Alzheimer's Research & Therapy最新文献

Background: Germany's aging population, driven by rising life expectancy and declining birth rates, has resulted in an increasing number of elderly individuals and various health-related challenges, with dementia being one of the most prevalent chronic diseases. Dementia is an umbrella term encompassing various medical conditions that cause progressive cognitive decline. It is linked to a substantially higher risk of death. However, data on the mortality of dementia in Germany are limited. Therefore, this study aims to estimate the all-cause mortality and mortality rate ratio (MRR) of individuals diagnosed with dementia between 2016 and 2021.

Methods: The age- and sex-specific mortality of people with dementia aged 65 and older, as well as the MRR between the years 2016 and 2021, were estimated using a partial differential equation. The estimation relied on the incidence and prevalence of dementia diagnoses among individuals covered by statutory health insurance and on mortality in the general German population, sourced from the German Federal Statistical Office.

Results: The standardized overall mortality of individuals diagnosed with dementia increased slightly from 18,845 to 20,238 per 100,000, reflecting a rise of 7.4% between 2016 and 2021, with males typically showing higher rates. Overall, mortality increases exponentially with age. However, the age-related mortality rates remained relatively stable from 2016 to 2021, with only a slight upward trend. Individuals with dementia had a higher risk of death compared to individuals without dementia. Females diagnosed with dementia had up to 11 times higher risk of death compared to those not diagnosed with dementia at the same age, while for males it was up to 9 times higher. This difference was most pronounced in the 65- to 70-year age group, but diminished with increasing age.

Conclusions: A dementia diagnosis is associated with increased mortality across all age groups, particularly among younger individuals, although the relative risk declines with age as dementia becomes one of several comorbidities. Targeted interventions to prevent dementia, delay onset, and prolong milder stages remain essential to reduce mortality of people with dementia.

Background: Neuroinflammation is implicated in Alzheimer's disease (AD) pathogenesis, yet how changes in TSPO PET signal are associated with tau deposition, and how brain network architecture shapes this relationship remain poorly understood.

Methods: We conducted a prospective, multimodal neuroimaging study in 56 participants: 35 amyloid-positive individuals across the AD spectrum (ADS) and 21 amyloid-negative healthy controls (HC). Amyloid status was classified primarily by CSF Aβ42/Aβ40 and, when eligible CSF was unavailable, by baseline amyloid PET. Participants underwent TSPO PET using [18 F]GE-180 and resting-state fMRI at baseline. A longitudinal subgroup additionally underwent follow-up tau PET using [18 F]PI-2620 (n = 24) and repeat TSPO PET (n = 18) approximately 18 months later.

Results: Baseline TSPO did not differ significantly between groups. Baseline TSPO was associated with regional tau in both groups; the reciprocal association between tau and TSPO change was numerically weaker in AD, but this group difference was not statistically significant. Connectivity to baseline-TSPO epicenters was associated with higher tau in both groups, whereas connectivity to TSPO-change epicenters was associated with lower tau in AD but not controls (group-by-connectivity interaction p < 0.001, participant-level slope difference p = 0.012), a dissociation replicated in independent participants.

Conclusion: These findings suggest that connectivity to established versus emerging TSPO epicenters carries distinct spatial information about tau in the AD spectrum, a pattern shaped by functional brain connectivity and absent in healthy controls. (ClinicalTrials.gov: NCT06224920).

Background: Diabetes is associated with dementia, but how this association varies with attained age and cumulative exposure remains unclear. We integrated time-updated exposure histories with repeated age-specific landmark cohorts, enabling complementary evaluation of overall and age-conditional dementia risk.

Methods: We analysed 18,028 dementia-free participants aged 50 years or older from the Health and Retirement Study. Incident dementia was classified using the Langa-Weir algorithm. Time-updated Cox models evaluated risk according to current diabetes status. Age-anchored landmark models used delayed entry at six prespecified ages from 50 to 75 years. Formal age interactions and competing mortality were also assessed.

Results: Diabetes was associated with higher dementia risk in the time-updated analysis (HR, 1.29; 95% CI, 1.19-1.41). The association attenuated with older attained age but remained evident across the landmark cohorts. An estimated interval exceeding 10 years since first diabetes ascertainment identified groups at higher risk. The findings remained consistent after accounting for competing death.

Conclusions: Diabetes was associated with dementia throughout later life, with stronger associations at younger attained ages and among participants with a longer estimated interval since first ascertainment. These observational findings support considering the timing of diabetes ascertainment in cognitive risk assessment.

Background: Peptidylglycine α-amidating monooxygenase (PAM) is the key enzyme responsible for the C-terminal amidation of multiple vasoactive and neuroactive peptide hormones. Among these, amidated bioactive adrenomedullin (bio-ADM) is a critical regulator of endothelial- and blood-brain barrier (BBB) integrity and vascular homeostasis. Impaired peptide amidation may contribute to endothelial dysfunction and neurovascular dysregulation, mechanisms implicated in the pathogenesis of Alzheimer's disease (AD).

Methods: In 4543 dementia-free participants from the Malmö preventive project (MPP), plasma levels of mid-regional pro-adrenomedullin (MR-proADM), bio-ADM, and PAM activity (PAM-AMA) were measured at baseline, and incident dementia was ascertained through national registry data during follow-up. Associations were evaluated using Cox proportional hazards models with multivariable adjustment for common risk factors, false discovery rate correction, BMI-stratified analyses, and sensitivity analyses.

Results: During a mean follow-up of 4.75 ± 1.3 years, 205 participants developed incident AD and 93 developed vascular dementia (VD). Lower PAM-AMA was associated with increased risk of incident AD (adjusted hazard ratio per 1 standard deviation decrease (aHR): 2.30; 95% confidence interval (CI): 1.31-4.02; q = 0.01). Lower bio-ADM levels were also associated with increased Alzheimer's risk (aHR: 1.62; 95% CI: 1.13-2.33; q = 0.01). A reduced bio-ADM/MR-proADM ratio and its interaction with PAM-AMA further strengthened AD risk estimates. Associations were independent of APOE ε4 carrier status, more pronounced among individuals with BMI < 30 and remained directionally consistent in sensitivity analyses. No consistent associations were observed for VD after multivariable adjustment.

Conclusions: Reduced PAM-AMA and lower bio-ADM levels were associated with increased risk of incident AD, but not VD. A reduced ADM-ratio further indicates precursor peptide accumulation. These findings suggest that impaired peptide hormone amidation may represent an early systemic marker of neurovascular vulnerability and support further investigation of C-terminal peptide amidation pathways in translational AD research, including studies with a longer follow-up period and biomarker-confirmed dementia diagnoses.

Background: Aggregation of amyloid-β (Aβ) and tau is central to Alzheimer's disease (AD) pathogenesis and forms the basis of established cerebrospinal fluid (CSF) and imaging biomarkers. However, increasing evidence suggests that AD involves systemic processes beyond the central nervous system. We previously demonstrated the presence of fecal Aβ aggregates. Here, we assessed the detectability of tau aggregates in human feces and examined the diagnostic value of combined fecal Aβ and tau quantification in cognitive impairment.

Methods: Using surface-based fluorescence intensity distribution analysis (sFIDA), a single-particle assay selective for aggregated species, we quantified fecal Aβ and tau aggregates in individuals with cognitive impairment (dementia, MCI, SCD) and cognitively normal controls. Associations with CSF biomarkers were assessed, and classification performance was evaluated using cross-validated logistic regression models.

Results: Tau aggregates were detectable in fecal samples. Both fecal Aβ and tau aggregate concentrations were significantly elevated in cognitively impaired individuals and remained independently associated with patient status after adjustment for age and sex. Fecal Aβ aggregates showed inverse associations with CSF tau biomarkers, particularly phosphorylated tau. In cross-validated models, fecal tau aggregates achieved stronger classification performance than fecal Aβ (AUC ~ 0.80 vs. ~ 0.68), and integration of fecal aggregates with demographic predictors improved discrimination to an AUC of 0.90.

Conclusions: Detection of fecal tau aggregates extends previous observations on fecal Aβ and supports the concept that stool-based aggregate measurements capture systemic aspects of proteopathic biology associated with cognitive impairment. These findings suggest that fecal aggregate quantification may provide a minimally invasive biomarker approach that complements established CNS-based biomarkers and may be useful for patient stratification and monitoring in neurodegenerative disease.