Deep learning to predict rapid progression of Alzheimer's disease from pooled clinical trials: A retrospective study.

The rate of progression of Alzheimer's disease (AD) differs dramatically between patients. Identifying the most is critical because when their numbers differ between treated and control groups, it distorts the outcome, making it impossible to tell whether the treatment was beneficial. Much recent effort, then, has gone into identifying RPs. We pooled de-identified placebo-arm data of three randomized controlled trials (RCTs), EXPEDITION, EXPEDITION 2, and EXPEDITION 3, provided by Eli Lilly and Company. After processing, the data included 1603 mild-to-moderate AD patients with 80 weeks of longitudinal observations on neurocognitive health, brain volumes, and amyloid-beta (Aß) levels. RPs were defined by changes in four neurocognitive/functional health measures. We built deep learning models using recurrent neural networks with attention mechanisms to predict RPs by week 80 based on varying observation periods from baseline (e.g., 12, 28 weeks). Feature importance scores for RP prediction were computed and temporal feature trajectories were compared between RPs and non-RPs. Our evaluation and analysis focused on models trained with 28 weeks of observation. The models achieved robust internal validation area under the receiver operating characteristic (AUROCs) ranging from 0.80 (95% CI 0.79-0.82) to 0.82 (0.81-0.83), and the area under the precision-recall curve (AUPRCs) from 0.34 (0.32-0.36) to 0.46 (0.44-0.49). External validation AUROCs ranged from 0.75 (0.70-0.81) to 0.83 (0.82-0.84) and AUPRCs from 0.27 (0.25-0.29) to 0.45 (0.43-0.48). Aß plasma levels, regional brain volumetry, and neurocognitive health emerged as important factors for the model prediction. In addition, the trajectories were stratified between predicted RPs and non-RPs based on factors such as ventricular volumes and neurocognitive domains. Our findings will greatly aid clinical trialists in designing tests for new medications, representing a key step toward identifying effective new AD therapies.

The Impact of Routine Vaccinations on Alzheimer's Disease Risk in Persons 65 Years and Older: A Claims-Based Cohort Study using Propensity Score Matching.

BACKGROUND: Accumulating evidence suggests that adult vaccinations can reduce the risk of developing Alzheimer's disease (AD) and Alzheimer's disease related dementias. OBJECTIVE: To compare the risk for developing AD between adults with and without prior vaccination against tetanus and diphtheria, with or without pertussis (Tdap/Td); herpes zoster (HZ); or pneumococcus. METHODS: A retrospective cohort study was performed using Optum's de-identified Clinformatics® Data Mart Database. Included patients were free of dementia during a 2-year look-back period and were≥65 years old by the start of the 8-year follow-up period. We compared two similar cohorts identified using propensity score matching (PSM), one vaccinated and another unvaccinated, with Tdap/Td, HZ, or pneumococcal vaccines. We calculated the relative risk (RR) and absolute risk reduction (ARR) for developing AD. RESULTS: For the Tdap/Td vaccine, 7.2% (n = 8,370) of vaccinated patients and 10.2% (n = 11,857) of unvaccinated patients developed AD during follow-up; the RR was 0.70 (95% CI, 0.68-0.72) and ARR was 0.03 (95% CI, 0.02-0.03). For the HZ vaccine, 8.1% (n = 16,106) of vaccinated patients and 10.7% (n = 21,417) of unvaccinated patients developed AD during follow-up; the RR was 0.75 (95% CI, 0.73-0.76) and ARR was 0.02 (95% CI, 0.02-0.02). For the pneumococcal vaccine, 7.92% (n = 20,583) of vaccinated patients and 10.9% (n = 28,558) of unvaccinated patients developed AD during follow-up; the RR was 0.73 (95% CI, 0.71-0.74) and ARR was 0.02 (95% CI, 0.02-0.03). CONCLUSION: Several vaccinations, including Tdap/Td, HZ, and pneumococcal, are associated with a reduced risk for developing AD.

Do vaccinations influence the development of Alzheimer disease?

A growing literature supports a protective association between vaccines targeting an array of pathogens (e.g., influenza, pneumococcus, herpes zoster) and the risk of Alzheimer disease (AD). This article discusses the potential underlying mechanisms for this apparent protective effect of immunizations against infectious pathogens on the risk of AD; explores the basic and pharmacoepidemiologic evidence for this association, with particular attention paid to important methodological variations among the epidemiologic studies; and reviews the remaining uncertainties regarding the effects of anti-pathogen vaccines on Alzheimer disease and all-cause dementia, with recommendations for future directions to address those uncertainties.

Population-Based Mini-Mental State Examination Norms in Adults of Mexican Heritage in the Cameron County Hispanic Cohort.

BACKGROUND: Accurately identifying cognitive changes in Mexican American (MA) adults using the Mini-Mental State Examination (MMSE) requires knowledge of population-based norms for the MMSE, a scale which has widespread use in research settings. OBJECTIVE: To describe the distribution of MMSE scores in a large cohort of MA adults, assess the impact of MMSE requirements on their clinical trial eligibility, and explore which factors are most strongly associated with their MMSE scores. METHODS: Visits between 2004-2021 in the Cameron County Hispanic Cohort were analyzed. Eligible participants were ≥18 years old and of Mexican descent. MMSE distributions before and after stratification by age and years of education (YOE) were assessed, as was the proportion of trial-aged (50-85- year-old) participants with MMSE <24, a minimum MMSE cutoff most frequently used in Alzheimer's disease (AD) clinical trials. As a secondary analysis, random forest models were constructed to estimate the relative association of the MMSE with potentially relevant variables. RESULTS: The mean age of the sample set (n = 3,404) was 44.4 (SD, 16.0) years old and 64.5% female. Median MMSE was 28 (IQR, 28-29). The percentage of trial-aged participants (n = 1,267) with MMSE <24 was 18.6% overall and 54.3% among the subset with 0-4 YOE (n = 230). The five variables most associated with the MMSE in the study sample were education, age, exercise, C-reactive protein, and anxiety. CONCLUSION: The minimum MMSE cutoffs in most phase III prodromal-to-mild AD trials would exclude a significant proportion of trial-aged participants in this MA cohort, including over half of those with 0-4 YOE.

Risk of Alzheimer's Disease Following Influenza Vaccination: A Claims-Based Cohort Study Using Propensity Score Matching.

BACKGROUND: Prior studies have found a reduced risk of dementia of any etiology following influenza vaccination in selected populations, including veterans and patients with serious chronic health conditions. However, the effect of influenza vaccination on Alzheimer's disease (AD) risk in a general cohort of older US adults has not been characterized. OBJECTIVE: To compare the risk of incident AD between patients with and without prior influenza vaccination in a large US claims database. METHODS: Deidentified claims data spanning September 1, 2009 through August 31, 2019 were used. Eligible patients were free of dementia during the 6-year look-back period and≥65 years old by the start of follow-up. Propensity-score matching (PSM) was used to create flu-vaccinated and flu-unvaccinated cohorts with similar baseline demographics, medication usage, and comorbidities. Relative risk (RR) and absolute risk reduction (ARR) were estimated to assess the effect of influenza vaccination on AD risk during the 4-year follow-up. RESULTS: From the unmatched sample of eligible patients (n = 2,356,479), PSM produced a sample of 935,887 flu-vaccinated-unvaccinated matched pairs. The matched sample was 73.7 (SD, 8.7) years of age and 56.9% female, with median follow-up of 46 (IQR, 29-48) months; 5.1% (n = 47,889) of the flu-vaccinated patients and 8.5% (n = 79,630) of the flu-unvaccinated patients developed AD during follow-up. The RR was 0.60 (95% CI, 0.59-0.61) and ARR was 0.034 (95% CI, 0.033-0.035), corresponding to a number needed to treat of 29.4. CONCLUSION: This study demonstrates that influenza vaccination is associated with reduced AD risk in a nationwide sample of US adults aged 65 and older.

Multimodal Phenotyping of Alzheimer's Disease with Longitudinal Magnetic Resonance Imaging and Cognitive Function Data.

Alzheimer's disease (AD) varies a great deal cognitively regarding symptoms, test findings, the rate of progression, and neuroradiologically in terms of atrophy on magnetic resonance imaging (MRI). We hypothesized that an unbiased analysis of the progression of AD, regarding clinical and MRI features, will reveal a number of AD phenotypes. Our objective is to develop and use a computational method for multi-modal analysis of changes in cognitive scores and MRI volumes to test for there being multiple AD phenotypes. In this retrospective cohort study with a total of 857 subjects from the AD (n = 213), MCI (n = 322), and control (CN, n = 322) groups, we used structural MRI data and neuropsychological assessments to develop a novel computational phenotyping method that groups brain regions from MRI and subsets of neuropsychological assessments in a non-biased fashion. The phenotyping method was built based on coupled nonnegative matrix factorization (C-NMF). As a result, the computational phenotyping method found four phenotypes with different combination and progression of neuropsychologic and neuroradiologic features. Identifying distinct AD phenotypes here could help explain why only a subset of AD patients typically respond to any single treatment. This, in turn, will help us target treatments more specifically to certain responsive phenotypes.

Increased Vascular Pathology in Older Veterans With a Purple Heart Commendation or Chronic Post-Traumatic Stress Disorder.

The goal of this retrospective cohort study was to determine whether stressors related to military service, determined by a diagnosis of chronic post-traumatic stress disorder (cPTSD) or receiving a Purple Heart (PH), are associated with an increased risk of vascular risk factors and disease, which are of great concern for veterans, who constitute a significant portion of the aging US population. The Veterans Integrated Service Network (VISN) 16 administrative database was searched for individuals 65 years or older between October 1, 1997 to September 30, 1999 who either received a PH but did not have cPTSD (PH+/cPTSD-; n = 1499), had cPTSD without a PH (PH-/cPTSD+; n = 3593), had neither (PH-/cPTSD-; n = 5010), or had both (PH+/cPTSD+; n = 153). In comparison to the control group (PH-/cPTSD-), the PH+/cPTSD- group had increased odds ratios for incidence and prevalence of diabetes mellitus, hypertension, and hyperlipidemia. The PH-/cPTSD+ group had increased odds ratios for prevalence of diabetes mellitus and for the incidence and prevalence of hyperlipidemia. The PH-/cPTSD+ and PH+/cPTSD- groups were associated with ischemic heart disease and cerebrovascular disease, but not independently of the other risk factors. The PH+/cPTSD+ group was associated only with an increase in the incidence and prevalence of hyperlipidemia, though this group's much smaller sample size may limit the reliability of this finding. We conclude that certain physical and psychological stressors related to military service are associated with a greater incidence of several vascular risk factors in veterans aged 65 years or older, which in turn are associated with greater rates of ischemic heart disease and cerebrovascular disease.