Imaging the Treatment of Alzheimer Disease: 2030 Could Look Very Different.

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Learn more: PMC Disclaimer | PMC Copyright Notice editorial Radiology . 2025 Jun 24;315(3):e251704. doi: 10.1148/radiol.251704 Imaging in the Treatment of Alzheimer Disease: The Year 2030 Could Look Very Different Timothy M Shepherd 1, ✉ Author information Article notes Copyright and License information 1 Department of Radiology, New York University Langone Medical Center, 660 First Ave, 2nd Fl, New York, NY 10016 ✉ Address correspondence to: the author (email: timothy.shepherd@nyulangone.org ). ✉ Corresponding author. Received 2025 May 14; Revision requested 2025 Jun 6; Revised 2025 Jun 10; Accepted 2025 Jun 12; Collection date 2025 Jun. © 2025 by the Radiological Society of North America, Inc. PMC Copyright notice PMCID: PMC12314760  PMID: 40552995 See commentary " Modulation of Cortical and Hippocampal Functional MRI Connectivity Following Transcranial Alternating Current Stimulation in Mild Alzheimer Disease. " on page e241463. See also the article by Wang and Yan et al in this issue. Open in a new tab Dr Shepherd is a professor of radiology at New York University. He received his MD and PhD degrees from the University of Florida, with clinical training at University of California, San Francisco. He is the section chief for neuroradiology and director of PET/MRI at New York University. His research focuses on translation of advanced imaging techniques to improve the utility of clinical radiology for neurologic disease. In the past 2 years, we have entered a highly dynamic and exciting time for the clinical diagnosis and treatment of Alzheimer disease for individual patients. Brain imaging is a key driver of this ongoing change and will remain essential, yet what imaging is performed and how it is interpreted will be profoundly altered by this process. This is only the beginning, and the study by Wang and Yan et al ( 1 ) in this issue of Radiology suggests additional potential directions to our near future that deserve our attention. During my training (around 2010), trainees were simply taught to exclude hydrocephalus, confluent white matter disease, and mass effect in patients imaged for cognitive impairment, but this type of radiology report was rarely actionable. It was hard to get excited about imaging findings in those patients because treatment was perceived to be limited by all stakeholders. Now, multiple promising investigational pharmacologic and nonpharmacologic treatments for Alzheimer disease are reaching the later stages of clinical translation and placing new demands for advanced imaging methods like amyloid PET and resting-state functional MRI (fMRI). Radiologists may be drowning in stroke-code CT angiography examinations and feel overwhelmed by the pace of technologic change throughout our field, but these new treatments create an incredible and rewarding opportunity for us to incorporate newer imaging techniques. We can be highly relevant to clinical decision-making for one of the most important worldwide health challenges of the 21st century. Alzheimer disease is the most common neurodegenerative disease worldwide. In the United States and Europe, at 65 years of age approximately 10% of the population will have mild Alzheimer disease, and even 21% of patients that are cognitively normal will be amyloid positive on PET or CSF studies, indicating increased future risk for developing the disease ( 2 ). Antiamyloid immunotherapies have started to dramatically affect radiology and can serve as a heuristic for understanding the potential impact of applying transcranial stimulation therapies in the same patient population. Lecanemab and donanemab are highly effective at removing amyloid visible on PET scans, with more modest impacts on measurable clinical outcomes ( 3 – 4 ). Many patients with mild cognitive impairment have embraced this treatment, but it requires commitment: 1.5 years of monthly or bimonthly infusions, and at least four to six repeat MRI examinations that screen possible complications that can be clinically silent and only evident initially at MRI (amyloid-related imaging abnormality) ( 5 ). Patients also must undergo amyloid PET or lumbar puncture to confirm abnormal brain amyloid accumulation before the initiation of treatment. Some practices, like ours, pursue a second amyloid PET examination to help determine completion of therapy. To meet demand, medical centers have rushed to develop assessment, treatment, and monitoring protocols and expand infusion center capacity. Whereas the Imaging Dementia—Evidence for Amyloid Scanning (known as IDEAS) study demonstrated the clinical value of knowing the amyloid status of an individual patient ( 6 ), these treatments appear to be more responsible for a surging demand in amyloid imaging. For example, across the New York University radiology enterprise in 2022, we performed about 12 clinical amyloid PET studies per year; now we sometimes perform 12 per day! Everywhere, radiologists with a decade or more of posttraining experience have had to learn to read amyloid PET in the past 18 months. Radiology and neurology now carefully debate gradient-echo versus susceptibility-weighted imaging to help detect hemorrhage because this one choice of MRI sequence can determine who undergoes treatment. Unfortunately for the busy radiologist, the exact number of microhemorrhages in the report has become critical. Before, a hypothetical patient with cognitive impairment in the community might undergo a single outpatient CT or MRI examination. Now the same patient may undergo one or two PET and five or six MRI examinations over the first 2-year period. Besides the number of new imaging studies, antiamyloid therapy has completely changed engagement of the patient and the referrer with radiology for cognitive impairment—nuanced, expert interpretation of the images by a radiologist helps determine treatment decisions. In this issue of Radiology , Wang and Yan et al ( 1 ) add to growing evidence for using transcranial stimulation as an alternative or complementary nonpharmacologic treatment of Alzheimer disease ( 7 ). Transcranial magnetic or electrical stimulation can modulate brain activity, is considered safe, and may allow targeting of specific brain regions. The mechanism of action remains poorly understood, and treatment requires repeated sessions. Compared with transcranial magnetic stimulation, the transcranial alternative current stimulation (tACS) used in the study by Wang and Yan et al ( 1 ) can be less expensive and cumbersome for community-based interventions. It more specifically modulates oscillatory brain activity but has lower anatomic specificity, and the direct effects are limited to the superficial brain. In the study by Wang and Yan et al ( 1 ), tACS was administered to patients with mild Alzheimer disease using 40 Hz and 15-mA current for two 1-hour sessions per weekday over 3 straight weeks (30 hours total treatment). The 40-Hz gamma frequency chosen should entrain brain rhythms noninvasively, particularly in memory and attention affected by early Alzheimer disease. The patients who were treated with tACS demonstrated improved performance at blinded cognitive assessment at 3 weeks that appeared largely sustained 3 months later (an interesting finding that suggests tACS effects are not just temporary). Seed-based connectivity measured with resting-state fMRI demonstrated increased connectivity between the left hippocampus and the left middle cingulate or between the left hippocampus and the left middle frontal gyrus at 3 weeks. Left hippocampal functional connectivity to the left cingulate correlated with improved scores on the Boston Naming Test at 3 months, which could be an effect of tACS on the supplementary motor area in the language-dominant hemisphere (all patients were right-handed). Several canonical networks in resting-state fMRI also demonstrated increased connectivity with tACS treatment. This single-site study had multiple limitations. The 15-mA current chosen here is an aggressive current setting for tACS with theoretical increased risks for skin injury, seizures, or altered perceptions (no serious adverse events were observed). Further study is needed to better understand and optimize this approach for treating patients with different stages of Alzheimer disease, but the results appear promising. A traditionalist could argue that research for transcranial stimulation to treat Alzheimer disease belongs in a different journal, but I would challenge Radiology readers to better understand the future implications of this report. Noninvasive brain stimulation supports investigations of human brain structure–function relationships in vivo in a unique way that excites our referrers and is already used clinically for treating depression and other mental disorders ( 8 ). These techniques appear unfamiliar to most radiologists (like amyloid PET in 2020?), but it is time for us to pay more attention. The radiology perspective should be developed: What we care about are precise and reproducible objective imaging findings detectable in individual patients. Like functional neurosurgery, this is an area of potential rapid growth for clinical treatment of neurologic and psychiatric diseases, including perhaps safer, broadly applicable, and cost-effective treatment than antiamyloid immunotherapies for patients with cognitive impairment. Notably, like antiamyloid immunotherapy, imaging provided key data at all three points to assess the therapeutic response. The specific use of resting-state fMRI to help detect functional connectivity changes between targeted structures and networks after 40-Hz tACS was relatively novel within this field. Transcranial current stimulation must penetrate the scalp and calvarium—the current that reaches the brain parenchyma will be diffuse and superficial, unlikely to affect deep structures like the hippocampus directly. The main effect then is to entrain or modulate brain oscillations via the cerebral cortex. It is intuitive, then, that tACS-induced changes to brain network connectivity and specific structure-to-structure functional connectivity in patients with Alzheimer disease may best be depicted using resting-state fMRI. The observed connectivity changes with resting-state fMRI remain less specific and concrete than I would like but are still more objective and closer to the treatment mechanism than blinded Mini-Mental State Examination results or other clinical measures of cognition. This also strikes me as a much more accessible and potentially broad application of resting-state fMRI for future patient care than early narrow efforts just to reproduce task-based fMRI in patients undergoing neurosurgery. Previous studies have also demonstrated resting-state fMRI differences among stages of Alzheimer disease ( 9 ), albeit clinical use for individual patients remains unproven. Resting-state fMRI has been around for more than 25 years but is still not used in clinical patients. Perhaps, like the acceleration in the use of amyloid PET that is occurring now, transcranial stimulation for neurologic diseases, including dementia, will finally push radiologists to understand resting-state fMRI and use it in our practice. The evolution of imaging for the treatment of Alzheimer disease appears to be increasing. As more specialized imaging and therapeutic applications are integrated into clinical practice, there will be increasing demands on radiologists to learn interpretation skills we could scarcely imagine during our training (even if you graduated from a neuroradiology fellowship just last month). Footnotes Funding: T.M.S. supported by the National Institutes of Health (NIH NIA P30-AG066512, NIH NIA R01-AG092014, NIH NINDS R01-NS139531, NIH BIBIB R01-EB028774). Disclosures of conflicts of interest: T.M.S. Payment for expert testimony; support for attending meetings from the Australian and New Zealand Society for Neuroradiology, ASNR Ann Osborne International Visiting Professor; associate editor for Radiology ; stock/stock options for MICroStructure Imaging. References 1. Wang T , Yan S , Shan Y , et al . Modulation of Cortical and Hippocampal Functional MRI Connectivity following Transcranial Alternating Current Stimulation in Mild Alzheimer's Disease . Radiology 2025. ; 315 ( 3 ): e241463 . [ DOI ] [ PubMed ] [ Google Scholar ] 2. Jansen WJ , Janssen O , Tijms BM , et al. ; Amyloid Biomarker Study Group . Prevalence Estimates of Amyloid Abnormality Across the Alzheimer Disease Clinical Spectrum . JAMA Neurol 2022. ; 79 ( 3 ): 228 – 243 . [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] 3. van Dyck CH , Swanson CJ , Aisen P , et al . Lecanemab in Early Alzheimer's Disease . NEJM 2023. ; 388 ( 1 ): 9 – 21 . [ DOI ] [ PubMed ] [ Google Scholar ] 4. Sims JR , Zimmer JA , Evans CD , et al . Donanemab in Early Symptomatic Alzheimer Disease: The TRAILBALZER-ALZ2 Randomized Clinical Trial . JAMA 2023. ; 330 ( 6 ): 512 – 527 . [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] 5. Barakos J , Purcell D , Suhy J , et al . Detection and Management of Amyloid-Related Imaging Abnormalities in Patients with Alzheimer's Disease Treated with Anti-Amyloid Beta Therapy . J Prev Alzheimers Dis 2022. ; 9 ( 2 ): 211 – 220 . [ DOI ] [ PubMed ] [ Google Scholar ] 6. Rabinovici GD , Gatsonis C , Apgar C , et al . Association of Amyloid Positron Emission Tomography with Subsequent Change in Clinical Management Among Medicare Beneficiaries with Mild Cognitive Impairment or Dementia . JAMA 2019. ; 321 ( 13 ): 1286 – 1294 . [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] 7. Elder GJ , Taylor J-P

. Transcranial Magnetic Stimulation and Transcranial Direct Current Stimulation: Treatments for Cognitive and Neuropsychiatric Symptoms in the Neurodegenerative Dementias? Alzheimers Res Ther 2014. ; 6 ( 9 ): 74 . [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] 8. Sabé M , Hyde J , Cramer C , et al . Transcranial Magnetic Stimulation and Transcranial Direct Current Stimulation Across Mental Disorders: A Systematic Review and Dose-Response Meta-Analysis . JAMA Netw Open 2024. ; 7 ( 5 ): e2412616 . [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] 9. Ibrahim B , Suppiah S , Ibrahim N , et al . Diagnostic power of resting-state fMRI for detection of network connectivity in Alzheimer's disease and mild cognitive impairment: A systematic review . Hum Brain Mapp 2021. ; 42 ( 9 ): 2941 – 2968 . [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] Articles from Radiology are provided here courtesy of Radiological Society of North America ACTIONS View on publisher site PDF (224.9 KB) Cite Collections Permalink RESOURCES Similar articles Cited by other articles Links to NCBI Databases Follow NCBI NCBI on X (formerly known as Twitter) NCBI on Facebook NCBI on LinkedIn NCBI on GitHub NCBI RSS feed Connect with NLM NLM on X (formerly known as Twitter) NLM on Facebook NLM on YouTube National Library of Medicine 8600 Rockville Pike Bethesda, MD 20894 Web Policies FOIA HHS Vulnerability Disclosure Help Accessibility Careers NLM NIH HHS USA.gov Back to Top

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