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BackgroundClinical judgement is intrinsic to diagnostic strategies in general practice; however, empirical evidence for its validity is sparse.AimTo ascertain whether a GP’s global clinical judgement of future cognitive status has an added value for predicting a patient’s likelihood of experiencing dementia.Design and settingMulticentre prospective cohort study among patients in German general practice that took place from January 2003 to October 2016.MethodPatients without baseline dementia were assessed with neuropsychological interviews over 12 years; 138 GPs rated the future cognitive decline of their participating patients. Associations of baseline predictors with follow-up incident dementia were analysed with mixed-effects logistic and Cox regression.ResultsA total of 3201 patients were analysed over the study period (mean age = 79.6 years, 65.3% females, 6.7% incident dementia in 3 years, 22.1% incident dementia in 12 years). Descriptive analyses and comparison with other cohorts identified the participants as having frequent and long-lasting doctor–patient relationships and being well known to their GPs. The GP baseline rating of future cognitive decline had significant value for 3-year dementia prediction, independent of cognitive test scores and patient’s memory complaints (GP ratings of very mild (odds ratio [OR] 1.97, 95% confidence intervals [95% CI] = 1.28 to 3.04); mild (OR 3.00, 95% CI = 1.90 to 4.76); and moderate/severe decline (OR 5.66, 95% CI = 3.29 to 9.73)). GPs’ baseline judgements were significantly associated with patients’ 12-year dementia-free survival rates (Mantel–Cox log rank testPConclusionIn this sample of patients in familiar doctor–patient relationships, the GP’s clinical judgement holds additional value for predicting dementia, complementing test performance and patients’ self-reports. Existing and emerging primary care-based dementia risk models should consider the GP’s judgement as one predictor. Results underline the importance of the GP-patient relationship.

Hospitalization is a key driver of health care costs. Thus far, there are only a few longitudinal studies investigating whether changes in explanatory variables lead to hospitalization. Moreover, these longitudinal studies did not focus on individuals in highest age. The purpose of the current study was to examine the correlates of hospitalization among the oldest old in Germany longitudinally. A multicenter prospective cohort study [“Study on Needs, health service use, costs and health-related quality of life in a large sample of oldest-old primary care patients (85+)”, AgeQualiDe]. Primary care patients ≥ 85 years took part [n = 861 at follow-up (FU) 7, average age of 89.0 years; 85–100 years]. Two waves were used. Hospitalization in the last 6 months was used as outcome measure. Well-established scales were used to quantify the independent variables such as Instrumental Activities of Daily Living Scale, Global Deterioration Scale or Geriatric Depression Scale. Logistic random effects regressions showed that the probability of hospitalization in the preceding 6 months significantly increased with increases in the social network, more depressive symptoms, functional decline, and increase in chronic conditions, whereas it was not significantly associated with age, sex, marital status, education, and cognitive impairment. Social networks moderate the relationship between functional decline and hospitalization. The results of the present longitudinal study emphasize the association of depressive symptoms, functional decline, more social networks, and chronic conditions with hospitalization among the oldest old. Treatments with the aim to reduce or postpone these factors might also help to reduce hospitalization.

Background: One of the aims of the German student selection network (Studierendenauswahl-Verbund, stav) is to review existing procedures for selecting medical students and to relate their effectiveness to students’ career aspirations as well as to their further careers. Against the background of changes in the selection procedures and the introduction of the rural doctor quota (Landarztquote), the study conducted here aims at contributing to the current discussion on the future of GP (general practitioners) care, especially in rural areas. Methods: In 2019 and 2020, the stav conducted a German nationwide online survey among medical students towards the end of their “Practical Year” (Praktisches Jahr, final-year medical students in practical training). The associations between selection parameters and students’ interest in later working as a GP as well as students’ preference to later work in a place with a low population density were investigated. Furthermore, socio-demographic variables and variables related to medical studies were taken into account. Statistical comparisons were carried out using Chi2- and Mann-Whitney U tests. Results: A total of 1,055 students in their Practical Year (65.4% female, 27 years) completed the survey. As their final professional position, 12.1% aspired to own a GP practice or work as employed GP after completing medical specialist training in general medicine (interested students: 9.9%) or general internal medicine (interested students: 9.5%). Compared to their fellow students, those interested in working as a GP had been more often admitted to medical school via the waiting time quota and had more often already completed vocational training in a medical-related field. 39.1% of those interested in working as a GP wanted to work in a place with a low population density. Coming from a place with a low population density as well as completing the medical internship (Famulatur) for GP care in such a place turned out to be positive influencing factors. Discussion: The observed associations between waiting time quota and interest in working as a GP as well as between origin from a place with a low population density and preferring to later work in such a place go hand in hand with changes in the access regulations for medical studies, which concern both the waiting time quota (abolition of the latter) and a regulation of the number of rural doctors (rural doctor quota). In order to evaluate the current changes in the access regulations for medical studies, longitudinal studies are desirable that cover the time from the application to study up to the medical specialist examination and further career., Hintergrund: Der Studierendenauswahl-Verbund (stav) hat u.a. das Ziel, bestehende Instrumente zur Auswahl Medizinstudierender zu überprüfen und die Aussagekraft der Auswahlverfahren in Beziehung zu setzen zur angestrebten Berufstätigkeit bzw. zum Berufsverbleib. Vor dem Hintergrund der Neuerungen der Auswahlverfahren und Einführung der Landarztquote soll die hier durchgeführte Studie einen Beitrag leisten zur aktuellen Diskussion um die zukünftige hausärztliche Versorgung, v.a. in ländlich geprägten Gebieten. Methoden: In 2019 und 2020 führte der stav eine bundesweite Onlineumfrage unter Medizinstudierenden gegen Ende ihres PJ durch. Es wurde untersucht, welcher Zusammenhang zwischen Auswahlparametern und dem Wunsch besteht, eine hausärztliche Tätigkeit anzustreben und in einem Ort mit geringer Bevölkerungsdichte zu arbeiten. Weiterhin wurden soziodemographische Faktoren und Merkmale zum Studium berücksichtigt. Statistische Vergleiche erfolgten mittels Chi-Quadrat- und Mann-Whitney-U-Tests. Ergebnisse: Insgesamt 1.055 PJ-Studierende (65,4% weiblich, 27 Jahre) schlossen die Umfrage ab. Als endgültige berufliche Position erstrebten 12,1% eine Niederlassung oder eine Anstellung als Hausärzt*in nach absolvierter Weiterbildung in Allgemeinmedizin (interessierte PJ-Studierende: 9,9%) oder Innere Medizin ohne Schwerpunkt (interessierte PJ-Studierende: 9,5%). Im Vergleich zu ihren Kommiliton*innen hatten die Hausarztinteressierten ihren Studienplatz überzufällig häufig über die Wartezeitquote erhalten und hatten häufiger bereits eine medizinnahe Berufsausbildung abgeschlossen. In einem Ort mit geringer Bevölkerungsdichte zu arbeiten wünschten sich 39,1% der Hausarztinteressierten. Die Herkunft aus einem Ort mit geringer Bevölkerungsdichte sowie eine Ableistung der Famulatur zur hausärztlichen Patientenversorgung in einem solchen Ort stellten sich hier als positive Einflussfaktoren heraus. Diskussion: Die beobachteten Zusammenhänge zwischen Wartezeitquote und Hausarztpräferenz sowie zwischen Herkunft aus einer dünn besiedelten Region und Landarztpräferenz gehen zeitlich einher mit Veränderungen in den Zugangsregelungen zum Medizinstudium, die sowohl die Wartezeitquote (Abschaffung dieser) als auch eine Regulierung der Landarztzahlen (Landarztquote) betreffen. Um die aktuellen Veränderungen der Zugangsregelungen zum Medizinstudium zu evaluieren, sind längsschnittliche Studien erstrebenswert, die die Zeit von der Studienbewerbung bis hin zur fachärztlichen Prüfung und dem Ort der Tätigkeit umfassen.

ObjectivesTo examine how visual impairment affects physical and cognitive function in old age. DesignA longitudinal population-based prospective cohort study. SettingGeneral practitioner offices at six study centers in Germany. They were observed every 1.5 years over four waves. ParticipantsIndividuals aged 77-101 at follow-up Wave 2 (N = 2,394). MeasurementsPhysical and cognitive function were assessed using an adapted scale that had been previously developed, and visual impairment was rated on a Likert scale (none, mild, severe or profound). ResultsAdjusting for sociodemographic factors and comorbidity, linear fixed-effects regression showed that the onset of severe visual impairment was associated with a decline in physical function score in the total sample ( = -0.15, P = .01) and in women ( = -.15, P = .03). Moreover, the onset of severe visual impairment was associated with decline in cognitive function score in the total sample ( = -0.38, P < .001) and in women ( = -0.38, P < .001) and men ( = -0.37, P = .001). ConclusionVisual impairment affects physical and cognitive function in old age. Interventional strategies to postpone visual impairment may contribute to maintaining physical and cognitive function.

SummarySeveral proteins have been linked to neurodegenerative disorders (NDDs), but their molecular function is not completely understood. Here, we used quantitative interaction proteomics to identify binding partners of Amyloid beta precursor protein (APP) and Presenilin-1 (PSEN1) for Alzheimer’s disease (AD), Huntingtin (HTT) for Huntington’s disease, Parkin (PARK2) for Parkinson’s disease, and Ataxin-1 (ATXN1) for spinocerebellar ataxia type 1. Our network reveals common signatures of protein degradation and misfolding and recapitulates known biology. Toxicity modifier screens and comparison to genome-wide association studies show that interaction partners are significantly linked to disease phenotypes in vivo. Direct comparison of wild-type proteins and disease-associated variants identified binders involved in pathogenesis, highlighting the value of differential interactome mapping. Finally, we show that the mitochondrial protein LRPPRC interacts preferentially with an early-onset AD variant of APP. This interaction appears to induce mitochondrial dysfunction, which is an early phenotype of AD.

The identification of subjects at high risk for Alzheimer's disease is important for prognosis and early intervention. We investigated the polygenic architecture of Alzheimer's disease and the accuracy of Alzheimer's disease prediction models, including and excluding the polygenic component in the model. This study used genotype data from the powerful dataset comprising 17 008 cases and 37 154 controls obtained from the International Genomics of Alzheimer's Project (IGAP). Polygenic score analysis tested whether the alleles identified to associate with disease in one sample set were significantly enriched in the cases relative to the controls in an independent sample. The disease prediction accuracy was investigated in a subset of the IGAP data, a sample of 3049 cases and 1554 controls (for whom APOE genotype data were available) by means of sensitivity, specificity, area under the receiver operating characteristic curve (AUC) and positive and negative predictive values. We observed significant evidence for a polygenic component enriched in Alzheimer's disease (P = 4.9 × 10(-26)). This enrichment remained significant after APOE and other genome-wide associated regions were excluded (P = 3.4 × 10(-19)). The best prediction accuracy AUC = 78.2% (95% confidence interval 77-80%) was achieved by a logistic regression model with APOE, the polygenic score, sex and age as predictors. In conclusion, Alzheimer's disease has a significant polygenic component, which has predictive utility for Alzheimer's disease risk and could be a valuable research tool complementing experimental designs, including preventative clinical trials, stem cell selection and high/low risk clinical studies. In modelling a range of sample disease prevalences, we found that polygenic scores almost doubles case prediction from chance with increased prediction at polygenic extremes.

Background Thus far, only a few longitudinal studies investigated the impact of social engagement on health-related quality of life (HRQoL) and depressive symptoms in old age. Therefore, we aimed to examine the impact of social engagement on HRQoL and depressive symptoms in late life. Methods Individuals aged 75 years and over at baseline were interviewed every 1.5 years in a multicenter prospective cohort study in Germany. While HRQoL was quantified by using the Visual Analogue Scale (EQ VAS) of the EQ-5D instrument, depressive symptoms was assessed by using the Geriatric Depression Scale (GDS). Individuals reported the frequency (“never” to “every day”) of social engagement (e.g., engagement in the church, as a volunteer, in a party, or in a club) in the last four weeks. Fixed effects regressions were used to estimate the effect of social engagement on the outcome variables. Results After adjusting for age, marital status, functional status and chronic diseases, fixed effects regressions revealed that the onset of social engagement markedly increased HRQoL and considerably decreased depressive symptoms in the total sample and in women, but not men. Conclusions Our findings corroborate the relevance of social engagement for HRQoL and depressive symptoms in old age. Encouraging the individuals to start, maintain and expand social engagement in late life might help to maintain and improve HRQoL and decrease depressive symptoms.

BackgroundWhether late-onset depression is a risk factor for or a prodrome of dementia remains unclear. We investigated the impact of depressive symptoms and early- v. late-onset depression on subsequent dementia in a cohort of elderly general-practitioner patients (n = 2663, mean age = 81.2 years).MethodRisk for subsequent dementia was estimated over three follow-ups (each 18 months apart) depending on history of depression, particularly age of depression onset, and current depressive symptoms using proportional hazard models. We also examined the additive prediction of incident dementia by depression beyond cognitive impairment.ResultsAn increase of dementia risk for higher age cut-offs of late-onset depression was found. In analyses controlling for age, sex, education, and apolipoprotein E4 genotype, we found that very late-onset depression (aged ⩾70 years) and current depressive symptoms separately predicted all-cause dementia. Combined very late-onset depression with current depressive symptoms was specifically predictive for later Alzheimer's disease (AD; adjusted hazard ratio 5.48, 95% confidence interval 2.41–12.46, p ConclusionsDepression might be a prodrome of AD but not of dementia of other aetiology as very late-onset depression in combination with current depressive symptoms, possibly emerging as a consequence of subjectively perceived worrisome cognitive deterioration, was most predictive. As depression parameters and subjective memory impairment predicted AD independently of objective cognition, clinicians should take this into account.

Midlife motivational abilities, that is, skills to initiate and persevere in the implementation of goals, have been related to mental and physical health, but their association with risk of mild cognitive impairment (MCI) and Alzheimer's disease (AD) has not yet been directly investigated. This relation was examined with data from the German Study on Ageing, Cognition, and Dementia in Primary Care Patients (AgeCoDe). A total of 3,327 nondemented participants (50.3% of a randomly selected sample) aged 75-89 years were recruited in primary care and followed up twice (after 1.5 and 3 years). Motivation-related occupational abilities were estimated on the basis of the main occupation (assessed at follow-up II) using the Occupational Information Network (O* NET) database, which provides detailed information on worker characteristics and abilities. Cox proportional hazards models were used to evaluate the relative risk of developing MCI and AD in relation to motivation-related occupational abilities, adjusting for various covariates. Over the 3 years of follow-up, 15.2% participants developed MCI and 3.0% developed AD. In a fully adjusted model, motivation-related occupational abilities were found to be associated with a reduced risk of MCI (HR: 0.77; 95% CI: 0.64-0.92). Motivation-related occupational abilities were associated with reduced risk of AD in ApoE ε4 carriers (HR: 0.48; CI: 0.25-0.91), but not in noncarriers (HR: 0.99; CI: 0.65-1.53). These results suggest that midlife motivational abilities are associated with reduced risk of MCI in general and with reduced risk of AD in ApoE ε4 carriers. Revealing the mechanisms underlying this association may inform novel prevention strategies for decelerating cognitive decline in old age.

OBJECTIVE:Subjective cognitive decline (SCD) might represent the first symptomatic representation of Alzheimer's disease (AD), which is associated with increased mortality. Only few studies, however, have analyzed the association of SCD and mortality, and if so, based on prevalent cases. Thus, we investigated incident SCD in memory and mortality. METHODS:Data were derived from the German AgeCoDe study, a prospective longitudinal study on the epidemiology of mild cognitive impairment (MCI) and dementia in primary care patients over 75 years covering an observation period of 7.5 years. We used univariate and multivariate Cox regression analyses to examine the relationship of SCD and mortality. Further, we estimated survival times by the Kaplan Meier method and case-fatality rates with regard to SCD. RESULTS:Among 971 individuals without objective cognitive impairment, 233 (24.0%) incidentally expressed SCD at follow-up I. Incident SCD was not significantly associated with increased mortality in the univariate (HR = 1.0, 95% confidence interval = 0.8-1.3, p = .90) as well as in the multivariate analysis (HR = 0.9, 95% confidence interval = 0.7-1.2, p = .40). The same applied for SCD in relation to concerns. Mean survival time with SCD was 8.0 years (SD = 0.1) after onset. CONCLUSION:Incident SCD in memory in individuals with unimpaired cognitive performance does not predict mortality. The main reason might be that SCD does not ultimately lead into future cognitive decline in any case. However, as prevalence studies suggest, subjectively perceived decline in non-memory cognitive domains might be associated with increased mortality. Future studies may address mortality in such other cognitive domains of SCD in incident cases.

Background Mean body weight gradually increases with age. Yet, little data exists on the prevalence of excess weight in populations aged 80 years or older. Moreover, little is known about predictors of overweight and obesity in old age. Thus, the purpose of this study was: To present data on the prevalence of excess weight in old age in Germany, to investigate predictors of excess weight in a cross-sectional approach and to examine factors affecting excess weight in a longitudinal approach. Methods Subjects consisted of 1,882 individuals aged 79 years or older. The course of excess weight was observed over 3 years. Excess weight was defined as follows: Overweight (25 kg/m2 ≤ BMI

Type 2 diabetes mellitus (T2DM) is a risk factor of dementia. The effect of T2DM treatment quality on dementia risk, however, is unclear. 1,342 elderly individuals recruited via general practitioner registries (AgeCoDe cohort) were analyzed. This study analyzed the association between HbA1c level and the incidence of all-cause dementia (ACD) and of Alzheimer's disease dementia (referred to here as AD). HbA1c levels ≥6.5% were associated with 2.8-fold increased risk of incident ACD (p = 0.027) and for AD (p = 0.047). HbA1c levels ≥7% were associated with a five-fold increased risk of incident ACD (p = 0.001) and 4.7-fold increased risk of incident AD (p = 0.004). The T2DM diagnosis per se did not increase the risk of either ACD or AD. Higher levels of HbA1c are associated with increased risk of ACD and AD in an elderly population. T2DM diagnosis was not associated with increased risk if HbA1c levels were below 7%.

Background The evidence of undertreatment of pain in patients with dementia is inconsistent. This may largely be due to methodological differences and shortcomings of studies. In a large cohort of patients with incident dementia and age- and sex-matched controls we examined (1) how often they receive diagnoses indicating pain, (2) how often they receive analgesics and (3) in which agents and formulations. Methods Using health insurance claims data we identified 1,848 patients with a first diagnosis of dementia aged ≥ 65 years and 7,385 age- and sex-matched controls. We analysed differences in diagnoses indicating pain and analgesic drugs prescribed between these two groups within the incidence year. We further fitted logistic regression models and stepwise adjusted for several covariates to study the relation between dementia and analgesics. Results On average, patients were 78.7 years old (48% female). The proportions receiving at least one diagnosis indicating pain were similar between the dementia and control group (74.4% vs. 72.5%; p = 0.11). The proportion who received analgesics was higher in patients with dementia in the crude analysis (47.5% vs. 44.7%; OR: 1.12; 95% CI: 1.01-1.24), but was significantly lower when adjusted for socio-demographic variables, care dependency, comorbidities and diagnoses indicating pain (OR: 0.78; 95% CI: 0.68-0.88). Analgesics in liquid form such as metamizole and tramadol were more often used in dementia. Conclusions Our findings show a comparable documentation of diagnoses indicating pain in persons with incident dementia compared to those without. However, there still seems to be an undertreatment of pain in patients with dementia. Irrespective of dementia, analgesics seem to be more often prescribed to sicker patients and to control pain in the context of mobility.

GRB-associated binding protein 2 (GAB2) represents a compelling genome-wide association signal for late-onset Alzheimer's disease (LOAD) with reported odds ratios (ORs) ranging from 0.75-0.85. We tested eight GAB2 variants in four North American Caucasian case-control series (2,316 LOAD, 2,538 controls) for association with LOAD. Meta-analyses revealed ORs ranging from (0.61-1.20) with no significant association (all p>0.32). Four variants were hetergeneous across the populations (all p

Objective To compare the risk of developing Alzheimer's disease (AD) dementia in late mild cognitive impairment (LMCI), early MCI (EMCI), and subjective memory impairment (SMI) with normal test performance. Methods The baseline sample (n = 2892) of the prospective cohort study in nondemented individuals (German Study on Aging, Cognition and Dementia in Primary Care Patients) was divided into LMCI, EMCI, SMI, and control subjects by delayed recall performance. These groups were subdivided by the presence of self-reported concerns associated with experienced memory impairment. AD dementia risk was assessed over 6 years. Results Across all groups, risk of AD dementia was greatest in LMCI. In those with self-reported concerns regarding their memory impairment, SMI and EMCI were associated with a similarly increased risk of AD dementia. In those subgroups without concerns, SMI was not associated with increased risk of AD dementia, but EMCI remained an at-risk condition. Conclusions SMI and EMCI with self-reported concerns were associated with the same risk of AD dementia, suggesting that pre-LMCI risk conditions should be extended to SMI with concerns.

BACKGROUND: Current approaches for AD prediction are based on biomarkers, which are however of restricted availability in primary care. AD prediction tools for primary care are therefore needed. We present a prediction score based on information that can be obtained in the primary care setting. METHODOLOGY/PRINCIPAL FINDINGS: We performed a longitudinal cohort study in 3.055 non-demented individuals above 75 years recruited via primary care chart registries (Study on Aging, Cognition and Dementia, AgeCoDe). After the baseline investigation we performed three follow-up investigations at 18 months intervals with incident dementia as the primary outcome. The best set of predictors was extracted from the baseline variables in one randomly selected half of the sample. This set included age, subjective memory impairment, performance on delayed verbal recall and verbal fluency, on the Mini-Mental-State-Examination, and on an instrumental activities of daily living scale. These variables were aggregated to a prediction score, which achieved a prediction accuracy of 0.84 for AD. The score was applied to the second half of the sample (test cohort). Here, the prediction accuracy was 0.79. With a cut-off of at least 80% sensitivity in the first cohort, 79.6% sensitivity, 66.4% specificity, 14.7% positive predictive value (PPV) and 97.8% negative predictive value of (NPV) for AD were achieved in the test cohort. At a cut-off for a high risk population (5% of individuals with the highest risk score in the first cohort) the PPV for AD was 39.1% (52% for any dementia) in the test cohort. CONCLUSIONS: The prediction score has useful prediction accuracy. It can define individuals (1) sensitively for low cost-low risk interventions, or (2) more specific and with increased PPV for measures of prevention with greater costs or risks. As it is independent of technical aids, it may be used within large scale prevention programs.