AP collagen peptides (APCPs) promote hair growth by activating the GSK-3ß/ß-catenin pathway and improve hair condition.

AP collagen peptides (APCPs) are enzymatically decomposed collagen peptides that contain tri-peptides such as glycine-proline-hydroxyproline. We found that APCPs increased the proliferation of both human dermal papilla cells (hDPCs) and human outer root sheath cells (hORSCs). APCPs also stimulated the secretion of several growth factors, including IGFBP-6, PDGF-AB, PIGF and VEGF in hDPCs. Moreover, APCPs enhanced the phosphorylation of Akt(Ser473), GSK-3ß(Ser9) and ß-catenin(Ser675), indicating the activation of the GSK-3ß/ß-catenin signalling pathway. Ex vivo culture of human hair follicles (hHFs) tissue and in vivo patch assay revealed that APCPs promoted the elongation of hHFs and the induction of new hair shafts. In a mouse model, APCPs significantly promoted the transition from telogen to anagen phase and prolonged anagen phase, resulting in increased hair growth. APCPs also improved the thickness, amino acid content (cystine and methionine) and roughness of mouse hair. Taken together, these findings demonstrate that APCPs accelerate hair growth and contribute to overall hair health. Therefore, APCPs have the potential to be utilized as a food supplement and ingredient for preventing hair loss and maintaining hair health.

Microglia Gravitate toward Amyloid Plaques Surrounded by Externalized Phosphatidylserine via TREM2.

Microglia play a crucial role in synaptic elimination by engulfing dystrophic neurons via triggering receptors expressed on myeloid cells 2 (TREM2). They are also involved in the clearance of beta-amyloid (Aß) plaques in Alzheimer's disease (AD); nonetheless, the driving force behind TREM2-mediated phagocytosis of beta-amyloid (Aß) plaques remains unknown. Here, using advanced 2D/3D/4D co-culture systems with loss-of-function mutations in TREM2 (a frameshift mutation engineered in exon 2) brain organoids/microglia/assembloids, it is identified that the clearance of Aß via TREM2 is accelerated by externalized phosphatidylserine (ePtdSer) generated from dystrophic neurons surrounding the Aß plaques. Moreover, it is investigated whether microglia from both sporadic (CRISPR-Cas9-based APOE4 lines) and familial (APPNL-G-F/MAPT double knock-in mice) AD models show reduced levels of TREM2 and lack of phagocytic activity toward ePtdSer-positive Aß plaques. Herein new insight is provided into TREM2-dependent microglial phagocytosis of Aß plaques in the context of the presence of ePtdSer during AD progression.

FGFR3 drives Aß-induced tau uptake.

The amyloid cascade hypothesis suggests that amyloid beta (Aß) contributes to initiating subsequent tau pathology in Alzheimer's disease (AD). However, the underlying mechanisms through which Aß contributes to tau uptake and propagation remain poorly understood. Here, we show that preexisting amyloid pathology accelerates the uptake of extracellular tau into neurons. Using quantitative proteomic analysis of endocytic vesicles, we reveal that Aß induces the internalization of fibroblast growth factor receptor 3 (FGFR3). Extracellular tau binds to the extracellular domain of FGFR3 and is internalized by the FGFR3 ligand, fibroblast growth factor 2 (FGF2). Aß accelerates FGF2 secretion from neurons, thereby inducing the internalization of tau-attached FGFR3. Knockdown of FGFR3 in the hippocampus reduces tau aggregation by decreasing tau uptake and improving memory function in AD model mice. These data suggest FGFR3 in neurons as a novel tau receptor and a key mediator of Aß-induced tau uptake in AD.

Heat-treated Limosilactobacillus fermentum LM1020 with menthol, salicylic acid, and panthenol promotes hair growth and regulates hair scalp microbiome balance in androgenetic alopecia: A double-blind, randomized and placebo-controlled clinical trial.

BACKGROUND: Androgenetic alopecia (AGA) is a common and chronic problem characterized by hair follicle miniaturization. AIMS: In this study, heat-treated Limosilactobacillus fermentum LM1020 (HT-LM1020) was investigated in human follicle dermal papilla cell (HFDPC), scalp tissue, and clinical trials for patients with AGA. PATIENTS/METHODS: Cell proliferation and the expression of cyclins and cyclin-dependent kinases (CDKs) were measured in HFDPC. The relative gene expression of 5α-reductase and growth factors were investigated in hair scalp. This double-blind, randomized, placebo-controlled clinical trial was conducted over 24 weeks. Primary efficacy was evaluated by measuring hair density, and secondary efficacy was assessed by experts and self-assessment. Changes in the microbiota of the hair scalps were analyzed using 16S metagenome amplicon sequencing. RESULTS: HT-LM1020 promoted cell growth (p < 0.001) and cyclin B1 expression, and it reduced 5α-reductase and induced fibroblast growth factor 7 (FGF7), FGF10, and epithelial growth factor7 (EGF7) (p < 0.001). In the clinical trial, the experimental group demonstrated an increase in hair density from 133.70 to 148.87 n/cm2 at Week 24 (p < 0.001), while also expressing satisfaction with their hair density, reduced hair loss, and hairline. At Week 24, the total ratio of lactic acid bacteria operational taxonomic unit (OTU) in the scalp increased from 6.65% to 26.19%. At the same period, placebo-controlled group decreased Staphylococcus caprae OTU from 77.95% to 14.57% while experimental group decreased from 65.80% to 41.02%. CONCLUSIONS: These present results showed that HT-LM1020 was a co-effector of ingredients for anti-hair loss contributing to cell proliferation and the expression of CDKs.

Brain hypothyroidism silences the immune response of microglia in Alzheimer's disease animal model.

Thyroid hormone (TH) imbalance is linked to the pathophysiology of reversible dementia and Alzheimer's disease (AD). It is unclear whether tissue hypothyroidism occurs in the AD brain and how it affects on AD pathology. We find that decreased iodothyronine deiodinase 2 is correlated with hippocampal hypothyroidism in early AD model mice before TH alterations in the blood. TH deficiency leads to spontaneous activation of microglia in wild-type mice under nonstimulated conditions, resulting in lowered innate immune responses of microglia in response to inflammatory stimuli or amyloid-ß. In AD model mice, TH deficiency aggravates AD pathology by reducing the disease-associated microglia population and microglial phagocytosis. We find that TH deficiency reduces microglial ecto-5'-nucleotidase (CD73) and inhibition of CD73 leads to impaired innate immune responses in microglia. Our findings reveal that TH shapes microglial responses to inflammatory stimuli including amyloid-ß, and brain hypothyroidism in early AD model mice aggravates AD pathology by microglial dysfunction.

Quantitative Analysis of Hair Luster in a Novel Ultraviolet-Irradiated Mouse Model.

Hair luster is a key attribute of healthy hair and a crucial aspect of cosmetic appeal, reflecting the overall health and vitality of hair. Despite its significance, the advancement of therapeutic strategies for hair luster enhancement have been limited due to the absence of an effective experimental model. This study aimed to establish a novel animal model to assess hair gloss, employing ultraviolet (UV) irradiation on C57BL/6 mice. Specifically, UVB irradiation was meticulously applied to the shaved skin of these mice, simulating conditions that typically lead to hair luster loss in humans. The regrowth and characteristics of the hair were evaluated using a dual approach: an Investigator's Global Assessment (IGA) scale for subjective assessment and an image-based pixel-count method for objective quantification. These methods provided a comprehensive understanding of the changes in hair quality post-irradiation. To explore the potential reversibility of hair luster changes, oral minoxidil was administered, a treatment known for its effects on hair growth and texture. Further, to gain insights into the underlying biological mechanisms, bulk RNA transcriptomic analysis of skin tissue was conducted. This analysis revealed significant alterations in the expression of keratin-associated protein (KRTAP) genes, suggesting modifications in hair keratin crosslinking due to UV exposure. These changes are crucial in understanding the molecular dynamics affecting hair luster. The development of this new mouse model is a significant advancement in hair care research. It not only facilitates the evaluation of hair luster in a controlled setting but also opens avenues for the research and development of innovative therapeutic strategies. This model holds promise for the formulation of more effective hair care products and treatments, potentially revolutionizing the approach towards managing and enhancing hair luster.

Efficacy and safety of a home-use handheld multi-energy-based device for skin rejuvenation: clinical, ex vivo, and histological studies.

Alongside increases in the average lifespan and a growing interest in anti-aging remedies, the demand for at-home skincare devices is rapidly expanding in the cosmetic market. This study aimed to assess the safety and efficacy of a novel home-use handheld multi-energy-based device for skin rejuvenation that simultaneously emits low level light, low-dose radiofrequency, low-energy microcurrent, and low-intensity ultrasonic wave. This prospective, randomized, split-face clinical trial enrolled 36 healthy Korean women. After 8 weeks of device use, parameters associated with skin aging were assessed. Additionally, a preliminary ex vivo study and skin biopsy following device use were performed to confirm safety and efficiency of the device. Parameters associated with skin aging including skin hydration, elasticity, roughness, skin pore size, and eye wrinkle volume showed significant improvements after 8 weeks of the device use, relative to baseline measurements and the control side. No adverse effects were observed during the follow-up period. Results of ex vivo and in vivo skin tissue studies correlated with clinical findings, which showed an increase in the expression of type 1 collagen and a decrease in the expression of matrix metalloproteinase-1, which is related to the skin aging phenotype. The expression of loricrin and involucrin, major components of the epidermal skin barrier, also increased after the use of the device. Multi-energy-based device is effective for skin rejuvenation and tolerable, without any considerable adverse effects.

Exploring the Safety and Efficacy of Organic Light-Emitting Diode in Skin Rejuvenation and Wound Healing.

PURPOSE: Photobiomodulation (PBM), encompassing low-energy laser treatment and light-emitting diode (LED) phototherapy, has demonstrated positive impacts on skin rejuvenation and wound healing. Organic light-emitting diodes (OLEDs) present a promising advancement as wearable light sources for PBM. However, the biological and biochemical substantiation of their skin rejuvenation and wound healing effects remains limited. This study aimed to ascertain the safety and efficacy of OLEDs as a next-generation PBM modality through comprehensive in vitro and in vivo investigations. MATERIALS AND METHODS: Cell viability assays and human ex vivo skin analyses were performed after exposure to OLED and LED irradiation to examine their safety. Subsequent evaluations examined expression levels and wound healing effects in human dermal fibroblasts (HDFs) using quantitative reverse transcription-polymerase chain reaction, enzyme-linked immunosorbent assay, and wound healing assays post-irradiation. Additionally, an in vivo study was conducted using a ultra violet (UV)-irradiated animal skin model to explore the impact of OLED exposure on dermal collagen density and wrinkles, employing skin replica and tissue staining techniques. RESULTS: OLED irradiation had no significant morphological effects on human skin tissue, but caused a considerably higher expression of collagen than the control and LED-treated groups. Moreover, OLED irradiation reduced the expression levels of matrix metalloproteinases (MMPs) more effectively than did LED on HDFs. OLED irradiation group in HDFs had significantly higher expression levels of growth factors compared to the control group, but similar to those in the LED irradiation group. In addition, OLED irradiation on photo-aged animal skin model resulted in increased collagen fiber density in the dermis while reducing ultra violet radiation-mediated skin wrinkles and roughness, as shown in the skin replica. CONCLUSION: This study established comparable effectiveness between OLED and LED irradiation in upregulating collagen and growth factor expression levels while downregulating MMP levels in vitro. In the UV-irradiated animal skin model, OLED exposure post UV radiation correlated with reduced skin wrinkles and augmented dermal collagen density. Accelerated wound recovery and demonstrated safety further underscore OLEDs' potential as a future PBM modality alongside LEDs, offering promise in the realms of skin rejuvenation and wound healing.

Low-molecular-weight collagen peptides supplement promotes a healthy skin: A randomized, double-blinded, placebo-controlled study.

BACKGROUND: Oral collagen peptides supplementation was reported to improve skin integrity and counteract skin aging. AIMS: A randomized, double-blinded, placebo-controlled study was conducted to clinically evaluate the impact of low-molecular-weight collagen peptides on the human skin. PATIENTS/METHODS: Healthy adult participants (n = 100) were randomly assigned to receive a test product containing low-molecular-weight collagen peptides or a placebo. Parameters of skin wrinkles, elasticity, hydration, and whitening (melanin and erythema indexes) were measured at baseline and after 4, 8, and 12 weeks. RESULTS: Compared with the placebo group, the average skin roughness, maximum of all peak-to-valley values, maximum peak height of the wrinkle, and average maximum height of the wrinkle were significantly improved in the test group. Parameters of skin elasticity, including overall elasticity, net elasticity, and biological elasticity, were also significantly improved in the test group at Week 12 as compared with the placebo group. Moreover, skin hydration and whitening parameters changed more significantly in the test group than in the placebo group. None of the participants experienced adverse events related to the test product. CONCLUSIONS: Taken together, these findings suggest that low-molecular-weight collagen peptides supplementation can safely ehance human skin wrinkling, hydration, elasticity, and whitening properties.

Efficacy and safety of persimmon leaf formulated with green tea and sophora fruit extracts (BLH308) on hair growth: A randomized, double-blind, placebo-controlled clinical trial.

BACKGROUND: Recent research suggests that persimmon leaf extract (PLE) has an effect on inflammatory skin diseases. Previously, PLE is revealed to inhibit not only nitric oxide production but also inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) expression levels in mouse macrophages in vitro. Moreover, it significantly reduced IL-6 production and 5α-reductase expression in human follicle dermal papilla cells (HFDPCs). This study aimed to determine whether the PLE-containing BLH308 complex improves hair growth in clinical trials. MATERIALS AND METHODS: A total of 88 participants were recruited, and were instructed to orally take BLH308 or the placebo twice a day for 24 weeks. The mean age of the test group was 38.52 ± 7.98 years and that of placebo group was 38.98 ± 8.80 years. The study was conducted for 24 weeks, and hair density, thickness, and gloss were evaluated. All participants completed a satisfaction survey questionnaire. RESULTS: The test group showed significantly increased hair density and hair diameter at week 24 compared with the placebo group (p = 0.0015 and p = 0.0001, respectively). Although not statistically significant, the degree of gloss also showed higher improvement in the test group compared to the placebo group. CONCLUSIONS: Our data demonstrated that oral consumption of the BLH308 complex containing PLE significantly increased hair density and thickness compared to the placebo group, showing its possible role in promoting hair growth.

Age-related changes in scalp biophysical parameters: A comparative analysis of the 20s and 50s age groups.

BACKGROUND: Age-related changes in scalp parameters affect hair quality and scalp condition. However, detailed data on biophysical parameters of the scalp across age groups remain scarce. We aimed to investigate the differences in scalp parameters between individuals in their 20s and 50s and analyze their sex-specific variations. MATERIALS AND METHODS: Two hundred participants (160 women and 40 men) were equally divided into 20s and 50s age groups. Biophysical parameters of the scalp, including elasticity, pH, trans-epidermal water loss (TEWL), sebum production, desquamation, firmness, redness, and yellowness, were measured in the vertex, occipital, and temporal regions. Hair density and thickness were measured in the temporal region. The accumulation of advanced glycation end products (AGEs) in the skin was noninvasively measured in a subset of 60 women. RESULTS: Skin firmness and redness increased with age in women, whereas yellowness increased with age in both sexes. Sebum production and pH levels were significantly lower in the 50s age group than in the 20s age group, particularly in women. TEWL was lower in men in their 50s than in those in their 20s, particularly in the occipital region. A significant reduction in hair density was observed in the 50s age group in both sexes. AGE accumulation in the skin increased with age and was correlated with scalp skin yellowness. CONCLUSION: Age-related changes in scalp parameters have important implications for hair health and scalp condition. These findings emphasize the importance of considering age and sex when developing hair care strategies.

The QPLEX™ Plus Assay Kit for the Early Clinical Diagnosis of Alzheimer's Disease.

We recently developed a multiplex diagnostic kit, QPLEX™ Alz plus assay kit, which captures amyloid-ß1-40, galectin-3 binding protein, angiotensin-converting enzyme, and periostin simultaneously using microliters of peripheral blood and utilizes an optimized algorithm for screening Alzheimer's disease (AD) by correlating with cerebral amyloid deposition. Owing to the demand for early AD detection, we investigate the potential of our kit for the early clinical diagnosis of AD. A total of 1395 participants were recruited, and their blood samples were analyzed with the QPLEX™ kit. The average of QPLEX™ algorithm values in each group increased gradually in the order of the clinical progression continuum of AD: cognitively normal (0.382 ± 0.150), subjective cognitive decline (0.452 ± 0.130), mild cognitive impairment (0.484 ± 0.129), and AD (0.513 ± 0.136). The algorithm values between each group showed statistically significant differences among groups divided by Mini-Mental State Examination and Clinical Dementia Rating. The QPLEX™ algorithm values could be used to distinguish the clinical continuum of AD or cognitive function. Because blood-based diagnosis is more accessible, convenient, and cost- and time-effective than cerebral spinal fluid or positron emission tomography imaging-based diagnosis, the QPLEX™ kit can potentially be used for health checkups and the early clinical diagnosis of AD.

Functional effects of gut microbiota-derived metabolites in Alzheimer's disease.

The precise causation of Alzheimer's disease (AD) is unknown, and the factors that contribute to its etiology are highly complicated. Numerous research has been conducted to investigate the potential impact of various factors to the risk of AD development or prevention against it. A growing body of evidence suggests to the importance of the gut microbiota-brain axis in the modulation of AD, which is characterized by altered gut microbiota composition. These changes can alter the production of microbial-derived metabolites, which may play a detrimental role in disease progression by being involved in cognitive decline, neurodegeneration, neuroinflammation, and accumulation of Aß and tau. The focus of this review is on the relationship between the key metabolic products of the gut microbiota and AD pathogenesis in the brain. Understanding the action of microbial metabolites can open up new avenues for the development of AD treatment targets.

Topical Application of Peptide Nucleic Acid Antisense Oligonucleotide for MMP-1 and Its Potential Anti-Aging Properties.

Matrix metalloproteinase-1 (MMP-1) is a zinc-containing endopeptidase that degrades dermal collagen and other extracellular matrix molecules. It is recognized as one of the most important indicators of cellular senescence and age-related skin changes. Here, we introduced a novel MMP-1 peptide nucleic acid (PNA) derivative-PNA-20 carboxyethyl fluorene (CEF)-which can interact with and consequently silence the MMP-1 gene sequence. The investigation on the efficacy of PNA-20 CEF in MMP-1 silencing in human dermal fibroblasts revealed significantly decreased expression of MMP-1 at both gene and protein levels. Treatment with PNA-20 CEF showed significantly increased expression of collagen I protein, indicating its potential role in preventing the degradation of collagen I and consequently combating the skin aging process. Its topical application on 3D human skin tissue showed successful absorption into the epidermis and the upper dermis. Furthermore, the additional 4-week single-arm prospective study on 21 Asian women revealed improvements in facial wrinkles, skin moisture, elasticity, and density after the use of the topical PNA-20 CEF cosmeceutical formulation. Additional in-vitro and ex-vivo studies are needed for a comprehensive understanding of the skin anti-aging effects of MMP-1 PNA.

Sex differences in the progression of glucose metabolism dysfunction in Alzheimer's disease.

Alzheimer's disease (AD) is a common neurodegenerative disease characterized by amyloid plaques and impaired brain metabolism. Because women have a higher prevalence of AD than men, sex differences are of great interest. Using cross-sectional and longitudinal data, we showed sex-dependent metabolic dysregulations in the brains of AD patients. Cohort 1 (South Korean, n = 181) underwent Pittsburgh compound B-PET, fluorodeoxyglucose-PET, magnetic resonance imaging, and blood biomarker (plasma tau and beta-amyloid 42 and 40) measurements at baseline and two-year follow-ups. Transcriptome analysis of data from Cohorts 2 and 3 (European, n = 78; Singaporean, n = 18) revealed sex differences in AD-related alterations in brain metabolism. In women (but not in men), all imaging indicators displayed consistent correlation curves with AD progression. At the two-year follow-up, clear brain metabolic impairment was revealed only in women, and the plasma beta-amyloid 42/40 ratio was a possible biomarker for brain metabolism in women. Furthermore, our transcriptome analysis revealed sex differences in transcriptomes and metabolism in the brains of AD patients as well as a molecular network of 25 female-specific glucose metabolic genes (FGGs). We discovered four key-attractor FGG genes (ALDOA, ENO2, PRKACB, and PPP2R5D) that were associated with amyloid/tau-related genes (APP, MAPT, BACE1, and BACE2). Furthermore, these genes successfully distinguished amyloid positivity in women. Understanding sex differences in the pathogenesis of AD and considering these differences will improve development of effective diagnostics and therapeutic treatments for AD.

An Exploratory In Vivo Study on the Effect of Annurca Apple Extract on Hair Growth in Mice.

Hair loss is an important problem affecting the quality of life in modern society. Recent studies show that Annurca apple extract (AAE), enriched in procyanidin B2 and nutraceuticals, promotes hair growth and induces keratin production. In this study, we investigated the effects of AAE by orally administering AAE in six-week-old C57BL/6 mice once a day for 21 d. We observed improvement in hair length, thickness, weight, and density. The gene expression of two growth factors related to hair growth, vascular endothelial growth factor A (VEGFA) and fibroblast growth factor 7 (FGF-7), were measured using the quantitative reverse transcription polymerase chain reaction (qRT-PCR). The gene expression of both VEGFA and FGF-7 increased significantly in the AAE-treated group. Additionally, treatment with AAE suppressed the gene expression of type 1 5α-reductase. Histological analysis showed that protein levels of cytokeratin 5 and 10 were increased in the skin tissues of the AAE-treated group. These results suggest that AAE might be a potential therapeutic natural product that prevents hair loss by promoting the expression of hair growth-related factors.

Aß-induced mitochondrial dysfunction in neural progenitors controls KDM5A to influence neuronal differentiation.

Mitochondria in neural progenitors play a crucial role in adult hippocampal neurogenesis by being involved in fate decisions for differentiation. However, the molecular mechanisms by which mitochondria are related to the genetic regulation of neuronal differentiation in neural progenitors are poorly understood. Here, we show that mitochondrial dysfunction induced by amyloid-beta (Aß) in neural progenitors inhibits neuronal differentiation but has no effect on the neural progenitor stage. In line with the phenotypes shown in Alzheimer's disease (AD) model mice, Aß-induced mitochondrial damage in neural progenitors results in deficits in adult hippocampal neurogenesis and cognitive function. Based on hippocampal proteome changes after mitochondrial damage in neural progenitors identified through proteomic analysis, we found that lysine demethylase 5A (KDM5A) in neural progenitors epigenetically suppresses differentiation in response to mitochondrial damage. Mitochondrial damage characteristically causes KDM5A degradation in neural progenitors. Since KDM5A also binds to and activates neuronal genes involved in the early stage of differentiation, functional inhibition of KDM5A consequently inhibits adult hippocampal neurogenesis. We suggest that mitochondria in neural progenitors serve as the checkpoint for neuronal differentiation via KDM5A. Our findings not only reveal a cell-type-specific role of mitochondria but also suggest a new role of KDM5A in neural progenitors as a mediator of retrograde signaling from mitochondria to the nucleus, reflecting the mitochondrial status.

Association of B cell profile and receptor repertoire with the progression of Alzheimer's disease.

Alzheimer's disease (AD) is the most prevalent type of dementia. Reports have revealed that the peripheral immune system is linked to neuropathology; however, little is known about the contribution of B lymphocytes in AD. For this longitudinal study, 133 participants are included at baseline and second-year follow-up. Also, we analyze B cell receptor (BCR) repertoire data generated from a public dataset of three normal and 10 AD samples and perform BCR repertoire profiling and pairwise sharing analysis. As a result, longitudinal increase in B lymphocytes is associated with increased cerebral amyloid deposition and hyperactivates induced pluripotent stem cell-derived microglia with loss-of-function for beta-amyloid clearance. Patients with AD share similar class-switched BCR sequences with identical isotypes, despite the high somatic hypermutation rate. Thus, BCR repertoire profiling can lead to the development of individualized immune-based therapeutics and treatment. We provide evidence of both quantitative and qualitative changes in B lymphocytes during AD pathogenesis.

Multi-Omics-Based Autophagy-Related Untypical Subtypes in Patients with Cerebral Amyloid Pathology.

Recent multi-omics analyses paved the way for a comprehensive understanding of pathological processes. However, only few studies have explored Alzheimer's disease (AD) despite the possibility of biological subtypes within these patients. For this study, unsupervised classification of four datasets (genetics, miRNA transcriptomics, proteomics, and blood-based biomarkers) using Multi-Omics Factor Analysis+ (MOFA+), along with systems-biological approaches following various downstream analyses are performed. New subgroups within 170 patients with cerebral amyloid pathology (Aß+) are revealed and the features of them are identified based on the top-rated targets constructing multi-omics factors of both whole (M-TPAD) and immune-focused models (M-IPAD). The authors explored the characteristics of subtypes and possible key-drivers for AD pathogenesis. Further in-depth studies showed that these subtypes are associated with longitudinal brain changes and autophagy pathways are main contributors. The significance of autophagy or clustering tendency is validated in peripheral blood mononuclear cells (PBMCs; n = 120 including 30 Aß- and 90 Aß+), induced pluripotent stem cell-derived human brain organoids/microglia (n = 12 including 5 Aß-, 5 Aß+, and CRISPR-Cas9 apolipoprotein isogenic lines), and human brain transcriptome (n = 78). Collectively, this study provides a strategy for precision medicine therapy and drug development for AD using integrative multi-omics analysis and network modelling.