Mapping assistive technologies along the progression of Alzheimer's disease: A scoping review.

A growing population of people living with Alzheimer’s Disease urges improved support for aging in place and with dignity. Assistive technologies (ATs) can be used to delay institutionalization, reduce caregiver burden, and improve quality of life for this population and their care partners. The abilities and needs of this population change during disease progression, requiring a better understanding of which ATs could be used at each stage of the disease. The purpose of this scoping review is to generate knowledge on how ATs can be mapped on seven stages of Alzheimer’s Disease progression described by the Global Deterioration Scale. The review follows the Arksey and O’Malley framework to identify and harvest information from Medline OVID, Scopus, CINAHL, and Embase OVID databases. Inclusion criteria were Alzheimer’s Disease, technology interventions of any type and duration, English language, and the time frame between 2000-2023. Data was extracted and thematically analyzed using six predetermined domains of ATs for dementia, namely safety devices, clinical devices, memory aids, ATs for preventing social isolation, ATs for leisure activities, and ATs for supporting everyday tasks. A total of 53 articles were included. Findings show that a variety of ATs are available throughout the disease progression. High technology (e.g., tracking devices) mainly target early stages, while low technology (e.g., weighted blanket) target later stages. Some, such as music therapy, are present at every stage of disease. The map has the potential to inform people with dementia, care partners, technology companies, distributors, policy makers and service providers.

Moving Beyond Amyloid in Alzheimer's Therapeutics

Battle against Alzheimer's Disease: The Scope and Potential Value of Magnetic Resonance Imaging Biomarkers

Rac1b Increases with Progressive Tau Pathology within Cholinergic Nucleus Basalis Neurons in Alzheimer's Disease

Alzheimer's disease is the most common major neurocognitive disorder. Although currently, no cure exists, understanding the neurobiological substrate underlying Alzheimer's disease progression will facilitate early diagnosis and treatment, slow disease progression, and improve prognosis. In this study, we aimed to understand the morphological changes underlying Alzheimer's disease progression using structural magnetic resonance imaging data from cognitively normal individuals, individuals with mild cognitive impairment, and Alzheimer's disease via a contrastive variational autoencoder model. We used contrastive variational autoencoder to generate synthetic data to boost the downstream classification performance. Due to the ability to parse out the nonclinical factors such as age and gender, contrastive variational autoencoder facilitated a purer comparison between different Alzheimer's disease stages to identify the pathological changes specific to Alzheimer's disease progression. We showed that brain morphological changes across Alzheimer's disease stages were significantly associated with individuals' neurofilament light chain concentration, a potential biomarker for Alzheimer's disease, highlighting the biological plausibility of our results.

Alzheimer’s disease (AD) is a chronic neurodegenerative disease that worsens over time. The number of AD cases is growing, around 3 million new US cases each year. Although state-of-the-art research shows promise, predicting the disease’s rate of progression for a case by case basis remains a challenging problem. Current methods of predicting the progression of AD can delay treatment and lead to misdiagnosis. We propose a novel approach to simulate the rate of progression of AD and the atrophy of the brain over time. We seek to achieve this by generating synthetic magnetic resonance (MR) images via a series of Conditional Deep Convolutional Generative Adversarial Neural Networks (CDCGANs) and then analyze them by computing the fractal dimensionality of the cortical brain ribbons. This paper shows the feasibility of this proposal by cascading CDCGANs that simulate different stages of AD. It is possible to extend by a tandem of CDCGANs that would simulate the different stages of the disease. MR images used here are from ADNI(Alzheimer’s Disease Neuroimaging Initiative). The atrophy is measure using fractal dimension (box-counting method)of the cortical ribbon(CR). A decreasing fractal dimension is a confirmation that the disease progress over time.

To correlate different methods of measuring rates of brain atrophy from serial MRI with corresponding clinical change in normal elderly subjects, patients with mild cognitive impairment (MCI), and patients with probable Alzheimer disease (AD). One hundred sixty subjects were recruited from the Mayo Clinic Alzheimer's Disease Research Center and Alzheimer's Disease Patient Registry Studies. At baseline, 55 subjects were cognitively normal, 41 met criteria for MCI, and 64 met criteria for AD. Each subject underwent an MRI examination of the brain at the time of the baseline clinical assessment and then again at the time of a follow-up clinical assessment, 1 to 5 years later. The annualized changes in volume of four structures were measured from the serial MRI studies: hippocampus, entorhinal cortex, whole brain, and ventricle. Rates of change on several cognitive tests/rating scales were also assessed. Subjects who were classified as normal or MCI at baseline could either remain stable or convert to a lower-functioning group. AD subjects were dichotomized into slow vs fast progressors. All four atrophy rates were greater among normal subjects who converted to MCI or AD than among those who remained stable, greater among MCI subjects who converted to AD than among those who remained stable, and greater among fast than slow AD progressors. In general, atrophy on MRI was detected more consistently than decline on specific cognitive tests/rating scales. With one exception, no differences were found among the four MRI rate measures in the strength of the correlation with clinical deterioration at different stages of the disease. These data support the use of rates of change from serial MRI studies in addition to standard clinical/psychometric measures as surrogate markers of disease progression in AD. Estimated sample sizes required to power a therapeutic trial in MCI were an order of magnitude less for MRI than for change measures based on cognitive tests/rating scales.

OPINION article Front. Aging Neurosci., 26 August 2015Sec. Alzheimer's Disease and Related Dementias Volume 7 - 2015 | https://doi.org/10.3389/fnagi.2015.00164

Speech and phonological impairment across Alzheimer's disease severity

Circadian fragmentation: a harbinger of Alzheimer's disease?

Alzheimer's disease (AD) is the main neurodegenerative disease leading to dementia and cognitive impairment in the elderly. Considering AD to be an epidemic, an increase from the current 50 million to more than 150 million patients is expected by the year 2050. AD is characterized by a slow, progressive and asymptomatic onset; making it difficult to decipher the precise etiology. It is well established that AD presents two characteristic features, extracellular β-amyloid plaques and intracellular tau tangles, that eventually lead to the impairment of cognitive functions. Unfortunately, AD symptomatology shares many similarities with other dementias once is present, which makes it difficult an accurate premortem diagnosis. Although AD is mainly considered an aging-related condition that affects cognitive function, several cardio- and cerebrovascular comorbidities such as hypertension or diabetes are also risk factors for cognitive impairment. Accordingly, brain vascular-associated alterations underlie many pathophysiological mechanisms of AD. We have recently reviewed the latest evidence supporting the detrimental role of vascular and angiogenic alterations during AD (Custodia et al., 2022). Remarkably, cerebral blood-brain barrier (BBB) leakage and microbleeds are associated with cognitive decline in patients with mild cognitive impairment (MCI) and early AD. Accordingly, the two-hit vascular hypothesis points at initial damage in cerebral vasculature (hit one) that eventually induces the accumulation of β-amyloid (Aβ) in the brain (hit two; Zlokovic, 2005). CD34+ bone marrow-derived progenitor cells (BMPCs) define a group of stem and progenitor cell populations released by the bone marrow that covers different subpopulations of cells from the hematopoietic linage, including endothelial progenitor cells (EPCs). EPCs exhibit characteristics of both endothelial and stem cells, and, accordingly, proangiogenic early EPCs expressing both CD34 and CD133 (a progenitor surface marker) can be distinguished from late EPCs additionally expressing KDR and/or CD146 (endothelial markers), which participate in the process of angiogenesis and vasculogenesis (Figure 1). Therefore, EPCs participate in angiogenesis and the maintenance of the endothelium by acting as a cellular reservoir for the replacement of dysfunctional endothelial cells, or by the secretion of angiogenic growth factors.Figure 1: Beneficial roles of CD34+ BMPCs following CNS injury.CD34+ BMPCs and the EPCs subtypes, early and late, can promote both angiogenesis and vasculogenesis following CNS injury by specializing in endothelial cells, and/or indirectly by secreting free and exosome-enveloped growth factors. G-CSF is a glycoprotein that acts in the bone marrow to mobilize both EPCs and CD34+ BMPCs after damage. BMPCs: Bone marrow progenitor cells; CNS: central nervous system; EPCs: endothelial progenitor cells; G-CSF: granulocyte colony-stimulating factor. Created with BioRender.com.Given that both dysfunctional angiogenesis and compromised BBB integrity seem critical in the onset and/or progression of AD, CD34+ progenitor cells, primarily EPCs, appear as potential targets for the early diagnosis and/or treatment of the disease. In this way, early and late EPCs would work synergistically: early EPCs reach the site of injury due to the high concentration of angiogenic factors and inflammatory cytokines, from which they paracrinally release different factors promoting angiogenesis and recruiting late EPCs, which either restore the endothelium or form new vessels guided by the early EPCs. Here, we discuss recent work and ongoing human clinical trials testing the feasibility of CD34+ BMPCs and EPCs as early biomarkers of AD and pharmacological targets for future treatments. Association of circulating levels of CD34+ BMPCs and cognitive decline in healthy and MCI subjects: Several cross-sectional studies have shown that the number of circulating CD34+ BMPCs decreases with age, and this may impact cognition. In this regard, a longitudinal study regarding cognition and CD34+ BMPCs levels reported that older healthy subjects had lower levels of CD34+ BMPCs than younger counterparts at baseline measurements (Hajjar et al., 2016). Moreover, this investigation revealed that subjects with higher baseline levels of several subgroups of CD34+ BMPCs such as early and late EPCs, and CD34+/KDR+ cells, among others, had better executive-derived and working memory scores over 4 years of follow-up (Hajjar et al., 2016). Recently, a large transverse study has shown the association between CD34+ BMPCs and different memory-related tests in cognitively normal subjects with coronary artery disease (Moazzami et al., 2020). Notably, circulating numbers of late EPCs were positively correlated with a better performance in tasks assessing visual, logical, and verbal immediate/delayed memory. Therefore, the amount of circulating CD34+ BMPCs subtypes appears to be negatively correlated to the cognitive decline of both healthy subjects and patients with vascular-associated conditions. Although more longitudinal clinical studies are needed to fully confirm the harmful effect of low levels of CD34+ BMPCs on the cognitive state, and other factors may be also taking part in this cognitive decline, it is still plausible that larger amounts of circulating endothelial progenitors exert a protective effect, probably by the maintenance of vascular endothelium integrity. MCI often precedes clinical symptoms of AD, and MCI patients show an increased risk of developing dementia in the future. Thus, it is very interesting to study CD34+ BMPCs/EPCs levels in patients with MCI in order to test whether such levels can be used as potential non-invasive diagnostic biomarkers to detect cognitive decline or its progression from MCI to dementia. Some studies have observed a decrease in CD34+ BMPCs and EPCs populations from MCI patients (Nation et al., 2018; Callahan et al., 2020). In this sense, MCI patients with lower levels of circulating CD34+ BMPCs and both subtypes of EPCs exhibited worse scores in memory tests and reduced cortical thickness compared to control subjects (Nation et al., 2018). Considering the angiogenesis ratio (pro-angiogenic/non-angiogenic BMPCs, including early and late EPCs), Callahan et al. (2020) showed a positive association between angiogenesis ratio and white matter hyperintensities, but not with global cerebral blood flow, hippocampal volume, or accumulation of tau and Aβ. By contrast, measurements in an older cohort of MCI patients did not show significant changes in CD34+, early EPCs, and late EPCs circulating levels compared to control subjects (Breining et al., 2016). This discrepancy may highlight that aging decreases CD34+ BMPCs to such a reduced level that is no longer different in controls compared to MCI. In summary, it seems that the reduction in CD34+ BMPCs is directly related to vascular dysfunction, increasing brain white matter microlesions and impairing cognition in MCI patients. Association of circulating levels of CD34+ BMPCs and AD: Several studies have been performed in order to determine the relationship between CD34+ BMPCs/EPCs circulating levels and the progression of AD (Maler et al., 2006; Lee et al., 2009; Stellos et al., 2010; Bigalke et al., 2011; Kong et al., 2011; Breining et al., 2016; Callahan et al., 2020; Haiyuan et al., 2020). In this way, AD patients in the early symptomatic phase already showed lower levels of CD34+ and CD34+/KDR+ cells compared to their control counterparts (Maler et al., 2006; Haiyuan et al., 2020). Notably, CD34+ BMPCs counts have negatively correlated with levels of Aβ1–42 in cerebrospinal fluid and the Aβ ratio 42/40, two well-known biomarkers for AD, as well as with age, only in the early AD group (Maler et al., 2006). Furthermore, the homing capacity of EPCs from early AD patients was already impaired (Haiyuan et al., 2020). Overall, it is becoming clear that dysfunctional CD34+ BMPCs are related to a reduced ability to repair brain endothelial cells, which appears to mediate neurotoxicity by affecting the BBB permeability. On the other hand, different outcomes were described in studies assessing the number of progenitor cells during AD progression. Specifically, lower counts of CD34+ BMPCs and EPCs have been observed in moderate and severe AD patients compared to both early AD stage (Haiyuan et al., 2020) and control subjects (Lee et al., 2009; Kong et al., 2011; Haiyuan et al., 2020). Such studies also revealed that homing and adhesion features of EPCs from AD patients were impaired (Haiyuan et al., 2020), as well as EPCs levels were inversely correlated with the mini-mental state exam (MMSE) score (Lee et al., 2009; Stellos et al., 2010; Kong et al., 2011). Furthermore, moderate to severe AD patients displayed a reduced flow velocity of the middle cerebral artery (Kong et al., 2011). In contrast, other studies reported higher levels of CD34+ BMPCs and EPCs compared to controls (Stellos et al., 2010; Bigalke et al., 2011), or even no changes (Breining et al., 2016). Intriguingly, the work from Stellos and colleagues reported an increase in both CD34+ BMPCs and early EPCs counting when comparing moderate to severe AD patients versus control subjects; however, within the AD group, there was an inverse correlation between CD34+ BMPCs and early EPCs counting and the MMSE score. Although these results seem contrary to each other, it is noteworthy that most AD patients from this study (Stellos et al., 2010) were treated with cholinesterase inhibitor; a drug involved in EPCs proliferation. Therefore, this fact may bias the results and it could explain why cell counting in the AD group was higher than in controls, but they were inversely correlated with MMSE scores. The other study that showed increased levels of CD34+ BMPCs/EPCs (Bigalke et al., 2011) only measured the numbers of CD34+ BMPCs in early to moderate AD compared to controls, with no information regarding cholinesterase inhibitor treatment. In summary, most of the studies in later AD stages support the studies performed on MCI and early AD stages. Therefore, AD-mediated loss of CD34+ BMPCs/EPCs, as well as loss of EPCs-intrinsic features, are likely present in AD patients and may constitute novel diagnostic and therapeutic targets. Potential therapy with granulocyte colony-stimulating factor (G-CSF) in AD: The G-CSF is a glycoprotein secreted by endothelial and immune cells that acts as a hematopoietic growth factor (Figure 1). Among other beneficial mechanisms following vascular injury, the G-CSF can promote angiogenesis by mobilizing EPCs (Figure 1). Therefore, G-CSF may be a potential target to enhance vascular repair in AD patients. Indeed, it has been recently shown that a G-CSF treatment improved memory as well as reduced blood levels of amyloid and tau in mild to moderate patients of AD (Potter et al., 2021). Based on these achievements, it is currently conducting a phase2b clinical trial in order to evaluate the long-term treatment of G-CSF in AD patients (NCT04902703; ClinicalTrials.gov). It would be interesting to look at CD34+ BMPCs and EPCs levels from those clinical trials in order to elucidate whether such potential benefits promoted by G-CSF therapy are totally or partially mediated by increasing CD34+ BMPCs/EPCs mobilization. Future challenges: The body of evidence supporting a vascular component underlying AD onset and/or progression is growing. However, further studies are mandatory to elucidate whether such vascular component triggers AD, is a consequence of AD, or both. Moreover, longitudinal studies are needed to confirm the relationship between CD34+ BMPCs/EPCs levels and AD progression. Given that vascular-related diseases may influence the amount of circulating progenitor cells, especially in AD patients, comorbidities present in those subjects deserve special attention when interpreting the results. Likewise, pharmacological treatments, such as a cholinesterase inhibitor, may bias the results from studies giving uncorrected information. Despite the promising results in animal models of AD, the number of published results and clinical trials regarding the direct application of EPCs as a potential therapy in AD patients is absent. This is remarkable when there is compelling evidence that supports the role of endothelial dysfunction in the onset and progression of AD, and the potential of EPCs as a diagnostic biomarker and/or therapeutic target (Custodia et al., 2022). However, we were unable to find published data or ongoing clinical trials in humans using the application of EPCs to treat AD; as already seen in a stroke clinical trial (NCT01468064). Moreover, several recent studies have highlighted the beneficial role of EPCs secretome/exosomes by protecting and repairing the BBB following damage without using a cell-based therapy. So, clinical trials based on EPCs-derived secretome/exosomes might be a safer and more promising approach in AD research. Finally, only the GCSF-based treatment is being tested in AD patients at later stages, with modest but promising results. Given that endothelium-related impairments are already seen in MCI patients, it would be really interesting to test this GCSF-based treatment in those subjects in order to increase the benefits and protect against the progression to AD. This work was partially supported by grants from the Xunta de Galicia (IN607A2018/3 to TS, IN607D 2020/09 to TS, IN606A-2021/015 to AC; IN606B-2021/010 to DRS), and Science Ministry of Spain (RTI2018-102165-B-I00 to TS, RTC2019-007373-1 to TS). Furthermore, this work was also supported by grants from the INTERREG Atlantic Area (EAPA_791/2018_ NEUROATLANTIC project to TS), INTER-REG V A España Portugal (POCTEP) (0624_2IQBIONEURO_6_E to TS), and the European Regional Development Fund (ERDF). Moreover, DRS (CD21/00166) and TS (CPII17/00027) are recipients of research contracts from the Sara Borrell and Miguel Servet Programs, respectively, from the Instituto de Salud Carlos III. Availability of data and materials:All data generated or analyzed during this study are included in this published article and its supplementary information files. Open peer reviewers:Yali Jia, Beijing Institute of Radiation Medicine, China; Rongcan Luo, Kunming Institute of Zoology Chinese Academy of Sciences, China. Additional file:Open peer review reports 1 and 2.P-Reviewers: Jia Y, Luo R; C-Editors: Zhao M, Liu WJ, Wang Lu; T-Editor: Jia Y

Alzheimer's disease (AD) is a progressive disease that particularly affects memory with difficulties starting insidiously and gradually progressing. Anterograde amnesia for semantic and episodic types of declarative knowledge becomes the most prominent and disproportionately impaired cognitive symptom. By the middle stages of the disease, this memory loss progresses to severe impairment. The neuropathology of early AD involves the hippocampal complex, which is involved in new learning and storage of recent experiences. As the disease progresses, it involves neocortical areas, which are involved in the storage of more remote memories. Participants, including minimal stage AD, mild stage AD, moderate stage AD, and normal controls were interviewed using the Autobiographical Memory Interview (AMI), which consists of an autobiographical incidents component and a personal semantic component. They were also administered a brief mental status exam and tests of remote memory, anterograde memory, semantic category word fluency, and reading. Autobiographical memory was impaired in all three groups of AD patients. There was a temporally graded loss (poorer recall of recent than childhood memories) for the minimal and mild AD groups on the autobiographical incidents schedule of the AMI. The moderate group showed equal impairment across life periods. On the personal semantic memory schedule of the AMI, the mild and moderate AD groups showed a temporal gradient. Remote public memory was also impaired in all three groups of AD patients. All AD groups performed worse on the recent life period than on earlier time periods. Overall, there were low correlations between remote public memory and autobiographical memory for the AD groups, supporting the separability of these subcomponents. Deficits in autobiographical memory were significantly correlated with anterograde memory deficits when AD patients reached the moderate stage of disease. There was an increasing correlation between category fluency and autobiographical memory across groups from the minimal to the moderate AD group, lending support to concurrent deterioration of both semantic and autobiographical memory as the disease progresses. This pattern also fit the correlation between the two schedules of the AMI, autobiographical incidents and personal semantic memory.

Alzheimer's disease (AD) is a progressive neurodegenerative disease. Cognitive functions and communication skills worsen as the disease progresses, thereby reducing patients' independence levels. Therefore, recommending software that can be used at home may be a useful means of slowing down the cognitive and communicative decline in AD. To develop software that can be used at home to slow down the cognitive and communicative decline and increase independence in individuals with AD; and to examine the effect of this software on the cognitive communication skills of individuals with AD. The study was completed in four stages: the development of the application; the evaluation of the participants and their training for the application; their use of the application at home; and the re-evaluation of the participants. A total of 32 individuals who met the inclusion criteria were included in the study. These individuals were randomly divided into study and control groups, each consisting of a total of 16 participants, including six in the mild stage, six in the moderate stage, and four in the severe stages. The developed software was loaded on tablets and given to the participants in the study group. The participants in the control group only received their pharmacological treatment, while those in the study group received both their pharmacological treatment and used the developed application. All participants were evaluated with the Mini-Mental State Examination (MMSE) and Language Assessment Test for Aphasia (LATA) before and after application use. A survey was administered to the caregivers of the participants in the study group after the use of the application. The results revealed a positive change in the cognitive-communication skills of the individuals in the study group, even if they were in the severe stage, according to the LATA and MMSE, as well as the survey. The application led to the greatest improvements in grammar on the LATA and orientation on the MMSE. No rapid cognitive decline was seen in individuals at all stages in the control group. In this study, software was developed in Turkish that can be used in every stage of AD as part of a holistic cognitive-communication intervention programme offering alternative and supportive communication for individuals with AD, even those in the severe stage. Results prove the effectiveness of the developed software on the cognitive-communication skills of individuals with AD. What is already known on the subject There are a few (as far as is known, three) applications developed in English for cognitive-communication disorders due to dementia. What this study adds to the existing literature In this study, for the first time in Turkish, mobile-compatible software has been developed for both cognitive and communication disorders that is specific to individuals with AD and can be used by individuals at all stages of the disease. The effects of the application we developed on the cognitive-communication skills of individuals with AD were shown in a randomised controlled trial. What are the potential or actual clinical implications of this work? Using the app can help people with all stages of AD keep their cognitive and communication skills and have a better prognosis in terms of cognitive-communication skills, especially grammar and orientation.

BackgroundGenome wide genetic/epigenetic studies are revealing more risk loci associated with the Alzheimer’s disease (AD). One recent analysis of human epigenome‐wide association studies (EWAS) reports an association between variations in the gene PM20D1 and AD, showing hypermethylation in the brain tissues in patients with advanced‐stage AD.MethodsWe used whole genome DNA methylation data collected from peripheral blood mononuclear cells (PBMCs) in a cohort (n = 649) from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) and compared the DNA methylation level at baseline among different diagnosis groups. We also leveraged the longitudinal data up to 4 years, sampled at approximately 1 year intervals to model the alterations in the methylation levels detected at the differentially methylated regions (DMRs) to delineate the methylation change course over aging and disease progression. The dynamic pattern of DNA methylation level with disease progression at the PM20D1 locus in brain tissues were also modeled from the data in The Religious Orders Study and Memory and Aging Project (ROSMAP) Study cohort (n = 740).ResultsWhen compared with controls, patients with mild cognitive impairment (MCI) consistently displayed promoter hypomethylation at reported methylation QTL gene locus PM20D1. This promoter hypomethylation was even more prominent in patients with mild to moderate AD. This is in stark contrast with previously reported hypermethylation in brain tissues in patients with advanced‐stage AD. By leveraging longitudinal DNA methylation data, linear mixed‐effects (LME) modeling for the unchanged diagnosis groups and U‐shape testing for those with changed diagnosis (converters) indicate that, we observe initial promoter hypomethylation of PM20D1 during MCI and early stage AD, which reverses to eventual promoter hypermethylation in the transition to late stage AD. We also confirm this observation in ROSMAP cohort as neuropathology deteriorates. Correlation of DNA methylation between blood and brain tissues at PM20D1 promoter region also demonstrates the pattern is consistent across tissues.ConclusionsOur results confirm that PM20D1 is an mQTL for AD and demonstrate that it plays a dynamic role at different stages of the disease. Further in‐depth study is thus warranted to fully decipher its role in the evolution of AD, and potentially explore its utility as a blood‐based biomarker for AD.

BackgroundWhile Alzheimer’s disease (AD) remains one of the most challenging diseases to tackle, genome-wide genetic/epigenetic studies reveal many disease-associated risk loci, which sheds new light onto disease heritability, provides novel insights to understand its underlying mechanism and potentially offers easily measurable biomarkers for early diagnosis and intervention.MethodsWe analyzed whole-genome DNA methylation data collected from peripheral blood in a cohort (n = 649) from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) and compared the DNA methylation level at baseline among participants diagnosed with AD (n = 87), mild cognitive impairment (MCI, n = 175) and normal controls (n = 162), to identify differentially methylated regions (DMRs). We also leveraged up to 4 years of longitudinal DNA methylation data, sampled at approximately 1 year intervals to model alterations in methylation levels at DMRs to delineate methylation changes associated with aging and disease progression, by linear mixed-effects (LME) modeling for the unchanged diagnosis groups (AD, MCI and control, respectively) and U-shape testing for those with changed diagnosis (converters).ResultsWhen compared with controls, patients with MCI consistently displayed promoter hypomethylation at methylation QTL (mQTL) gene locus PM20D1. This promoter hypomethylation was even more prominent in patients with mild to moderate AD. This is in stark contrast with previously reported hypermethylation in hippocampal and frontal cortex brain tissues in patients with advanced-stage AD at this locus. From longitudinal data, we show that initial promoter hypomethylation of PM20D1 during MCI and early stage AD is reversed to eventual promoter hypermethylation in late stage AD, which helps to complete a fuller picture of methylation dynamics. We also confirm this observation in an independent cohort from the Religious Orders Study and Memory and Aging Project (ROSMAP) Study using DNA methylation and gene expression data from brain tissues as neuropathological staging (Braak score) advances.ConclusionsOur results confirm that PM20D1 is an mQTL in AD and demonstrate that it plays a dynamic role at different stages of the disease. Further in-depth study is thus warranted to fully decipher its role in the evolution of AD and potentially explore its utility as a blood-based biomarker for AD.