José Alejandro Luchsinger

Background: Disease-modifying treatment is available for patients diagnosed with early symptomatic Alzheimer disease [AD, mild cognitive impairment (MCI), and mild dementia]. Recognition and diagnosis of MCI and dementia occur every day in the primary care setting, but diagnostic challenges and delays are common. Over 90% of MCI cases are missed, and more than half of AD diagnoses occur when the disease is in the moderate or advanced stage, when crises and emergencies are more likely to occur. Discussion: Diagnostic delays limit opportunities to organize and implement proactive, comprehensive patient care and treatment and to prepare individuals and caregivers for the long-term implications of progressive dementia. With the advent of new diagnostic methods, including blood-based biomarkers, AD can now be diagnosed with greater precision and ease at a lower cost. Given the expected increase in prevalence of AD in the next 2 decades and the growing shortage of geriatricians and memory disorders specialists, the role of the PCP in diagnosing AD will be of even greater importance. However, many PCPs do not feel confident or equipped to recognize and diagnose patients with early symptomatic AD. To empower PCPs as key participants in diagnosis, we propose an approach aligned with the fundamental strengths of primary care, codified in the 4Cs (first contact, comprehensiveness, coordination, and continuity of care). Conclusion: Using the 4Cs framework, PCPs can increase the rate of timely diagnosis of symptomatic AD and be afforded more time to provide comprehensive care, using proactive rather than reactive management strategies throughout the diagnostic process.

Importance: Metformin may influence risk of dementia, with prior conflicting observations of protection or harm. Objective: To determine the association of randomization to metformin vs. placebo or intensive lifestyle intervention (ILS) in the Diabetes Prevention Program (DPP) with cognitive outcomes (cognitive impairment syndromes and trajectories of cognitive test performance) during the DPP Outcomes Study (DPPOS). Design, Setting & Participants: Prospective long-term follow-up of DPP/DPPOS participants at 27 U.S. centers among adults who were at high risk for type 2 diabetes (T2D) at baseline. Exposures: Randomization to metformin, placebo, or ILS (1996–1999) for 3.2 years followed by open-label metformin in the original randomized metformin group until 2021. Main Outcomes & Measures: Cognitive impairment syndromes were adjudicated in 2022– 2024 in 1,483 participants (median age 74 [IQR 68, 80]) using the National Alzheimer’s Coordinating Center Uniform Dataset version 3. Cognitive performance in executive and memory domains was ascertained with repeated cognitive tests between 2009 and 2024. Multinomial logistic regression and mixed-effects models were fit to examine associations of randomization to metformin with cognitive outcomes. Results: Total metformin exposure (mean ± SD) was 15.5 ±7.7 years/person in the metformin group. Persons in the placebo and ILS groups received out-of-study metformin usually after developing diabetes with mean metformin total exposure of 4.5 ±5.1 and 3.8 ±4.8 years/person in the placebo and ILS groups, respectively. Overall, the frequency distributions of the cognitive syndromes did not differ significantly by treatment group; however, randomization to metformin was associated with a 60% (OR 0.40 [95%CI 0.17, 0.97]) and 62% (OR 0.38 [95%CI 0.16, 0.89]) lower odds of dementia compared with placebo and ILS, respectively, after adjustment for demographics, education, income, and APOE-ε4 genotype. Randomization to metformin was also associated with significantly better memory performance over time (β=0.58; 95%CI: 0.09, 1.1; p=0.02; Cohen’s d=0.1). Conclusions and Relevance: Long-term metformin treatment is associated with a reduced risk of dementia and better memory performance among persons with pre-diabetes or T2D. Estimates were imprecise due to a limited number of dementia cases. Longer follow-up with more dementia cases is needed to confirm our findings. KEY POINTS: Question: Is chronic metformin treatment related to the risk of dementia and cognitive impairment? Findings: Randomization to metformin in the Diabetes Prevention Program was associated with a lower risk of dementia in the Diabetes Prevention Program Outcomes Study compared with the randomization to placebo or randomization to intensive lifestyle intervention, but the overall distribution of cognitive impairment syndromes did not differ significantly by treatment group. Randomization to metformin was also related to modestly better longitudinal performance in a memory test. Meaning: Chronic metformin treatment may decrease the risk of dementia.

Background and Objectives: Plasma biomarkers, particularly brain-derived phosphorylated-tau (BD-p-tau) species, hold promise as screening tools for Alzheimer’s disease (AD). However, their ability to reflect AD pathology remains understudied in community settings. In a community-based sample, we examined associations between plasma biomarkers and cerebral amyloid (Aβ) deposition, and whether kidney function modified these associations. Methods: This cohort study included cognitively unimpaired, late middle-aged adults with ¹⁸ F-Florbetaben PET imaging and NULISAseq-derived plasma biomarker measurements. Analyses were restricted to NULISAseq biomarkers related to AD pathology (Aβ38, Aβ40, Aβ42, ACHE, BACE1, BASP1, BD-p-tau181, BD-p-tau217, CD63, IGFBP7, KLK6, MAPT-tau, PSEN1, SFRP1, total p-tau181, p-tau217, and p-tau231). As a measure of kidney function, cystatin C–based estimated glomerular filtration rate was calculated and categorized by chronic kidney disease (CKD) stage as normal/high (≥90 mL/min/1.73 m ² ); mildly decreased (60–89 mL/min/1.73 m ² ); and moderately/severely decreased or failure (2 ). Bidirectional stepwise linear regression analysis was performed to identify plasma biomarkers associated with brain Aβ deposition. Linear regression models including plasma biomarker-by-CKD stage interactions tested effect modification by kidney function. Results: A total of 541 Hispanic, non-Hispanic Black, and non-Hispanic White participants were included. Stepwise linear regression retained plasma BD-p-tau217 (B = 0.22; 95% CI 0.19 to 0.25; p < 0.001), which was positively associated with brain Aβ deposition, alongside Aβ42 (B = −0.08; 95% CI −0.11 to −0.06; p < 0.001), IGFBP7 (B = −0.05; 95% CI −0.08 to −0.02; p = 0.004), and BACE1 (B = −0.04; 95% CI −0.07 to −0.01; p = 0.009), which were negatively associated with brain Aβ deposition. A significant BD-p-tau217-by-CKD stage interaction demonstrated a weaker association between BD-p-tau217 and brain Aβ deposition among individuals with moderately/severely decreased kidney function or failure than those with normal/high kidney function (B = −0.17; 95% CI −0.25 to −0.08; p < 0.001). Discussion: In a real-world sample, BD-p-tau217 emerged as the plasma biomarker most strongly associated with brain Aβ deposition, although this association may be attenuated in the presence of moderate/severe kidney dysfunction or kidney failure. IGFBP7 and BACE1 were identified as candidate plasma biomarkers of brain Aβ deposition, warranting replication in independent cohorts.

INTRODUCTION: The Diabetes Prevention Program (DPP) was a randomized clinical trial designed to prevent type 2 diabetes (T2D) in adults with prediabetes. The DPP Outcomes Study (DPPOS) is the 30-year follow-up of this cohort, focusing on T2D, prediabetes, and related complications. Cognitive assessments began in 2009 and expanded in 2022 to examine cognitive impairment, including Alzheimer’s disease (AD) and AD related dementias (ADRD), in the surviving cohort. To support these aims, the National Alzheimer’s Coordinating Center Uniform Data Set version 3 (NACC-UDSv3), the standardized framework used by Alzheimer’s Disease Research Centers, was implemented in DPPOS in 2022 to enable data sharing with NACC. These forms were complemented by cognitive tests administered in DPPOS. We aimed to integrate the NACC-UDSv3 into the existing longitudinal DPPOS framework while maintaining fidelity to its structure and developing automated reports to streamline cognitive outcomes adjudication. METHODS: Items from the 16 NACC-UDSv3 data forms were compared with those already collected within DPPOS to integrate overlapping similar items, add missing NACC-UDSv3 items, and create a dataset harmonized with NACC-UDSv3. Forms were adapted for electronic data capture (EDC) using the MIDAS (Multimodal Integrated Data Acquisition System, George Washington University). Automated reports integrated current and prior neuropsychological scores to support adjudications. In the first wave of the DPPOS-AD/ADRD study, 1561 cognitive adjudications were successfully completed using the harmonized DPPOS and NACC-UDSv3 data implemented into MIDAS. DISCUSSION: The DPPOS-AD/ADRD project demonstrated that NACC-UDSv3 can be successfully integrated into a long-standing longitudinal cohort not originally designed for AD/ADRD research. The harmonization, electronic capture, and automated adjudication processes may provide a practical framework for other cohorts seeking to incorporate NACC-UDSv3 to align with national AD/ADRD research standards.

Introduction: The Diabetes Prevention Program Outcomes Study (DPPOS) is an established cohort of aging persons with pre-diabetes and type 2 diabetes with 25 years of median follow-up. In 2022 DPPOS added Alzheimer’s disease (AD), and AD related dementias (ADRD) phenotyping using the National Alzheimer’s Coordinating Center (NACC) Uniform Data Set (UDSv3), which included a standardized neurological examination across 25 clinical sites, administered by clinical staff and interpreted centrally by clinicians. Methods: A DPPOS video-based asynchronous neurological examination (DPPOS-VANE) was developed iteratively through consensus from research clinicians and staff feedback to harmonize with UDSv3 to identify common neurological diagnoses aside from dementia including diabetic cranial neuropathies, stroke and parkinsonism. DPPOS-VANE was designed to be conducted without direct participant contact by the examiner, reproducible, and independent of clinical skills of PCs. An iPad™ camera recorded the video exam, comprised of assessments of extraocular and facial movements, visual fields, speech, gross motor strength, pronator drift, praxis and parkinsonism. A 10-minute training video demonstrated the examination step-by-step with scripts and instructions in English and Spanish. Site-specific performance review, feedback, and staff certification preceded central reading of video recordings by physicians. After two years of implementation, 1286 DPPOS-VANEs led to 1284 examination reviews. Of these, 1204 (93%) were completed by having the examiner follow the standard script. Overall, 1237 examinations (96%) were delivered as planned, 41 (3%) had minor errors but were still usable, and 6 (0.4%) had major deviations in exam technique; two additional recorded evaluations were not usable as recorded videos were inaccessible due to technical errors. Each examination was completed within 10-15 minutes. Each site on average completed 51.4 examinations (range 14-92). Discussion: Engaging 55 research staff across 25 sites and 3 physician-reviewers, this study is the first to demonstrate feasibility of a VANE as an efficient neurological examination model enabled by commonly used devices. Such a multisite standardized VANE represents a novel paradigm for large epidemiological studies.

Objective: We explore associations that four weight-sensitive and neuroactive cytokines – adiponectin, leptin, interleukin-6 (IL-6), and vascular endothelial growth factor (VEGF) – have with cross-sectional brain volumes among adults with obesity or overweight and with type 2 diabetes (T2D). Methods: Cytokine concentrations were assayed at baseline and proximal to the end of two 10-year lifestyle interventions among 233 Look AHEAD trial participants. Magnetic resonance imaging measured total, white, and gray matter brain volumes. Associations that cytokine concentrations and changes in concentrations had with brain volumes and weight changes were assessed. Results: Higher IL-6 and VEGF concentrations were associated with smaller total brain volumes (β=-3.00 [95% CI -14.82,-3.07] and β=-2.79 [-10.08,-1.74] log-units/cc respectively). Higher leptin concentrations were associated with higher white matter volumes (β=2.00 [-0.06,6.92] log-units/cc). Increases in adiponectin were associated with greater total brain volumes (β=2.14 [0.50,11.94] log-units/cc). Higher leptin and IL-6 concentrations were associated cross-sectionally with greater body mass index (BMI) and increases in leptin, IL-6, and VEGF concentrations were associated with increases in BMI. Neither lifestyle intervention nor changes in BMI materially affected associations between cytokines and brain volumes. Conclusions: Weight-sensitive neuroactive cytokine concentrations are related to brain volumes. Weight changes and lifestyle interventions targeting weight loss may not materially influence these associations in adults with T2D.

The association of type 2 diabetes (T2D) treatment with Alzheimer's disease (AD) is unclear. We examined T2D treatment status in relation to amyloid beta (Aβ) burden and AD-related downstream processes. This cross-sectional study included 546 cognitively unimpaired adults (mean age = 64.2 ± 3.2 years, 65% women), classified into normal glucose tolerance (NGT; hemoglobin A1c [HbA1c] < 5.7%), prediabetes/untreated T2D (HbA1c ≥ 5.7%), and treated T2D groups. Multiple regression analyses assessed group differences in Aβ (¹⁸F-florbetaben) and tau (¹⁸F-MK-6240) positron emission tomography burden, magnetic resonance imaging-based AD signature cortical thickness, white matter hyperintensity (WMH) volume, and memory performance. Compared to the NGT group, prediabetes/untreated T2D had greater anterior/posterior cingulate and superior parietal cortex Aβ burden, whereas treated T2D had lower cortical thickness and greater WMHs, independent of demographics and apolipoprotein E ε4 status. No group differences were found in tau or memory outcomes. Prediabetes/untreated T2D, but not treated T2D, was associated with early Aβ deposition. Diabetes medications may mitigate brain Aβ burden.

Importance: Sex differences in Alzheimer disease (AD) neuropathology have not been examined extensively across multiple pathological constructs within broadly representative samples. Objective: To examine sex differences in neuroimaging biomarkers of AD-related pathologies in a racially and ethnically diverse cohort. Design, Setting, and Participants: Data for this cross-sectional study were collected from a community-based sample of adults without cognitive impairment aged 60 to 69 years in New York City from March 1, 2016, to September 31, 2022, and analyzed in March 2025. Exposure: The primary exposure was self-reported sex (women or men). Main Outcomes and Measures: The outcomes were global amyloid burden measured with florbetaben labeled with fludeoxyglucose 18 ( ¹⁸ F) positron emission tomography (PET), tau burden in Braak stages I to VI measured with ¹⁸ F-MK-6240 PET, and magnetic resonance imaging (MRI)–derived AD signature cortical thickness and white matter hyperintensity volumes. Linear regression analyses were performed to examine sex differences in the outcomes. Covariates included demographics, APOE ε4 status, and vascular health–related factors. Sex × age, sex × APOE ε4, and sex × race and ethnicity interactions were additionally examined on the outcomes. False discovery rate (FDR) correction for multiple comparisons were also performed. Results: A total of 503 participants (mean [SD] age, 64.6 [2.8] years; 321 [63.8%] women; 305 [60.6%] Hispanic, 120 [23.9%] non-Hispanic Black, and 78 [15.5%] non-Hispanic White) with Aβ PET, MRI (n = 501), and tau PET (n = 355) data were studied. Compared with men, women had greater amyloid burden (B = 0.05; 95% CI, 0.02-0.07; P < .001), Braak stages III and IV (B = 0.05; 95% CI, 0.02-0.08; P = .003) and Braak stages V and VI (B = 0.09; 95% CI, 0.06-0.12; P < .001) tau burden, and AD signature thickness (B = 0.04; 95% CI, 0.02-0.05; P < .001). A significant sex × APOE ε4 interaction was observed, with women showing greater Braak stages I and II (B = 0.15; 95% CI, 0.04-0.25; P = .006) and Braak stages III and IV (B = 0.08; 95% CI, 0.02-0.14; P = .01) tau burden than men among APOE ε4 carriers. All findings remained statistically significant after FDR correction. No significant sex × age or sex × race and ethnicity interactions were observed on any outcome. Conclusions and Relevance: This cross-sectional study of community-based adults found greater AD pathology yet better preserved structural brain integrity in women compared with men. Sex differences in tau burden across early to middle Braak stages were more pronounced among APOE ε4 carriers compared with noncarriers. These findings were not modified by age or race and ethnicity. Overall, the results underscore sex-specific distinctions in AD pathology burden and brain structure at the cross-sectional level.