Incident Alzheimer's Disease Dementia Research Articles

Mitochondrial DNA abundance in blood is associated with Alzheimer's disease- and dementia-risk.

The mitochondrial cascade hypothesis of Alzheimer's disease (AD) has been portrayed through molecular, cellular, and animal studies; however large epidemiological studies are lacking. This study aimed to explore the association of mitochondrial DNA copy number (mtDNAcn), a marker representative of mtDNA abundance per cell, with risk of incident all-cause dementia, AD, and vascular dementia diagnosis within 17 years and dementia-related blood biomarkers (P-tau181, GFAP, and NfL). Additionally, sex-stratified analyses were completed. In this German population-based cohort study (ESTHER), 9940 participants aged 50-75 years were enrolled by general practitioners and followed for 17 years. Participants were included in this study if information on dementia status and blood-based mtDNAcn measured via real-time polymerase chain reaction were available. In a nested case-control approach, a subsample of participants additionally had measurements of P-tau181, GFAP, and NfL in blood samples taken at baseline. Of 4913 participants eligible for analyses, 386 were diagnosed with incident all-cause dementia, including 130 AD and 143 vascular dementia cases, while 4527 participants remained without dementia diagnosis within 17 years. Participants with low mtDNAcn (lowest 10%) experienced 45% and 65% percent increased risk of incident all-cause dementia and AD after adjusting for age and sex (all-cause dementia: HRadj, 95%CI:1.45, 1.08-1.94; AD: HRadj, 95%CI: 1.65, 1.01-2.68). MtDNAcn was not associated to vascular dementia diagnosis and was more strongly associated with all-cause dementia among women. In the nested case-control study (n = 790), mtDNAcn was not significantly associated with the dementia-related blood biomarkers (P-tau181, GFAP, and NfL) levels in blood from baseline before dementia diagnosis. This study provides novel epidemiological evidence connecting mtDNA abundance, measured via mtDNAcn, to incident dementia and AD at the population-based level. Reduced mitochondrial abundance may play a role in pathogenesis, especially among women.

MRI-Derived AD Signature of Cortical Thinning and Plasma P-Tau217 for Predicting Alzheimer Dementia Among Community-Dwelling Older Adults.

Structural brain MRI and blood-based phosphorylated tau (p-tau) measures are among the least invasive and least expensive Alzheimer's disease (AD) biomarkers to date. The extent to which these biomarkers may outperform one another in predicting future Alzheimer dementia diagnosis is poorly understood, however. This study investigated 2 specific AD biomarkers, i.e., a cortical thickness signature of AD (AD-CT) and plasma p-tau217, for predicting Alzheimer dementia. Data came from community-dwelling older participants of the Religious Orders Study or the Rush Memory and Aging Project. AD-CT was obtained from 3T MRI scans using a magnetization-prepared rapid acquisition gradient echo sequence and by averaging thickness from previously identified cortical regions implicated in AD. Plasma p-tau217 was quantified using an immunoassay developed by Lilly Research Laboratories on the MSD platform. Both MRI scans and blood specimens were collected at the same visits, and subsequent diagnoses of Alzheimer dementia were determined through annual detailed clinical evaluations. Cox proportional hazards models examined the associations of the 2 biomarkers with incident Alzheimer dementia, and prediction accuracy was assessed using c-statistics. A total of 198 older adults, on average 84 years of age, were included. Over a mean follow-up of 4 years, 60 (30%) individuals developed Alzheimer dementia. AD-CT (hazard ratio: 1.71, 95% CI 1.26-2.31) and separately plasma p-tau217 (hazard ratio: 2.57, 95% CI 1.83-3.61) were associated with incident Alzheimer dementia. The c-statistic for prediction accuracy was consistently higher for plasma p-tau217 (between 0.74 and 0.81) than AD-CT (between 0.70 and 0.75) across a range of time horizons. Furthermore, with both biomarkers included in the same model, there was only modest improvement in the c-statistic due to AD-CT. Plasma p-tau217 outperforms an imaging-based cortical thickness signature of AD in predicting future Alzheimer dementia diagnosis. Furthermore, the AD cortical thickness signature adds little to the prediction accuracy above and beyond plasma p-tau217.

Statin Initiation and Risk of Incident Alzheimer Disease and Cognitive Decline in Genetically Susceptible Older Adults.

The association of statin initiation with incident Alzheimer disease (AD) dementia and cognitive decline by the APOE ε4 allele is unknown. Our objective was to examine whether the association of statin initiation with incident AD dementia and cognitive decline differs by the APOE ε4 allele. This population-based longitudinal cohort study was conducted in 4 urban communities in Chicago, IL, United States, consisting of 4,807 participants. Statin initiation is based on the inspection of medications during home assessments. Clinical diagnosis for incident AD used the NINCDS-ADRDA criteria, and longitudinal measurements of global cognition consisted of episodic memory, perceptual speed, and the Mini-Mental State Examination tests. The study participants had a mean age of 72 years, consisting of 63% female individuals and 61% non-Hispanic Black individuals. During the study period, 1,470 (31%) participants reported statin initiation. In a covariate-adjusted competing risk model, statin initiation was associated with a reduced risk of incident clinical AD [hazard ratio (HR) 0.81 (95% CI 0.70-0.94)] compared with nonusers. This association was statistically significantly lower (p interaction = 0.015) among participants with the APOE ε4 allele [HR 0.60 (95% CI 0.49-0.74)] compared with those without the APOE ε4 allele [HR 0.96 (95% CI 0.82-1.12)]. The annual decline in global cognition (β = 0.021, 95% CI 0.007-0.034) and episodic memory (β = 0.020, 95% CI 0.007-0.033) was also substantially slower among participants with the APOE ε4 allele after statin initiation compared with nonusers. However, the association of statin initiation with cognitive decline was not significant among those without the APOE ε4 allele. Our findings suggest that statins might be associated with a lower risk of incident AD among individuals with the APOE ε4 allele. The benefits of statin therapy need further consideration in randomized clinical trials, especially among those with the APOE ε4 allele. This study provides Class II evidence that among those aged 65 years or older, statin initiation was associated with a reduced risk of Alzheimer disease, especially in the presence of an APOE-e4 allele.

Serum 25-Hydroxyvitamin D, Vitamin D Receptor, and Vitamin-D-Binding Protein Gene Polymorphisms and Risk of Dementia Among Older Adults With Prediabetes.

The association between vitamin D and dementia risk in those with prediabetes remains uncertain. We aimed to evaluate the association of serum 25-hydroxyvitamin D (25OHD) with incident dementia among older adults with prediabetes, and examine whether apolipoprotein E (APOE) genotypes, vitamin D receptor (VDR), and vitamin-D-binding protein (VDBP) gene polymorphisms may modify this association. A total of 34237 participants aged ≥60 with prediabetes (HbA1c <6.5% and ≥5.7%) and without dementia at baseline were included from the UK Biobank. Serum 25-hydroxyvitamin D (25OHD) was measured using chemiluminescent immunoassay method. The primary outcome was incident all-cause dementia. Secondary outcomes included incident Alzheimer's disease (AD) and vascular dementia, respectively. The VDR and VDBP gene polymorphisms included single nucleotide polymorphisms of rs7975232, rs1544410, rs2228570, rs731236, and rs7041, rs4588, respectively. During a median follow-up of 11.8 years, 941 (2.7%) participants developed incident all-cause dementia. Overall, serum 25OHD was inversely associated with all-cause dementia (per standard deviation increment, adjusted hazard ratio: 0.82; 95% confidence interval: 0.75, 0.89). Similar trends were found for incident AD and vascular dementia. Furthermore, there was a stronger inverse relationship between serum 25OHD and all-cause dementia among VDR rs7975232 C allele noncarriers (p-interaction < 0.05). However, APOE Ɛ4, other VDR, and VDBP gene polymorphisms did not significantly modify the relation of serum 25OHD with incident all-cause dementia (all p-interactions >.05). There was an inverse association between serum 25OHD and incident dementia among older adults with prediabetes, especially in VDR rs7975232 AA allele carriers.

A longitudinal multimodal biomarker study of memory clinic MCI patients with MBI – are there links to Alzheimer disease?

AbstractBackgroundMild cognitive impairment (MCI) and mild behavioral impairment (MBI) are at‐risk states for incident dementia. MBI represents behavioral risk, and MCI represents cognitive risk. In memory clinic MCI patients, we interrogated the relationship between MBI status (+/‐), cerebral atrophy, cerebrospinal fluid (CSF) biomarkers, and incident all‐cause dementia and incident Alzheimer disease (AD) dementia.MethodMBI was operationalized as persistent neuropsychiatric symptoms (NPS) in MEMENTO study participants. MRI regions were selected a priori for Braak stages I‐V. CSF markers included amyloid‐β (Aβ), hyperphosphorylated‐tau (p‐tau), and tau. Linear regression models were fitted with regional thickness/volume or CSF markers as dependent variables, and MBI status as independent variable, adjusted for age, sex, and education. Logistic regression was conducted to investigate if MBI status was associated with amyloid‐β positivity (defined as &lt;813 pg/mL), with MBI status as predictor, adjusting for age, sex, education and MMSE. Kaplan‐Meier curves were generated for dementia‐free survival out to 6 years. Cox proportional hazard regressions, adjusted for age, sex, education, MMSE score, and MCI subtype were utilized to investigate the rates of incident all‐cause dementia, as well as incident AD dementia, in MBI+ vs MBI‐ patients with MCI.ResultOf the 820 participants (mean age(±SD) 72.54(8.21), 57.80% female), 29.5% had MBI. Compared to MBI‐, MBI+ status was associated with lower entorhinal thickness (b = –0.066, p = 0.04) and smaller hippocampal volume (b = –0.069, p&lt; 0.01). In the CSF subsample (n = 154, mean age = 69.6, 48.1% female), MBI predicted amyloid‐β positivity (odds ratio = 2.19, p = 0.05), and was associated with 7.4% lower Aβ42 level (p = 0.01), 17.8% higher CSF p‐tau/Aβ42 (p&lt;0.01) and 18.9% higher t‐tau/Aβ42 ratio (p = 0.02). Longitudinally, MBI+ had lower dementia‐free survival (log rank test; p&lt;0.0001), with adjusted hazard ratios (HRs) of 2.76 (95%CI 1.99‐3.8; p&lt;0.001) for all‐cause dementia and 2.73 (95%CI 1.83‐4.07; p&lt;0.001) for AD dementia.ConclusionMBI served as a clinical marker to identify a subgroup of MCI patients with Alzheimer disease‐related morphological changes in the entorhinal cortex and hippocampus, and CSF biomarkers consistent with AD. MCI with MBI had a greater incidence rate of AD dementia than MCI without MBI. MBI case status may be used to improve detection of prodromal AD in MCI.

Peripheral inflammatory biomarkers are associated with cognitive function and dementia: Framingham Heart Study Offspring cohort.

Inflammatory protein biomarkers induced by immune responses have been associated with cognitive decline and the pathogenesis of Alzheimer's disease (AD). Here, we investigate associations between a panel of inflammatory biomarkers and cognitive function and incident dementia outcomes in the well-characterized Framingham Heart Study Offspring cohort. Participants aged ≥40 years and dementia-free at Exam 7 who had a stored plasma sample were selected for profiling using the OLINK proteomics inflammation panel. Cross-sectional associations of the biomarkers with cognitive domain scores (N = 708, 53% female, 22% apolipoprotein E (APOE) ε4 carriers, 15% APOE ε2 carriers, mean age 61) and incident all-cause and AD dementia during up to 20 years of follow-up were tested. APOE genotype-stratified analyses were performed to explore effect modification. Higher levels of 12 and 3 proteins were associated with worse executive function and language domain factor scores, respectively. Several proteins were associated with more than one cognitive domain, including IL10, LIF-R, TWEAK, CCL19, IL-17C, MCP-4, and TGF-alpha. Stratified analyses suggested differential effects between APOE ε2 and ε4 carriers: most ε4 carrier associations were with executive function and memory domains, whereas most ε2 associations were with the visuospatial domain. Higher levels of TNFB and CDCP1 were associated with higher risks of incident all-cause and AD dementia. Our study found that TWEAK concentration was associated both with cognitive function and risks for AD dementia. The association of these inflammatory biomarkers with cognitive function and incident dementia may contribute to the discovery of therapeutic interventions for the prevention and treatment of cognitive decline.

Cardiovascular health, infection burden, and incident dementia in the UK Biobank.

Among older adults, total and hospitalized infection may be associated with incidence of all-cause and Alzheimer's disease (AD) dementias, with variation by cardiovascular health (CVH). We used Cox proportional hazards (PH) models to examine the relationships between International Classification of Diseases-10th revision(ICD-10)-specific viral and bacterial infectious agents and incident all-cause and AD dementia among 355,046 UK Biobank participants ≥50 years at baseline. Life's Essential 8 (LE8) index reflected CVH. In both sexes, total infection burden (yes vs. no) was associated with all-cause dementia, with significant interactions by LE8 tertiles, whereby this relationship was significant only in the lowest LE8 tertile. Hospital-treated infection burden (yes vs no) was significantly related to all-cause and AD dementia, with no significant interaction with LE8 tertile. Age group patterns were detected. AD and all-cause dementia were related to hospital-treated infections, while CVH modified the relationship of total infection burden with all-cause dementia. Highlights Secondary analysis on>355,000 UK Biobank participants ≥50 years at baseline. Alzheimer's disease and all-cause dementia are both related to hospital-treated infection. Cardiovascular health modifies association of infection burden with all-cause dementia.

Cardiovascular health and cognitive outcomes: Findings from a biracial population-based study in the United States.

The aim of this study was to evaluate the association of cardiovascular health (CVH) with cognitive outcomes, including incident Alzheimer's dementia, rate of cognitive decline, and measures of brain injury and structure. This study consisted of 1702 Black or African American and White participants living in the south side of Chicago, Illinois, and enrolled in the Chicago Health and Aging Project, a population-based cohort since 1993. CVH was based on seven risk factors, including diet, physical activity, body mass index, smoking, dyslipidemia, hypertension, and diabetes. In a multivariable-adjusted model, CVH was associated with a lower risk of Alzheimer's dementia. The hazard ratio per 1 additional point in CVH score was 0.84 (95% CI 0.76, 0.94). CVH was also associated with a slower rate of cognitive decline and less volume (injury) in white matter hyperintensities. Promoting CVH in communities with Black residents may lower the future risk of Alzheimer's dementia.

Reproductive Markers in Alzheimer's Disease Progression: The Framingham Heart Study.

Reproductive status, such as the age of menarche or menopause, may be linked to cognitive abilities and risk for incident Alzheimer's disease (AD) but the evidence is conflicting. It is also not fully known if these factors interact with cortical beta-amyloid deposition. To study the relationship between reproductive risks, sex hormone markers and risk for decline in specific cognitive domains in women. We analyzed the association of reproductive markers (age at menarche, number of births, age at menopause, sex hormone-binding globulin, estradiol, estrone, total testosterone, free testosterone) with incident AD and annualized cognitive decline in the community-based longitudinal Framingham Heart Study (FHS) Offspring women 60 years and older (n=772, mean age 68 years, mean follow-up 10.7 ± 3 years). We used the Cox proportional hazards regression model and linear regression model, adjusting for covariates. Incident AD dementia as well as the annualized change in memory, language, attention and executive functions. Older age at menopause was associated with a lower risk of incident AD dementia (p = 0.047, 6% lower risk per older year) after adjusting for baseline age, education, hormone therapy status, and MMSE score. Older age at menopause was significantly associated with a slower annualized decline in memory (beta = 0.085, p = 0.00059). The lower level of plasma Aβ42 was also associated with a higher risk of incident AD (HR = 0.97, 95% CI = 0.95, 0.99; p = 0.0039) but there was no significant interaction effect with age at menarche, age at menopause or plasma sex hormone levels. Younger age at menopause is a risk factor for late-life memory decline and incident AD. This risk appears to be independent of Aβ42 pathology. Further studies to understand the biological and social mechanisms underlying the differential effects of reproductive risks are warranted.

An Alzheimer's dementia cumulative risk model in a sample of general population over 65: Public health implications

Background and objectivesWith the population ageing, the identification of modifiable risk factors for dementia represents a public health priority. Co-occurrence of risk factors in the same individual is more frequent than an isolated appearance and may create synergistic effects, with an increased risk of negative outcomes such as dementia and mortality. We aim to study the cumulative risk of incident Alzheimer's Dementia (AD) in a community sample aged >65 (n= 3044). MethodsTo this end, we will examine the impact on the risk of AD of the co-occurrence of variables that have previously been shown to increase risk: age, gender, education, marital status, depression, anxiety, body mass index (BMI) and hearing loss. ResultsThe most frequent number of co-occurring risk factors was 3. We found a cumulative increased risk of both death and AD by the confluence of 2 or more risk factors. Using a competing risk regression model, each increase in a co-occurring risk factor was associated with a significant increase in the risk of incident AD of more than two-fold. By the analysis of the Population Attributable Fractions (PAF) of AD due to several risk factors, we found that if 4 or more co-occurring risk factors could be eliminated from the population, the prevalence of AD would be reduced by approximately 38%. ConclusionOur study offers an estimate of the impact that preventive interventions could have if the number of modifiable risk factors of AD at a population level.

MRI-Visible Perivascular Spaces and Risk of Incident Dementia: The Framingham Heart Study.

Perivascular spaces (PVS) visible on MRI scans may represent key aspects in the pathophysiology of stroke and dementia, including cerebral small vessel disease and glymphatic dysfunction. This study aimed to determine the association between MRI-visible PVS burden and the risk of incident dementia. This study included community-dwelling Framingham Heart Study Original and Offspring cohort participants with available brain MRI-PVS ratings, free of stroke and dementia. Multivariable Cox proportional hazard regression was used to obtain hazard ratios (HRs) and 95% CIs of the association between MRI-visible PVS and incident dementia. PVS were rated using validated methods in the basal ganglia (BG) and centrum semiovale (CSO). The outcomes included all-cause dementia, Alzheimer dementia (AD), and vascular dementia (VaD). One thousand four hundred forty-nine participants 50 years or older (46% male) were included. Over a median follow-up period of 8.3 years, the incidence of all-cause dementia, AD, and VaD was 15.8%, 12.5%, and 2.5%, respectively. In models that adjusted for vascular risk factors and cardiovascular disease, the hazard for dementia increased steadily as PVS burden increased, rising 2-fold for those with grade II PVS (HR 2.44, 95% CI 1.51-3.93) to 5-fold in participants with grade IV (HR 5.05, 95% CI 2.75-9.26) compared with grade I PVS in CSO. In the BG, hazards increased 1.6-fold (HR 1.62, 95% CI 1.15-2.27) for grade II to 2.6-fold (HR 2.67, 95% CI 1.04-6.88) for grade IV compared with grade I PVS. The association remained significant for CSO but not for BG, after adjustment for white matter hyperintensity volume (WMHV), covert infarcts, and total brain volume. Similar findings were observed for AD, but VaD, limited by a small number of events, was not statistically significant. Higher burden of PVS in CSO was associated with increased risk of developing dementia, independent of vascular risk factors, total brain volume, WMHVs, and covert infarcts. This finding supports a role for PVS as a subclinical MRI marker to identify individuals in subclinical stages at high risk of developing dementia who may benefit from early intervention.

Association of Serum Antioxidant Vitamins and Carotenoids With Incident Alzheimer Disease and All-Cause Dementia Among US Adults.

Serum antioxidant vitamins and carotenoids may protect against neurodegeneration with age. We examined associations of these nutritional biomarkers with incident all-cause and Alzheimer disease (AD) dementia among US middle-aged and older adults. Using data from the third National Health and Nutrition Examination Surveys (1988-1994), linked with Centers for Medicare & Medicaid follow-up data, we tested associations and interactions of serum vitamins A, C, and E and total and individual serum carotenoids and interactions with incident AD and all-cause dementia. Cox proportional hazards regression models were conducted. After ≤26 years follow-up (mean 16-17 years, 7,283 participants aged 45-90 years at baseline), serum lutein+zeaxanthin was associated with reduced risk of all-cause dementia (65+ age group), even in the lifestyle-adjusted model (per SD: hazard ratio [HR] 0.93, 95% CI 0.87-0.99; p = 0.037), but attenuated in comparison with a socioeconomic status (SES)-adjusted model (HR 0.92, 95% CI 0.86-0.93; p = 0.013). An inverse relationship was detected between serum β-cryptoxanthin (per SD increase) and all-cause dementia (45+ and 65+) for age- and sex-adjusted models (HR 0.86, 95% CI 0.80-0.93; p < 0.001 for 45+; HR 0.86, 95% CI 0.80-0.93; p = 0.001 for 65+), a relationship remaining strong in SES-adjusted models (HR 0.89, 95% CI 0.82-0.96; p = 0.006 for 45+; HR 0.88, 95% CI 0.81-0.96; p = 0.007 for 65+), but attenuated in subsequent models. Antagonistic interactions indicate putative protective effects of 1 carotenoid may be observed at lower levels other carotenoids or antioxidant vitamin. Incident all-cause dementia was inversely associated with serum lutein+zeaxanthin and β-cryptoxanthin levels. Further studies with time-dependent exposures and randomized trials are needed to test neuroprotective effects of supplementing the diet with select carotenoids. This study provides Class II evidence that incident all-cause dementia was inversely associated with serum lutein+zeaxanthin and β-cryptoxanthin levels.

FC081: Cholinesterase Inhibitors and Kidney Function Decline in Patients with Alzheimer's Dementia

Abstract BACKGROUND AND AIMS Preclinical evidence shows that activation of the cholinergic anti-inflammatory pathway (CAP) may have direct and indirect beneficial effects on the kidney. Cholinesterase inhibitors (ChEIs) are specific Alzheimer's dementia (AD) therapies that block the action of cholinesterases and activate CAP. This study explores a plausible effect of ChEIs on slowing kidney function decline. METHOD Observational study with a landmark design of patients with incident AD from the Swedish Dementia Registry (SveDem) 2007–2018 with complete extraction of routine serum creatinine tests from the Stockholm CREAtinine Measurements (SCREAM) registry to evaluate estimated glomerular filtration rate (eGFR) over time. Patients starting on ChEI within 90 days of an AD diagnosis were compared to patients with AD not receiving ChEI. The primary study outcome was CKD progression, defined as the composite of a sustained eGFR decline of &amp;gt;30% from baseline, initiation of kidney replacement therapy or death attributed to kidney disease. Secondary outcome was death. Inverse probability of treatment weighting Cox models were used to estimate hazard ratios, balancing 45 confounders. RESULTS We included 11 898 incident patients, of whom 6803 started on ChEI and 5095 did not. Mean age was 80 years, 64% were women and mean baseline eGFR was 68 mL/min/1.73 m2. After weighting, and during median follow-up time of 3.0 (IQR 1.3–4.5) years, 1231 events of CKD progression occurred, along with 5691 deaths. Compared to noninitiators, ChEI use was associated with a 18% lower risk of CKD progression [adjusted hazards ratio (aHR) 0.82; 95% confidence interval (95% CI) 0.70–0.96] and a 21% lower risk of death (aHR 0.79; 0.72–0.86). Results were consistent across subgroups of age, sex, and across ChEI subclasses and after accounting for competing risks. CONCLUSION In routinely cared patients with incident AD diagnosis, use of ChEI (versus no-use) was associated with lower risk of CKD progression and death, lending support to the role of CAP activation on preservation of kidney function.

Daytime napping and Alzheimer's dementia: A potential bidirectional relationship.

Daytime napping is frequently seen in older adults. The longitudinal relationship between daytime napping and cognitive aging is unknown. Using data from 1401 participants of the Rush Memory and Aging Project, we examined the longitudinal change of daytime napping inferred objectively by actigraphy, and the association with incident Alzheimer's dementia during up to 14-year follow-up. Older adults tended to nap longer and more frequently with aging, while the progression of Alzheimer's dementia accelerates this change by more than doubling the annual increases in nap duration/frequency. Longer and more frequent daytime naps were associated with higher risk of Alzheimer's dementia. Interestingly, more excessive (longer or more frequent) daytime napping was correlated with worse cognition a year later, and conversely, worse cognition was correlated with more excessive naps a year later. Excessive daytime napping and Alzheimer's dementia may possess a bidirectional relationship or share common pathophysiological mechanisms.

Intravesical Bacillus Calmette-Guérin Treatment Is Inversely Associated With the Risk of Developing Alzheimer Disease or Other Dementia Among Patients With Non-muscle-invasive Bladder Cancer.

The immune system plays an important role in the pathogenesis of Alzheimer disease (AD), but it remains unclear whether bacillus Calmette-Guérin (BCG) may affect the risk of AD or not. Using retrospective chart review, we collected data regarding demographics, comorbidities, cancer diagnosis, BCG treatment, and subsequent diagnosis of AD or other dementia in a racially/ethnically diverse cohort of patients with non-muscle-invasive bladder cancer (NIMBC) receiving treatment between 1984 and 2020 in the Bronx, New York. We used Cox proportional hazard models to examine association between BCG treatment and risk of incident AD or other dementia, adjusting for age, gender, race/ethnicity, and major comorbidities. In our cohort of 1290 patients with NMIBC, a total of 99 (7.7%) patients developed AD or other dementia during follow-up. Patients who received BCG treatment (25%) had a 60% lowered incidence of AD or other dementia (adjusted hazard ratio [HR], 0.41; 95% confidence interval [CI], 0.21-0.80) in comparison to those who did not receive BCG. There was also suggestive evidence that the reduction in risk of AD or other dementia associated with BCG treatment was stronger in men (adjusted HR, 0.34; 95% CI, 0.15-0.81) but not in women (adjusted HR, 0.75; 95% CI 0.25-2.24). When we stratified the patients who received BCG by type of treatments, patients who received both induction and maintenance rounds of BCG had a further lowered incidence of AD or other dementia (HR, 0.23; 95% CI, 0.06-0.96) than patients who did not receive BCG. To our knowledge, our study is one of the first to suggest that BCG treatment is associated with a reduced risk of developing AD or other dementia in a multiethnic population, independent of significant comorbidities. Larger cohort studies are needed to corroborate our findings.

Association of Performance on Dichotic Auditory Tests With Risk for Incident Dementia and Alzheimer Dementia

Age-related hearing difficulties can include problems with signal audibility and central auditory processing. Studies have demonstrated associations between audibility and dementia risk. To our knowledge, limited data exist to determine whether audibility, central processing, or both drive these associations. To determine the associations between signal sensitivity, central auditory processing, and dementia and Alzheimer dementia (AD) risk. This follow-up observational study of a sample from the prospective Adult Changes in Thought study of dementia risk was conducted at Kaiser Permanente Washington, a western Washington health care delivery system, and included 280 volunteer participants without dementia who were evaluated from October 2003 to February 2006 with follow-up through September 2018. Analyses began in 2019 and continued through 2021. Hearing tests included pure tone signal audibility, a monaural word recognition test, and 2 dichotic tests: the Dichotic Sentence Identification (DSI) test and the Dichotic Digits test (DDT). Cognition was assessed biennially with the Cognitive Abilities Screening Instrument (range, 1-100; higher scores are better), and scores of less than 86 prompted clinical and neuropsychological evaluations. All data were reviewed at multidisciplinary consensus conferences, and standardized criteria were used to define incident cases of dementia and probable or possible AD. Cox proportional hazard models were used to determine associations with hearing test performance. A total of 280 participants (177 women [63%]; mean [SD] age, 79.5 [5.2] years). As of September 2018, there were 2196 person-years of follow-up (mean, 7.8 years) and 89 incident cases of dementia (66 not previously analyzed), of which 84 (94.4%) were AD (63 not previously analyzed). Compared with people with DSI scores of more than 80, the dementia adjusted hazard ratio (aHR) for DSI scores of less than 50 was 4.18 (95% CI, 2.37-7.38; P < .001); for a DSI score of 50 to 80, it was 1.82 (95% CI, 1.10-3.04; P = .02). Compared with people with DDT scores of more than 80, the dementia aHR for DDT scores of less than 50 was 2.66 (95% CI, 1.31-5.42; P = .01); for a DDT score of 50 to 80, it was 2.40 (95% CI, 1.45-3.98; P = .001). The AD results were similar. Pure tone averages were weakly and insignificantly associated with dementia and AD, and associations were null when controlling for DSI scores. In this cohort study, abnormal central auditory processing as measured by dichotic tests was independently associated with dementia and AD risk.

Helicobacter pylori infection and risk for developing dementia: an evidence-based meta-analysis of case-control and cohort studies.

Background: Infection with multiple pathogens may play a key role in the pathogenesis of dementia. Whether Helicobacter pylori (H. pylori) infection is associated causally with dementia is controversial.Objective: We conduct a meta-analysis of case-control and cohort studies on the association between H. pylori infection and the risk for all-cause and Alzheimer’s disease (AD) dementia.Methods: Two independent reviewers searched the PubMed, Cochrane Library, and Embase databases with English language restrictions from the date of conception to September 18, 2020. The primary analysis was as follows: the exposure variable was H. pylori infection, and the outcome was incident all-cause and AD dementia. Pooled odds ratios (OR), relative risk (RR), and corresponding 95% confidence intervals (CI) were obtained using the fixed-or random-effect model. Forest plots were generated to summarize the results.Results: Ten studies involving 96,561 participants were included in the meta-analysis: 5 case-control studies and 5 cohort studies. The overall pooled cohort studies showed a significant positive association between H. pylori infection and all-cause dementia with pooled RR of 1.36 (95% CI, 1.11-1.67). There was no association between H. pylori infection and risk for developing AD: RR of 1.33 (95% CI, 0.86-2.05) in cohort studies, and OR of 1.72 (95% CI, 0.97-3.04) in case-control studies. Significant heterogeneity was showed in each comparison group.Conclusion: This meta-analysis supports a positive association between H. pylori infection and the risk of all-cause dementia, but not AD dementia. Due to the interference of confounding factors, randomized controlled trials are needed to prove their causality.

Cognitive Activity and Onset Age of Incident Alzheimer Disease Dementia.

To test the hypothesis that higher level of cognitive activity predicts older age at dementia onset in Alzheimer disease (AD) dementia. As part of a longitudinal cohort study, 1,903 older persons without dementia at enrollment reported their frequency of participation in cognitively stimulating activities. They had annual clinical evaluations to diagnose dementia and AD, and the deceased underwent neuropathologic examination. In analyses, we assessed the relation of baseline cognitive activity to age at diagnosis of incident AD dementia and to postmortem markers of AD and other dementias. During a mean of 6.8 years of follow-up, 457 individuals were diagnosed with incident AD at a mean age of 88.6 (SD 6.4, range 64.1-106.5) years. In an extended accelerated failure time model, higher level of baseline cognitive activity (mean 3.2, SD 0.7) was associated with older age at AD dementia onset (estimate 0.026; 95% confidence interval 0.013-0.039). Low cognitive activity (score 2.1, 10th percentile) was associated with a mean onset age of 88.6 years compared to a mean onset age of 93.6 years associated with high cognitive activity (score 4.0, 90th percentile). Results were comparable in subsequent analyses that adjusted for potentially confounding factors. In 695 participants who died and underwent a neuropathologic examination, cognitive activity was unrelated to postmortem markers of AD and other dementias. A cognitively active lifestyle in old age may delay the onset of dementia in AD by as much as 5 years.

Purpose in Life May Delay Adverse Health Outcomes in Old Age

Test the hypothesis that a higher level of purpose in life is associated with an older age of Alzheimer's dementia onset and later mortality. Prospective cohort studies of aging and Alzheimer's dementia. Community-based. Two thousand five hundred fifty-eight older adults initially free of dementia underwent assessments of purpose in life and detailed annual clinical evaluations to document incident Alzheimer's dementia and mortality. General accelerated failure time models examined the relation of baseline purpose in life with age at Alzheimer's dementia diagnosis and mortality. Purpose in life was assessed at baseline. Alzheimer's dementia diagnosis was documented annually based on detailed clinical evaluations and mortality was documented via regular contacts and annual evaluations. During a mean of 6.89 years of follow-up, 520 individuals were diagnosed with incident Alzheimer's dementia at a mean age of 88 (SD=6.7; range: 64.1-106.5). They had a mean baseline level of purpose in life of 3.7 (SD=0.47; range: 1-5). A higher level of purpose in life was associated with a considerably later age of dementia onset (estimate=0.044; 95% CI: 0.023, 0.065); specifically, individuals with high purpose (90th percentile) developed Alzheimer's dementia at a mean age of about 95 compared to a mean age of about 89 for individuals with low purpose (10th percentile). Further, the estimated mean age of death was about 89 for individuals with high purpose compared to 85 for those with low purpose. Results persisted after controlling for sex and education. Purpose in life delays dementia onset and mortality by several years. Interventions to increase purpose in life among older persons may increase healthspan and offer considerable public health benefit.

Sarcopenia is associated with incident Alzheimer's dementia, mild cognitive impairment, and cognitive decline.

We examined whether sarcopenia is associated with the occurrence of late-life cognitive impairment. Nondemented older adults (N=1175) underwent annual testing with 17 cognitive tests summarized as a global cognitive score. A composite sarcopenia score was constructed based on muscle mass measured with bioelectrical impedance and muscle function based on grip strength. Cox proportional hazard models were employed to examine associations of sarcopenia with incident Alzheimer's dementia (AD) and incident mild cognitive impairment (MCI). Linear mixed-effect models determined the association of sarcopenia with cognitive decline. All models controlled for age, sex, education, race, and height squared. Average follow-up was 5.6 years. More severe sarcopenia at baseline was associated with a higher risk of incident AD (hazard ratio [HR], 1.50 [95% confidence interval 1.20-1.86]; p < 0.001) and of MCI (1.21 [1.01-1.45]; 0.04) and a faster rate of cognitive decline (estimate=-0.013; p=0.01). Analyses of the individual components of sarcopenia showed that muscle function was associated with incident AD, incident MCI, and cognitive decline with and without a term for lean muscle mass in the model. In contrast, lean muscle mass was not associated with incident cognitive impairment or cognitive decline when a term for muscle function was included in the model. Poor muscle function, but not reduced lean muscle mass, drives the association of sarcopenia with late-life cognitive impairment. Further work is needed to identify features of muscle structure, which may increase the specificity of sarcopenia for identifying older adults at risk for late-life cognitive impairment.