10/2025 journal articles
EDITORIAL: HARNESSING COMBINATION THERAPY: CURRENT TREATMENTS, RECENT ADVANCEMENTS, AND FUTURE DIRECTIONS IN ALZHEIMER\'S DISEASE
Howard M Fillit, Jacques Touchon, Bruno Vellas, Laura K Nisenbaum, Aaron H Burstein
J Prev Alz Dis 2025;10(12)
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CITATION:
Howard M Fillit ; Jacques Touchon ; Bruno Vellas ; Laura K Nisenbaum ; Aaron H Burstein (2025): Editorial: Harnessing combination therapy: Current treatments, recent advancements, and future directions in Alzheimer's disease. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100327
ALZHEIMER COMBINATION THERAPIES: OVERVIEW AND SCENARIOS
Jeffrey L Cummings, Aaron H Burstein, Howard Fillit
J Prev Alz Dis 2025;10(12)
Show summaryHide summaryProgress in understanding the complexity of Alzheimer's disease informs the search for combination therapies that can successfully prevent or substantially slow the progression of the disease. Anti-amyloid monoclonal antibodies are the first approved disease targeted therapies; they slow disease progression by approximately 30 %. Building on these agents in add-on therapies is one avenue to designing combination treatments. Development of combination drugs consisting of two or more novel interventions is an alternate pathway for combination treatment development. Combination therapies can involve small molecule drugs, biological agents, devices, stem cells, gene therapies, lifestyle interventions, or cognitive training. Nonclinical assessment of drug combinations may involve animal models or new approach methodologies such as induced pluripotent stem cells or organoids. Phase 1 trials are required to characterize each member of a novel combination. Phase 2 trials may use a 2-by-2 factorial design comparing each drug to placebo and the drug combination. In Phase 3, comparison of the novel combination to standard of care may be sufficient or more complex designs may be required. Targets for combination therapies beyond amyloid-related processes include tau abnormalities, inflammation, neurodegeneration, and co-pathologies such as alpha-synuclein and TDP-43. The choice of combination therapies will depend on the strength of the information regarding the target, biomarkers to guide clinical trials, and a candidate agent with the appropriate mechanism of action. Computational strategies based on network analysis of disease and drugs, validation in non-clinical models, and use of real-world data may facilitate prioritization of candidates for combination treatments.
CITATION:
Jeffrey L Cummings ; Aaron H Burstein ; Howard Fillit (2025): Alzheimer Combination Therapies: Overview and Scenarios. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100328
ADD-ON COMBINATION THERAPY WITH MONOCLONAL ANTIBODIES: IMPLICATIONS FOR DRUG DEVELOPMENT
Jeffrey Cummings, Aaron H Burstein, Howard Fillit
J Prev Alz Dis 2025;10(12)
Show summaryHide summaryThree anti-amyloid monoclonal antibodies (MABs) including aducanumab, lecanemab, and donanemab have been approved by the FDA and lecanemab and donanemab are available in the US market and a variety of other national markets. The increasing use of anti-amyloid MABs to treat early AD will require that development of novel agents occur as add-on treatment to MABs. There is limited experience with add-on therapy to anti-amyloid agents. In most cases, it is prudent to initiate novel agents after at least six-months exposure to the MAB at the highest dose. Agents with extensive data on pharmacokinetics and pharmacodynamics and well-known safety may employ alternative approaches. Anti-amyloid MABs have different mechanisms of action, titration, and side effect profiles suggesting that add-on trials include only one type of MAB if possible. Demonstration of clinical benefit with add-on therapy will require showing additional slowing beyond that provided by the anti-amyloid MAB. Anti-amyloid therapies have profound effects on biomarkers including amyloid positron emission tomography and plasma p-tau and plasma GFAP measures. Definition of the biomarker profile of a novel agent prior to initiation of add-on therapies, inclusion of target engagement biomarkers specific to the novel intervention, assessment of biomarkers not known to be affected by anti-amyloid MABs, and interrogation of the magnitude, timing, and trajectory of biomarker change in the add-on context compared to monotherapy with MABs will provide insight into the biological impact of the novel therapy on AD. Patient convenience in terms of formulation and timing of add-on therapies will be important to successful clinical implementation. Add-on therapies are an important step in addressing the complexity of AD and optimizing patient outcomes.
CITATION:
Jeffrey Cummings ; Aaron H Burstein ; Howard Fillit (2025): Add-on combination therapy with monoclonal antibodies: Implications for drug development. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100359
THE ROLE FOR ARTIFICIAL INTELLIGENCE IN IDENTIFYING COMBINATION THERAPIES FOR ALZHEIMER’S DISEASE
Feixiong Cheng, Zhendong Sha, Yadi Zhou, Yuan Hou, Pengyue Zhang, Andrew A. Pieper, Jeffrey Cummings
J Prev Alz Dis 2025;10(12)
Show summaryHide summaryDespite substantial investment in biomedical and pharmaceutical research over the past two decades, the global prevalence of Alzheimer’s disease (AD) and AD-related dementias (AD/ADRD) is still rising. This underscores the significant unmet need for identifying effective disease-modifying therapies. Here, we provide a critical perspective on the application of data science and artificial intelligence (AI) to the rational design of drug combinations in AD and ADRD, addressing their potential to transform therapeutic development. We examine AI’s current and prospective capabilities in therapeutic discovery, identify areas where AI-driven strategies can enhance drug combination development, and outline how multidisciplinary professionals in the field, including clinical trialists, neuropsychiatrists, pharmacologists, medicinal chemists, and computational scientists, can leverage these tools to address therapeutic gaps. We also highlight AI’s role in synthesizing the rapidly growing amount of biomedical data in the field of AD/ADRD, especially clinical trials, biomarkers, multi-omics data (genomics, transcriptomics, proteomics, metabolomics, interactomics, and radiomics), and real-world patient data. We further explore AI’s utility in prioritizing potential drug combination regimens and estimating clinical effect size in combination therapy trials for AD/ADRD. Lastly, we emphasize AI-powered network medicine methodologies for prioritizing drug combinations targeting AD/ADRD co-pathologies and summarize the challenges of their translation to clinical practice.
CITATION:
Feixiong Cheng ; Zhendong Sha ; Yadi Zhou ; Yuan Hou ; Pengyue Zhang ; Andrew A. Pieper ; Jeffrey Cummings (2025): The role for artificial intelligence in identifying combination therapies for Alzheimer’s disease. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100366
THE IMPACT OF RECENT APPROVALS ON FUTURE ALZHEIMER’S DISEASE CLINICAL DEVELOPMENT: STATISTICAL CONSIDERATIONS FOR COMBINATION TRIALS
Samuel P Dickson, Craig Mallinckrodt, Aaron H Burstein, Laura Nisenbaum, Howard M Fillit, Chenge Zhang, Suzanne B Hendrix
J Prev Alz Dis 2025;10(12)
Show summaryHide summaryBACKGROUND: A new era of Alzheimer’s disease (AD) research is beginning with multiple approved anti-amyloid monoclonal antibodies (mABs). These drugs are currently not widely used, but may be soon, especially at clinical trial sites. Putative disease-modifying therapies (DMTs) may alter the progression rate, potentially reducing our ability to detect effects on top of mABs. Co-administration of amyloid-targeted agents may diminish benefit (antagonism, due to the overlapping mechanism of action); alternatively, complementary treatment mechanisms may increase benefit (synergy).
METHOD: We consider several clinical trial design scenarios: a 2-arm trial added-on to a mAB, a 2-arm combination compared to double placebo, and a 4-arm full factorial trial. We calculate the required sample sizes for the shortest practical study for secondary prevention (prevention of AD clinical diagnosis in biomarker positive individuals, 2-year study), early AD (18-months), and mild-to-moderate AD (1-year). We consider additivity, antagonism, and synergy.
RESULT: The expected interaction between investigational and mAB treatment can have a large effect on power and study design. Antagonistic treatment effects often require double the sample size of synergistic effects. The 4-arm scenario required ∼10-fold increase compared to a 2-arm combination study.
CONCLUSION: Studies evaluating investigational therapies as add-on to mABs are complex, and their cost will depend on the interaction between treatments. An inescapable fact in add-on trials is the slower progression of the control arm; and it is difficult to further slow already slow progression. Treatments that are likely to work better with amyloid removal will be easier to study due to their complementary MOA. Symptomatic treatments may require fewer additional subjects than disease-modifying treatments since they are less affected by the presence or absence of mABs.
CITATION:
Samuel P Dickson ; Craig Mallinckrodt ; Aaron H Burstein ; Laura Nisenbaum ; Howard M Fillit ; Chenge Zhang ; Suzanne B Hendrix (2025): The impact of recent approvals on future alzheimer’s disease clinical development: Statistical considerations for combination trials. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100391
STATISTICAL INNOVATIONS IN CLINICAL TRIAL DESIGN WITH A FOCUS ON DRUG COMBINATIONS, FACTORIALS, AND OTHER MULTIPLE THERAPY ISSUES
Donald A. Berry
J Prev Alz Dis 2025;10(12)
Show summaryHide summaryStatistical methods in clinical research tend to become entrenched. Innovations threaten the status quo. The “right way” becomes frozen in lore. This is so even when the “right way” is not best. “Statistical significance” and the associated requirement of “high power” is an example. This attitude is an impediment to efficient design. Willingness to address some design issues with moderate power enables building highly informative and highly efficient clinical trials. This article considers several types of clinical trials, including dose-finding, combinations, and factorial designs. Bayesian adaptive methods are used to show that trials can be made more efficient and more informative. Surprisingly, the approach is consistent with many attitudes of the widely regarded “Father of Modern Statistics,” R.A. Fisher. Fisher was anti-Bayesian in rejecting its subjective interpretations. But Fisher and Bayes come to the same conclusion in many applied matters. Fisher invented factorial design. Its principal attraction for him was enabling addressing two or more questions with a single experiment. He complained about attitudes that hindered progress: “No aphorism is more frequently repeated in connection with field trials [and clinical trials], than that we must ask Nature few questions, or, ideally, one question at a time… this view is wholly mistaken.” Fisher’s primary analysis required modeling and making assumptions. For example, his first analysis in a factorial setting assumed no interactions among the factors. He investigated possibilities of interactions but he did not see the need for doing so with high power.
CITATION:
Donald A. Berry (2025): Statistical innovations in clinical trial design with a focus on drug combinations, factorials, and other multiple therapy issues. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100392
RISK REDUCTION AND PRECISION PREVENTION ACROSS THE ALZHEIMER’S DISEASE CONTINUUM: A SYSTEMATIC REVIEW OF CLINICAL TRIALS COMBINING MULTIDOMAIN LIFESTYLE INTERVENTIONS AND PHARMACOLOGICAL OR NUTRACEUTICAL APPROACHES
Erika Bereczki, Francesca Mangialasche, Mariagnese Barbera, Paola Padilla, Yuko Hara, Howard Fillit, Alina Solomon, Miia Kivipelto
J Prev Alz Dis 2025;10(12)
Show summaryHide summaryTo effectively combat dementia onset and progression, lifestyle-based interventions targeting multiple risk factors and disease mechanisms through a multidomain approach - tailored and implemented early in the disease process - have emerged as promising. Electronic databases and relevant websites (clinicaltrials.gov, euclinicaltrials.eu, PubMed and EMBASE) were systematically searched for randomized controlled trials (RCTs) testing the combination of multidomain lifestyle and pharmacological interventions. Studies were included if 1) lifestyle intervention was multimodal (≥2 domains); 2) it was combined with drugs, supplements, or medical food; 3) the study population was within the Alzheimer’s disease (AD) and related dementias continuum, including cognitively normal individuals at-risk for dementia, people with subjective cognitive decline (SCD), mild cognitive impairment (MCI), or prodromal AD; 4) outcomes included cognitive or dementia-related measure(s), and 5) intervention lasted at least 6 months. Twelve combination RCTs were identified, incorporating 2 to 7 lifestyle domains (physical exercise, cognitive training, dietary guidance, social activities, sleep hygiene, cardiovascular/metabolic risk management, psychoeducation or stress management), combined with pharmacological components (e.g., Omega-3, Tramiprosate, vitamin D, BBH-1001, epigallocatechin gallate, Souvenaid, and metformin). Seven RCTs targeted participants with prodromal AD, MCI or early dementia, five focused on at risk individuals or SCD. Additionally, 2 studies adopted a precision medicine approach by enriching populations with APOE-ε4 carriers. Findings suggest that well-designed interventions - tailored to the right individuals, implemented at the optimal time - may effectively improve cognition. However, further refinement of the RCT methodology is warranted, for better alignment with the multifaceted nature of dementia prevention and management.
CITATION:
Erika Bereczki ; Francesca Mangialasche ; Mariagnese Barbera ; Paola Padilla ; Yuko Hara ; Howard Fillit ; Alina Solomon ; Miia Kivipelto (2025): Risk reduction and precision prevention across the Alzheimer’s disease continuum: a systematic review of clinical trials combining multidomain lifestyle interventions and pharmacological or nutraceutical approaches. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100367
IDENTIFYING SYNERGISTIC COMBINATIONS OF REPURPOSED TREATMENTS FOR ALZHEIMER’S DISEASE
Clive Ballard, Janet Sultana, Pat Doherty, Gareth Williams, Anne Corbett
J Prev Alz Dis 2025;10(12)
Show summaryHide summaryThere is considerable opportunity to fast-track novel treatments for Alzheimer’s Disease (AD) through repurposing of existing licensed medications as a way of complementing ongoing drug discovery efforts. Given the complex interplay between AD neuropathological mechanisms, there is also a strong rationale that treatment benefits may be enhanced by examining combinations of treatments to identify potential synergies that would address multiple disease-modifying mechanisms. A Delphi consensus programme combined with a pragmatic analysis of primary care data has identified a series of individual and combined therapies that warrant further investigation in pre-clinical and clinical trials. These include treatments which target well-established neurodegeneration pathways and more explorative agents, including hormonal and anti-infective agents, which align to emerging hypotheses relating to endocrine and immune pathways in AD. Whilst caution is critical when considering combined therapy due to the risks of interaction and polypharmacy, this study provides valuable indications of potential synergistic drug pairs that warrant further investigation.
CITATION:
Clive Ballard ; Janet Sultana ; Pat Doherty ; Gareth Williams ; Anne Corbett (2025): Identifying synergistic combinations of repurposed treatments for Alzheimer’s Disease. The Journal of Prevention of Alzheimer’s Disease (JPAD).https://doi.org/10.1016/j.tjpad.2025.100329
ASSOCIATION BETWEEN ALCOHOLIC BEVERAGE CONSUMPTION AND CEREBRAL SMALL VESSEL DISEASE BURDEN
Ben-Bo Xiong, Zi-Jie Wang, Zhi-Ming Li, Tian-Nan Yang, Xiang-Yu Li, Meng-Jie Lu, Qi Li
J Prev Alz Dis 2025;10(12)
Show summaryHide summaryBACKGROUND: The relationship between alcohol consumption and cerebral small vessel disease (CSVD) remains uncertain, particularly regarding drinking patterns and beverage types. We investigated how total alcohol intake, drinking frequency, and beverage-specific consumption are associated with CSVD burden using cross-sectional data.
METHODS: We included 27,326 UK Biobank (UKB) participants with MRI data, among whom 21,130 were current drinkers with full alcohol intake data. Alcohol consumption (frequency and beverage type) was self-reported. CSVD burden was measured via normalized white matter hyperintensity volume (WMHV) on T2-FLAIR MRI. Multivariable linear regression models adjusted for demographics, lifestyle, and vascular risk factors were used to examine associations.
RESULTS: Compared with non-drinkers, alcohol consumers had greater CSVD burden (Beta = 0.07; 95 % CI, 0.00–0.15). Among them, higher drinking frequency (≥5 times/week) was associated with increased CSVD burden (Beta = 0.10; 95 % CI, 0.07–0.13). High consumption of red wine, white wine/champagne, and spirits (≥7 servings/week) correlated positively with CSVD burden. In contrast, low-to-moderate beer/cider intake (≤3 servings/week) was inversely associated with burden. A dose-response relationship between total ethanol intake and CSVD burden was observed, with minimal intake (<1.97 g/day) showing a mild negative association, and higher levels increasing risk.
CONCLUSION: Greater frequency and volume of alcohol intake, especially from wine and spirits, are linked with higher CSVD burden. Conversely, low beer/cider consumption may be inversely associated with CSVD burden. These findings underscore the importance of moderating alcohol consumption to maintain cerebrovascular health.
CITATION:
Ben-Bo Xiong ; Zi-Jie Wang ; Zhi-Ming Li ; Tian-Nan Yang ; Xiang-Yu Li ; Meng-Jie Lu ; Qi Li (2025): Association between alcoholic beverage consumption and cerebral small vessel disease burden. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100322
BRAIN PATTERNS AND RISK FACTORS IN THE FINGER RCT MULTIMODAL LIFESTYLE INTERVENTION
Giulia Lorenzon, Anna Marseglia, Rosaleena Mohanty, Jenni Lehtisalo, Konstantinos Poulakis, Tiia Ngandu, Alina Solomon, Miia Kivipelto, Eric Westman
J Prev Alz Dis 2025;10(12)
Show summaryHide summaryIMPORTANCE: Despite the emergence of anti-amyloid therapies for Alzheimer's disease, targeting modifiable risk factors remains the most effective primary prevention strategy for dementia. While cognitive benefits of multimodal lifestyle interventions have been demonstrated, the underlying effects on brain structure remain unclear, likely due to heterogeneity in brain structure among at-risk individuals.
OBJECTIVE: To investigate how distinct subgroups of at-risk individuals, defined by cortical and subcortical grey matter (GM) patterns, differ in their response to the FINGER intervention, as well as in their demographic, vascular, and lifestyle profiles.
CITATION:
Giulia Lorenzon ; Anna Marseglia ; Rosaleena Mohanty ; Jenni Lehtisalo ; Konstantinos Poulakis ; Tiia Ngandu ; Alina Solomon ; Miia Kivipelto ; Eric Westman (2025): Brain patterns and risk factors in the FINGER RCT multimodal lifestyle intervention. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2025.8
DESIGN: Observational study employing unsupervised clustering of MRI-based cortical thickness and subcortical volume metrics, followed by longitudinal assessment of a lifestyle intervention.
SETTING: The FINGER randomized controlled trial (RCT), a population-based, multidomain lifestyle intervention targeting older adults (aged 60–77) with elevated cardiovascular risk (CAIDE score ≥ 6) and average to slightly below-average cognitive performance.
PARTICIPANTS: A total of 120 participants (61 intervention, 59 control) with available baseline MRI data.
INTERVENTION: Participants were randomly assigned (1:1, double-blind) to a 2-year multidomain lifestyle intervention group – targeting diet, physical activity, cognitive training, social engagement, and metabolic and vascular risk management – or to a control group receiving standard health advice.
MAIN OUTCOMES AND MEASURES: Sociodemographic, vascular, and lifestyle factors, medical comorbidities, and cognitive performance, were assessed at baseline (pre-intervention). Additionally, brain structural outcomes (mean cortical thickness, Alzheimer’s disease and resilience-related cortical signatures, hippocampal volume), and cognition (global, executive function, processing speed, memory) were analysed post-intervention using hierarchical linear models stratified by GM cluster.
RESULTS: Clusters with diffuse or frontal-predominant cortical thinning, but with more favourable vascular profiles, characterized by lower blood pressure and reduced obesity, showed significantly less cortical thinning (mean thickness, AD-signature, and resilience-signature regions; all p < 0.05) following the intervention.
CONCLUSIONS AND RELEVANCE: Stratifying at-risk individuals by GM patterns and vascular risk revealed differential brain responses to the FINGER intervention. These findings underscore the value of brain-based subtyping to optimize personalized dementia prevention strategies in heterogeneous at-risk populations.
CITATION:
Giulia Lorenzon ; Anna Marseglia ; Rosaleena Mohanty ; Jenni Lehtisalo ; Konstantinos Poulakis ; Tiia Ngandu ; Alina Solomon ; Miia Kivipelto ; Eric Westman (2025): Brain patterns and risk factors in the FINGER RCT multimodal lifestyle intervention. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100390
ASSOCIATION BETWEEN CEREBRAL MICROBLEEDS AND COGNITION IN A MEMORY CLINIC POPULATION
Young Min Choe, Hyewon Baek, Min Soo Byun, Dahyun Yi, Hyejin Ahn, Gijung Jung, Chul-Ho Sohn, Dong Young Lee
J Prev Alz Dis 2025;10(12)
Show summaryHide summaryBACKGROUND: The cognitive consequences of cerebral microbleeds (CMBs) in memory clinic population with a diverse cognitive spectrum remain unclear.
OBJECTIVES: This study aimed to investigate how CMBs at different locations are associated with cognitive performance in a memory clinic population and whether these associations are independent of related small vessel disease (SVD) markers.
DESIGN: A cross-sectional study.
SETTING: A university hospital memory clinic. Data were collected from December 2004 to September 2014 and analyzed in June 2024.
PARTICIPANTS: A total of 910 participants, composed of 64 individuals with subjective cognitive decline, 399 with mild cognitive impairment (MCI), 339 with Alzheimer disease dementia (AD), 58 with vascular dementia and mixed dementia, and 50 with other types of dementia, were included.
MAIN OUTCOMES AND MEASURES: Summary scores for global cognition, memory, language, visuospatial function, and executive function measured by the Consortium to Establish a Registry for Alzheimer’s disease (CERAD) neuropsychological battery.
RESULTS: In the overall population, the presence of deep/infratentorial CMBs was significantly associated with executive dysfunction; however, this association was attenuated after adjusting for related SVD markers. When stratified by diagnostic subgroup, strictly lobar CMBs were significantly associated with impairments in global cognition and memory in the MCI group, independent of related SVD markers. In contrast, no significant associations between CMBs and cognitive domains were observed in the AD group.
CONCLUSIONS: These findings, based on memory clinic population with a broad cognitive spectrum, suggest that CMBs, depending on their location, may have different implications for cognitive function.
CITATION:
Young Min Choe ; Hyewon Baek ; Min Soo Byun ; Dahyun Yi ; Hyejin Ahn ; Gijung Jung ; Chul-Ho Sohn ; Dong Young Lee (2025): Association between cerebral microbleeds and cognition in a memory clinic population. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100340
PULSE PRESSURE AS A PREDICTOR OF ALZHEIMER’S DISEASE BIOMARKERS AND COGNITIVE DECLINE: THE MODERATING ROLE OF APOE Ε4
Joon Hyung Jung, Nayeong Kong, Seunghoon Lee, A4 and LEARN Study Teams
J Prev Alz Dis 2025;10(12)
Show summaryHide summaryBACKGROUND: Elevated pulse pressure (PP), indicative of arterial stiffness, has been implicated in cognitive impairment and Alzheimer’s disease (AD) pathology. However, its role in preclinical AD and interactions with genetic risk factors like apolipoprotein E ε4 (APOE4) remain unclear.
OBJECTIVES: To investigate the association between baseline PP and AD biomarkers (amyloid-beta (Aβ) and tau) and cognitive decline, and to determine whether APOE4 carrier status moderates these relationships.
DESIGN: Prospective cohort study and secondary analysis of the Anti-Amyloid Treatment in Asymptomatic Alzheimer’s (A4) randomized clinical trial
SETTING: Multicenter observational cohort and randomized clinical trial conducted at 67 sites across the United States, Canada, Australia, and Japan.
PARTICIPANTS: This study included 1690 cognitively unimpaired older adults from the A4 and Longitudinal Evaluation of Amyloid Risk and Neurodegeneration (LEARN) studies. Participants underwent baseline PP assessment, Aβ and tau PET imaging, and cognitive testing with longitudinal follow-up over 240 weeks.
MEASUREMENTS: Blood pressure was measured at baseline, with PP calculated as the difference between systolic and diastolic pressures. AD pathologies were assessed through Aβ PET imaging using 18F-Florbetapir, and regional tau deposition in inferior temporal and meta-temporal regions using 18F-Flortaucipir PET imaging. Cognitive performance was measured using the Preclinical Alzheimer Cognitive Composite (PACC).
RESULTS: Higher baseline PP was significantly associated with increased Aβ (β = 0.078; p = 0.001), inferior temporal tau (β = 0.110; p = 0.032), and meta-temporal tau deposition (β = 0.116; p = 0.022). In longitudinal analyses, elevated PP predicted greater decline in PACC scores (β = −0.020; p < 0.001). APOE4 status moderated these associations, with significant effects of PP on tau deposition and cognitive decline observed exclusively among APOE4 carriers. Mediation analysis indicated that tau deposition significantly mediated the association between PP and cognitive decline (indirect effect β = −0.068; 95 % CI [−0.126, −0.011]).
CONCLUSIONS: Elevated PP is associated with increased AD biomarker burden and accelerated cognitive decline in cognitively unimpaired older adults, particularly among APOE4 carriers. Our study suggests that arterial stiffness may contribute to AD pathogenesis and progression via tau pathology. These results highlight the potential of vascular health management as an early intervention target for AD prevention, especially in genetically at-risk populations.
CITATION:
Joon Hyung Jung ; Nayeong Kong ; Seunghoon Lee ; A4 and LEARN Study Teams (2025): Pulse pressure as a predictor of Alzheimer’s disease biomarkers and cognitive decline: The moderating role of APOE ε4. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100363
CORTICAL MICROSTRUCTURE IN FAMILIAL FRONTOTEMPORAL DEMENTIA ASSOCIATED WITH MAPT, GRN, AND C9ORF72 PATHOGENIC VARIANTS: LOOKING BEYOND ATROPHY
Lijuan Wang, Si Cen, Li Zhao, Junfeng Tang, Pengcheng Xu, Pusheng Quan, Wencai Ding, ARTFL-LEFFTDS Longitudinal Frontotemporal Lobar Degeneration (ALLFTD) Research Consortium
J Prev Alz Dis 2025;10(12)
Show summaryHide summaryBACKGROUND: This study aimed to evaluate cortical mean diffusivity (cMD) as a sensitive biomarker for early neurodegenerative changes in familial frontotemporal lobar degeneration (FTLD) associated with C9orf72, GRN, and MAPT mutations. We compared cMD with cortical thickness (cTH) in detecting subtle microstructural alterations and examined its association with clinical severity and neurofilament light chain (NFL) concentrations.
METHODS: We analyzed data from 322 participants, including symptomatic carriers of C9orf72 (n = 85), GRN (n = 56), and MAPT (n = 58) mutations, along with 123 healthy controls. Cortical microstructure was assessed using both cTH and cMD. Clinical severity was evaluated with the CDR plus NACC FTLD scale, and plasma NFL was measured as a marker of neuroaxonal injury.
RESULTS: C9orf72 carriers exhibited the most widespread cortical thinning and increased cMD, while GRN and MAPT carriers showed more regionally restricted alterations. Across all mutation groups, cMD demonstrated higher sensitivity than cTH in detecting early changes. Furthermore, cMD values were significantly correlated with CDR plus NACC FTLD scores and NFL concentrations, underscoring its relevance to disease progression.
CONCLUSION: Cortical mean diffusivity outperforms cortical thickness in detecting early microstructural changes in familial FTLD. Its strong association with both clinical severity and neurodegeneration biomarkers highlights its potential utility for early diagnosis, disease monitoring, and individualized therapeutic strategies in FTLD.
CITATION:
Lijuan Wang ; Si Cen ; Li Zhao ; Junfeng Tang ; Pengcheng Xu ; Pusheng Quan ; Wencai Ding ; ARTFL-LEFFTDS Longitudinal Frontotemporal Lobar Degeneration (ALLFTD) Research Consortium (2025): Cortical microstructure in familial frontotemporal dementia associated with MAPT, GRN, and C9orf72 pathogenic variants: Looking beyond atrophy. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100306
CHOLINERGIC BASAL FOREBRAIN ATROPHY ACCELERATES COGNITIVE DECLINE VIA CORTICAL THINNING: THE MODERATING ROLE OF AMYLOID-Β PATHOLOGY IN PRECLINICAL ALZHEIMER’S DISEASE
Si Cen, Lijuan Wang, Meiling Qiu, Zhongqiang Xu, Li Xu, Rui Bao, Xiaolei Tang, Juanyu Gong, Jinting Wu, Zhiding Shao, Tonghua Zhang, Fan Yang, Wencai Ding, on behalf of the Harvard Aging Brain Study (HABS)
J Prev Alz Dis 2025;10(12)
Show summaryHide summaryBACKGROUND: Cholinergic basal forebrain (cBF) atrophy is a critical early marker of neurodegeneration in Alzheimer’s disease (AD). While cBF degeneration is linked to cognitive decline, the role of cortical thinning in this process, especially during the preclinical phase of AD, remains underexplored. Additionally, the impact of amyloid-β (Aβ) pathology on these relationships warrants further examination.
METHODS: We analyzed longitudinal structural MRI and PIB-PET data from 230 cognitively normal older adults enrolled in the Harvard Aging Brain Study, with a mean follow-up of six years. cBF volume and cortical thickness were quantified using FreeSurfer. Cognitive performance was assessed with the Preclinical Alzheimer Cognitive Composite-5 (PACC5). Linear mixed-effects models were used to investigate the longitudinal associations between cBF atrophy, cortical thinning, and cognitive decline. Mediation analyses explored whether cortical thinning mediated the relationship between cBF degeneration and cognitive decline, and the moderating role of Aβ burden was examined.
RESULTS: Progressive cortical thinning in multiple cognition-related regions was significantly associated with cBF atrophy. Mediation analysis revealed that cortical thinning accounted for approximately 44 % of the relationship between cBF degeneration and cognitive decline. These associations were more pronounced in individuals with elevated Aβ, suggesting a synergistic interaction between amyloid pathology and cholinergic system degeneration.
CONCLUSIONS: Our findings suggest that cBF atrophy accelerates cognitive decline through its impact on cortical thinning, with Aβ pathology further exacerbating these effects. These results highlight the potential of cBF and cortical thinning as early biomarkers for preclinical AD and underscore the importance of targeting cholinergic dysfunction in early intervention strategies.
CITATION:
Si Cen ; Lijuan Wang ; Meiling Qiu ; Zhongqiang Xu ; Li Xu ; Rui Bao ; Xiaolei Tang ; Juanyu Gong ; Jinting Wu ; Zhiding Shao ; Tonghua Zhang ; Fan Yang ; Wencai Ding ; on behalf of the Harvard Aging Brain Study (HABS) (2025): Cholinergic basal forebrain atrophy accelerates cognitive decline via cortical thinning: The moderating role of amyloid-β pathology in preclinical Alzheimer’s disease. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100315
BLOOD PRESSURE AND ALZHEIMER’S DISEASE BIOMARKERS IN COGNITIVELY UNIMPAIRED ADULTS: A MULTICENTER STUDY
Mariona Osset-Malla, Aitana Martínez-Velasco, Gonzalo Sánchez-Benavides, Mariateresa Buongiorno, Alejandro de la Sierra, Mahnaz Shekari, Carolina Minguillon, Gwendlyn Kollmorgen, Clara Quijano-Rubio, Henrik Zetterberg, Kaj Blennow, David Vállez García, Marc Suárez-Calvet, Juan Domingo Gispert, Oriol Grau-Rivera, ALFA Study
J Prev Alz Dis 2025;10(12)
Show summaryHide summaryBACKGROUND: Hypertension is a modifiable risk factor for dementia, potentially influencing Alzheimer's disease (AD) pathology. Understanding this relationship is essential for developing interventions to reduce dementia risk.
OBJECTIVES: We investigated cross-sectional and longitudinal associations between blood pressure and AD biomarkers in cerebrospinal fluid (CSF) and amyloid (Aβ) positron emission tomography (PET) in cognitively unimpaired adults.
DESIGN: Prospective observational study.
SETTING: We analyzed data from cognitively unimpaired participants from three observational prospective European studies: ALFA+ (NCT02485730), EPAD-LCS (NCT02804789), and AMYPAD PNHS (EudraCT: 2018–002,277–22).
MEASUREMENTS: ALFA+ participants had either CSF biomarkers (CSF Aβ42, Aβ40, p-tau181, t-tau) and/or Aβ PET data. EPAD participants had CSF biomarkers (CSF Aβ42, p-tau181, t-tau), and AMYPAD participants had Aβ PET data. All participants had available data about diabetes, use of hypertensive medication, and waist-to-hip ratio. Multivariable linear regression models were used to analyze cross-sectional associations between systolic blood pressure (SBP), diastolic blood pressure (DBP), and pulse pressure (PP) with CSF biomarkers or Aβ PET (Centiloid units, CL); longitudinal associations were tested by means of delta CL scores between baseline and follow-up to assess Aβ PET changes over time.
RESULTS: We included 405 participants from ALFA+ (mean age 61.1 years; 60 % female), 1104 from EPAD (mean age 64.8 years; 59.1 % female), and 340 from AMYPAD (mean age 71.8 years; 60 % female). In ALFA+, DBP was negatively associated with CSF Aβ40 (p = 0.016) and p-tau181 (p = 0.050), while there was a non-significant trend towards a positive association between SBP and CL over time (p = 0.058). In EPAD, DBP was negatively associated with CSF Aβ42 (p < 0.001) and p-tau181 (p = 0.014), while PP was positively associated with CSF Aβ42 (p = 0.024). In AMYPAD, SBP (p = 0.002) and PP (p = 0.003) were positively associated with CL at baseline, with a similar non-significant trend being found for DBP (p = 0.089). Higher DBP (p = 0.042) was significantly associated to increased CL over time, with a similar non-significant trend being found for SBP (p = 0.072). We did not find significant associations between blood pressure and longitudinal changes in CSF biomarkers.
CONCLUSIONS: Elevated blood pressure was associated with increased Aβ PET accumulation in cognitively unimpaired individuals. Further research is warranted to elucidate potential mechanisms underlying the negative associations between DBP and CSF biomarkers, which do not reflect the typical AD molecular signature. These findings highlight the relevance of high blood pressure as a potential risk factor for cognitive decline.
CITATION:
Mariona Osset-Malla ; Aitana Martínez-Velasco ; Gonzalo Sánchez-Benavides ; Mariateresa Buongiorno ; Alejandro de la Sierra ; Mahnaz Shekari ; Carolina Minguillon ; Gwendlyn Kollmorgen ; Clara Quijano-Rubio ; Henrik Zetterberg ; Kaj Blennow ; David Vállez García ; Marc Suárez-Calvet ; Juan Domingo Gispert ; Oriol Grau-Rivera ; ALFA Study (2025): Blood pressure and Alzheimer’s disease biomarkers in cognitively unimpaired adults: a multicenter study. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100304
LETTER TO THE EDITOR: CLARIFYING WHAT BP PREDICTS: COMMENTARY ON CSF AΒ42/40, P-TAU181, AND CENTILOID IN UNIM-PAIRED POPULATIONS
Shaoxiang Huang, Xueyu Wang, Peili Zhang
J Prev Alz Dis 2025;10(12)
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CITATION:
Shaoxiang Huang ; Xueyu Wang ; Peili Zhang (2025): Letter to the Editor: Clarifying what BP Predicts: Commentary on CSF Aβ42/40, p-tau181, and centiloid in unimpaired populations. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100372
CORRIGENDUM TO SYNERGISTIC EFFECTS OF MULTIPLE PATHOLOGICAL PROCESSES ON ALZHEIMER\'S DISEASE RISK: EVIDENCE FOR AGE-DEPENDENT STROKE INTERACTIONS [THE JOURNAL OF PREVENTION OF ALZHEIMER\'S DISEASE (2025) 100268]
Fen Liu, Xuesong Xia, Chengjie Zheng, Feng Liu, Min Jiang
J Prev Alz Dis 2025;10(12)
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CITATION:
Fen Liu ; Xuesong Xia ; Chengjie Zheng ; Feng Liu ; Min Jiang (2025): Corrigendum to Synergistic Effects of Multiple Pathological Processes on Alzheimer's Disease Risk: Evidence for Age-Dependent Stroke Interactions [The Journal of Prevention of Alzheimer's Disease (2025) 100268]. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100371