An exercise program including moderate-to-vigorous-intensity aerobic and strength training does not slow cognitive impairment in people with mild-to-moderate dementia, randomized trial suggests [58, 59]. More research is needed to explore the relationship between physical activities and cognition.

There are also numerous reports on the effects of cognitive training on MCI. Cognitive stimulation therapy (CST) as a cost-effective dementia therapy was one of the non-pharmacological cognitive training programs developed in the UK [60]. CST has been shown to improve and maintain cognition and quality of life in the United States. Another cognitive training program called SAIDO Learning has been shown to enhance cognitive performance by focusing on improving working memory [61]. The Body Brain Life for Cognitive Decline (BBL-CD) interventions are a suite of multi-domain, primary dementia risk reduction interventions that have been shown to improve cognitive performance in individuals with subjective cognitive decline (SCD) or MCI [62, 63]. A meta-analysis of 31 RCTs of cognitive training studies reported significant cognitive improvement after intensive or specific cognitive training procedures [64]. Cognitive exercises are a scientific evaluation and systematic training of cognitive ability designed according to the theory of neuroplasticity. The neurons and glia are connected to each other through synapses. Although the individual role of each neuron or functional brain region cannot be ignored, the network formed by these neurons or brain regions, as well as the mutual coordination and interaction between different parts of the network, are the fundamental reasons why individuals exhibit comprehensive behavior. Learning is the process of forming new connections and practice is the process of consolidating existing connections. Under certain conditions, these structures and networks of connections in the brain can be strengthened or weakened, a process known as neuroplasticity [65]. Changes in connections between neurons or brain networks can alter cognitive abilities, so neuroplasticity is the theoretical basis for cognitive exercises [66, 67].

In addition to the above domains, other factors are thought to play important roles in preventing dementia. According to 2020 report of the Lancet Commission, among middle-aged adults aged 45–65, obesity (body-mass index ≥30), hypertension, alcohol (>21 units/week), traumatic brain injury, and hearing loss are identified as risk factors, and in people over 65 years old, smoking, depression, diabetes, air pollution, etc., may increase the risk of dementia. Basic diseases such as hypertension and diabetes have been reported as risk factors for dementia, and the intervention of these diseases have a certain effect on reducing the risk of dementia [68 –70]. Several unhealthy lifestyle habits, such as excessive alcohol consumption, smoking, and sleep disturbances, have been reported to be associated with cognitive impairment [71 –73]. Developing healthy habits is able to prevent dementia.

CONCLUSION

This case is an MCI patient with a clear family history who is homozygous for APOE ɛ4. However, after 4 years of nutrition intervention, social contacts, and physical exercises, the patient’s cognitive function and living status improved. Decreased amyloid deposition in the brain and improved hippocampal atrophy were also observed. Both the literature review and this case suggested that a multi-domain lifestyle intervention might be more protective in individuals with predisposition to neurodegeneration or cognitive impairment (e.g., those with brain amyloid positivity or carriers of APOE ɛ4). The studies showed that multi-domain lifestyle interventions are more effective than single-domain intervention. Early interventions are essential to delay the progression of the disease. Other factors that influenced interventions effectiveness included participants’ adherence to and intensity to interventions. Multi-domain lifestyle interventions may reduce the risk of disease progression due to reduced Aβ deposition in the brain and other diverse pathologic mechanisms. As for the weight and specific mechanisms of various intervention factors, this case cannot draw a clear conclusion. But the effect of non-pharmacological interventions on APOE ɛ4 carriers offers a promising direction. There are still many unknown areas for multi-domain lifestyle interventions in MCI and early AD, including standardization of interventions for different populations, specific mechanisms of cognitive improvement, and the interaction patterns between genes and the environment in APOE ɛ4 carriers. Large samples and rigorous RCT studies are urgently needed to provide more clinical evidence for achieving healthy aging.

Footnotes

ACKNOWLEDGMENTS

The authors acknowledge fellow colleagues at Department of Geriatrics, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital for their stimulating and inspiring discussions. We would like to express our gratitude to Ms. Liu for her cooperation and providing detailed information in this case report.

This study was funded by grants from Shanghai Natural Science Foundation (No. 19ZR1438800).

Authors’ disclosures available online ().

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Cognitive Improvement After Multi-Domain Lifestyle Interventions in an APOE ɛ4 Homozygous Carrier with Mild Cognitive Impairment: A Case Report and Literature Review

Abstract

Keywords

INTRODUCTION

CASE DESCRIPTION

Clinical manifestations

Cognitive assessment scales

The APOE genotype and family history

Multi-domain lifestyle interventions

18F-AV45 PET examination

MRI examination

DISCUSSION

CONCLUSION

Footnotes

ACKNOWLEDGMENTS

References

¹⁸F-AV45 PET examination