Research

Magnetic Resonance Imaging (MRI) of the brain is a powerful tool for studying aging and neurodegenerative diseases. This non-invasive scan provides superb anatomical detail, distinguishing tissue such as gray and white matter, and cerebrospinal fluid. With age, there is a visible reduction in global brain volume along with white matter (WM) and hippocampal volumes; patchy hyperintensities or lesions in the WM (WML) also become more prominent and numerous. In addition to tissue loss and injury, there are prominent vascular changes that occur, including cerebral microbleeds, perivascular, and small vessel changes. Vascular integrity supports the brain's demand for oxygen and glucose, prevents entry of unwanted molecules, and clears metabolic waste products - all of which become less effective with age. Some changes observed with normal aging overlap and are more conspicuous in Alzheimer's Disease (AD). As the disease advances, certain regions of the brain reveal specific, temporal atrophy patterns which can be tracked with structural MRI to observe pathological progression after amyloid plaques begin to accumulate. 

Serena Tang is a graduate student in Dr. Tosun's lab who recently leveraged deep learning-based MRI segmentation maps to analyze the spatial associations between enlarged perivascular spaces (EPVS) and WML across the AD continuum. PVS are fluid-filled compartments surrounding the brain's microvasculature that serve as the structural conduit for glymphatic flow, a waste clearance mechanism in the brain. Enlargement of PVS may be a compensatory response to dysfunctional or blocked clearance. EPVS and WML are both consequences of microvascular injury.…

It is a well known fact that men and women age differently. There have been several studies that have looked at differences in tissue, molecular clocks, and longevity profiles from simple, clinical blood tests. Women generally live longer, but tend to be more frail due to certain chronic conditions as they age. Men perform better physically, but tend to have more chronic conditions later in life. Untangling the web of underlying causes is challenging.

In Alzheimer's Disease (AD), sex differences are well known across pathophysiology and clinical presentation. For example, women show greater vulnerability to certain AD risk factors including the presence of the APOE ε4 allele, higher tau burden, more neurodegeneration, and faster disease progression. Interestingly, women show resilience to pathology in early stages of the disease. 

These early stages are the focus of clinical trials, where amyloid plaques are targeted for destruction before clinical symptoms occur. Marta Milà-Alomà has been investigating sex effects that could improve trial enrichment. In this study, Marta and her colleagues investigated whether sex directly modifies plasma biomarkers that are used clinically for monitoring AD pathology and progression.

It is no secret that an individual's overall health and well-being are connected to their life circumstances. A broad spectrum of environmental and background factors are increasingly being recognized as contributors to risk and progression of certain diseases such as Alzheimer's (AD) and related dementias. Neighborhood characteristics such as education, income, employment, and housing quality, can be ranked and quantified using the Area Deprivation Index (ADI) which is calculated from Census group data. ADI has been linked to health conditions such as cardiovascular diseases, chronic stress, kidney disease, obesity, and diabetes - all of which are well-established risk factors for AD and related dementias. However, a direct link between neighborhood-level characteristics and neuropathology is less clear due to conflicting studies.

The progression of Alzheimer's disease may span decades, and cognitive symptoms occur after the hallmark pathologies of amyloid-beta (Aβ) plaques, followed by tau tangles, and finally neurodegeneration in the brain. Early diagnosis has been a strong research focus in recent years. In fact, several clinical trials have targeted Aβ plaques (anti-amyloid treatments) to prevent, or significantly slow, disease progression altogether. Being able to accurately detect AD-specific forms of these proteins in the blood has been groundbreaking. A simple blood test can accurately capture AD-specific blood-based biomarkers presumably before they have begun to aggregate. Having a robust and accurate blood test available creates a viable option for communities that may not have access to neuroimaging.

Alison Myoraku led a…

Alzheimer's Disease (AD) pathology can span decades before cognitive symptoms are recognized. Progression of this pathology follows a well known cascade of events, beginning with accumulation of beta-amyloid (Aβ) plaques, followed by tangles of tau proteins, neuronal atrophy, and finally cognitive impairment. Neuroimaging with PET MRI has become the gold standard in Alzheimer's research, allowing early, quantifiable detection and the opportunity for intervention. 

In recent years, researchers have been optimizing methods that may detect AD pathology in the early stages of Aβ and tau accumulation. A simple blood draw can now test for levels of AD biomarkers that can be statistically modeled to accurately predict eventual outcomes. High levels of biomarkers in the blood may indicate that they have not yet traveled to the brain where plaque and tangle accumulation occur. A recent study, led by Marta Milà-Alomà, compared blood-based biomarkers tested across six different company platforms. This data was then used to estimate the age at which participants would reach amyloid PET positivity, tau PET positivity, and the onset of AD symptoms. This "biological clock" approach can be used to align an individual's biomarker trajectories based on estimated years from key events in the cascade.

Alzheimer's disease (AD) pathology occurs over many years, typically decades before clinical symptoms present. The amyloid cascade hypothesis posits that beta-amyloid (Aβ) plaque burden occurs first, followed by tau neurofibrillary tangles, and ultimately neurodegeneration which manifests as cognitive impairment.

PET MRI is the gold standard for detection of Aβ and tau pathology. Amyloid PET can accurately detect Aβ burden very early on, and is also used to monitor disease progression in clinical trials. However, the expense, time commitment, and invasive nature of this procedure can be prohibitive. Blood-based (or plasma) biomarkers - amyloid peptide ratio Aβ42/40 and phosphorylated tau (p-tau) species - have recently proven to be valuable prognostic indicators of early AD pathology. A simple blood draw is less expensive, faster, and accurate, making clinical patients more open to participation in trials and long-term monitoring.

Dr. Marta Mila Aloma is a post-doctoral fellow in Dr. Tosun's lab, who has found that different levels of biomarkers in men vs women may affect how they are used for interpretation. At AD/PD in Lisbon, Portugal, she gave a talk presenting results from an analysis of plasma biomarkers in men and women from two independent cohorts. They examined 354 cognitively unimpaired (CU) participants from the ADNI, 450 CU from ALFA+ cohort, and 494 ADNI individuals with mild cognitive impairment (MCI) with available plasma biomarker measures. They studied differences in the association of baseline plasma biomarkers with longitudinal cognitive change (up to 5years) in three different cognitive measures: mPACC…

Even when collected simultaneously, fluid (blood/plasma) and imaging (PET/MRI) biomarkers do not necessarily reflect concurrent biological processes, as they capture fundamentally different aspects of Alzheimer's disease (AD) progression. Clara Sorensen is a graduate student in Dr Tosun's lab who uses AI for the discovery and validation of multi-modal biomarkers of neurodegenerative diseases including AD and Parkinson's disease (PD). She has been working on building computational biomarkers using graph neural networks to both predict the progression of AD pathology and to predict protein accumulation (Aβ and tau isoforms, glial fibrillary acidic protein (GFAP), and neurofilament light (NfL)) from multimodal image-based (structural MRI, diffusion MRI, and PET) graphs.

At AD/PD 2025 in Vienna, Austria, Clara presented her work to better understand temporal changes in how plasma biomarkers reflect PET-detectable AD pathology. This work found that the associations between PET and plasma biomarkers evolved distinctly over time -- variance in plasma Aβ42/40 was better explained by future PET imaging (up to 4 years ahead), while plasma p-tau217 maintained consistently strong associations across all timeframes (plasma sampling 0-4 years ahead of PET). Similarly, p-tau biomarkers showed highest sensitivity for time-matched PET status, whereas Aβ42/40 sensitivity actually improved when predicting PET status 4 years post-plasma collection.

Alzheimer’s disease (AD) is the predominant form of age-related dementia, and presents with multifactorial etiology. The accumulation of amyloid (Aβ) plaques, followed by tau tangles, ultimately contributes to synaptic dysfunction, atrophy, and eventually cognitive decline. The glymphatic system works to clear waste from the brain. Emerging evidence suggests that dysfunctional clearance of Aβ may exacerbate its aggregation and accelerate AD progression, particularly in the preclinical stages of the disease. The exact mechanism is unknown.

Serena Tang is a graduate student in Dr Tosun's lab who has been working on characterizing the role of glymphatic clearance in AD by designing computational tools to quantify perivascular spaces, the structural component of the glymphatic system. She is using statistical methods to unravel their relationship to drivers of glymphatic function and biomarkers of AD, namely cerebrovascular function and sleep. In leveraging large, multi-modal datasets (e.g. the Alzheimer’s Disease Neuroimaging Initiative (ADNI)) and experimental datasets to study these relationships across the AD continuum, her work will provide a better understanding of the brain’s waste clearance system to unravel the early pathophysiology of AD and unveil modifiable factors that can slow AD progression and preserve cognitive health.

Serena presented her work at two conferences in poster format, sharing results from an investigation of relationships between enlarged perivascular spaces (EPVS) as a measure of glymphatic clearance integrity, white matter hyperintensities (WMH) as a measure of cerebrovascular integrity, along with Aβ…