Neue Perspektiven auf Früherkennung und Therapie der Alzheimer-Erkrankung durch statistische Modellierung kognitiver Fähigkeiten

Die Alzheimer-Erkrankung ist die häufigste Ursache von Demenzen. Erste pathologische Veränderungen entwickeln sich bereits Jahrzehnte vor der Ausbildung einer Demenz und leichte kognitive und affektive Veränderungen treten Jahre vor der Demenzdiagnose auf. Dies eröffnet Möglichkeiten zur Früherkennung und Prävention. Da nicht alle Personen mit einer Alzheimer-Pathologie zu Lebzeiten eine Demenz entwickeln, stellt sich die Frage, welche weiteren Prozesse im Gehirn auftreten müssen, die aus einer Alzheimer-Erkrankung eine Demenz entstehen lassen. Ein Ziel der vorliegenden Arbeit ist es, Indikatoren dieser Prozesse im frühen symptomatischen Stadium der Alzheimer-Erkrankung zu identifizieren, um die Vorhersage des weiteren Verlaufs der kognitiven Entwicklung zu verbessern und so einen Beitrag zur Früherkennung von Personen mit hohem Demenzrisiko zu leisten. Ein weiteres Ziel ist es, Faktoren zu identifizieren, die mit einem langsameren Verlauf dieser Prozesse in Verbindung stehen und somit die Auswirkungen von Pathologie auf Kognition mindern. Dies könnte dazu beitragen, neue Therapieansätze der Alzheimer-Erkrankung zu entwickeln. Um diese Ziele zu erreichen, wurden im Rahmen von vier Studien unterschiedliche methodische Ansätze verfolgt und Hausarzt- und Gedächtnisambulanzstichproben untersucht. Zum einen wurden statistische Modellierungen, wie Strukturgleichungsmodelle, verwendet, um den Verlauf kognitiver Funktionen im Rahmen der Alzheimer-Erkrankung zu charakterisieren und Zusammenhänge mit dem subjektiven Erleben und den Lebenserfahrungen der untersuchten Personen zu beschreiben. Zum anderen wurden Längsschnittdaten zur kognitiven Entwicklung mit genetischen Informationen kombiniert, um das Zusammenspiel biologischer Prozesse mit dem symptomatischen Verlauf der Erkrankung zu untersuchen. In Studie I wurde die zeitliche Reihenfolge von subjektiver Wahrnehmung kognitiver Verschlechterung einerseits und depressiven Symptomen andererseits im Verlauf des kognitiven Abbaus untersucht. Studie II untersuchte die Assoziation eines genetischen Risikoscores mit der längsschnittlichen Entwicklung einer Demenz bei Personen aus der Allgemeinbevölkerung und Individuen mit leichten kognitiven Einschränkungen. In Studie III wurde die Assoziation zwischen der seltenen Variante p.P522R im Gen PLCG2 und dem kognitiven Abbau sowie Biomarkern der Alzheimer-Erkrankung bei Patienten mit leichten kognitiven Einschränkungen untersucht. Studie IV untersuchte die Assoziation zwischen beruflichen kognitiven Anforderungen im mittleren Lebensalter, Biomarkern der Alzheimer-Erkrankung und kognitiven Fähigkeiten im späteren Lebensalter. Durch die gemeinsame Betrachtung und Modellierung von psychologischen Variablen (kognitive Fähigkeiten, subjektives Erleben, lebenslange Erfahrungen) einerseits und von biologischen Faktoren (Genetik, Biomarker der Alzheimerpathologie) andererseits konnten die vier Studien einige Merkmale und Einflussgrößen von demenzbezogenen Prozessen neu identifizieren und in ihrem Zusammenwirken verständlich machen

New insights into the genetic etiology of Alzheimer's disease and related dementias

Characterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele

New insights into the genetic etiology of Alzheimer’s disease and related dementias

Characterization of the genetic landscape of Alzheimer’s disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/‘proxy’ AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele

Eicosapentaenoic Acid Is Associated with Decreased Incidence of Alzheimer’s Dementia in the Oldest Old

Background. Omega-3 (n-3) and omega-6 (n-6) polyunsaturated fatty acids (PUFAs) may have different effects on cognitive health due to their anti- or pro-inflammatory properties. Methods. We aimed to prospectively examine the relationships between n-3 and n-6 PUFA contents in serum phospholipids with incident all-cause dementia and Alzheimer’s disease dementia (AD). We included 1264 non-demented participants aged 84 ± 3 years from the German Study on Ageing, Cognition, and Dementia in Primary Care Patients (AgeCoDe) multicenter-cohort study. We investigated whether fatty acid concentrations in serum phospholipids, especially eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), alpha-linolenic acid (ALA), linoleic acid (LA), dihomo-γ-linolenic acid (DGLA), and arachidonic acid (AA), were associated with risk of incident all-cause dementia and AD. Results. During the follow-up window of seven years, 233 participants developed dementia. Higher concentrations of EPA were associated with a lower incidence of AD (hazard ratio (HR) 0.76 (95% CI 0.63; 0.93)). We also observed that higher concentrations of EPA were associated with a decreased risk for all-cause dementia (HR 0.76 (95% CI 0.61; 0.94)) and AD (HR 0.66 (95% CI 0.51; 0.85)) among apolipoprotein E ε4 (APOE ε4) non-carriers but not among APOE ε4 carriers. No other fatty acids were significantly associated with AD or dementia. Conclusions. Higher concentrations of EPA were associated with a lower risk of incident AD. This further supports a beneficial role of n-3 PUFAs for cognitive health in old age

Do self-reported hearing and visual impairments predict longitudinal dementia in older adults?

Background Sensory impairments have been associated with dementia in older adults. However, the contribution of different impairments and how they interact in the development of dementia is not clear. We examined the independent and interaction effects of hearing impairment (HI) and visual impairment (VI) on incident dementia. Design Multi-centric population-based prospective cohort study. Setting Data were taken from the AgeDifferent.de platform, pooling participants aged 75 and older from the German LEILA75+ and AgeCoDe/AgeQualiDe cohorts. Participants Older adults (N = 3497) with mean age 79.8 years, 67.2% female. Measurements Standardized interviews and questionnaires were used to assess self-reported HI and VI at baseline and all-cause dementia in 9 follow-ups, spanning over 20 years. Methods Competing risk regression models were conducted to test the main and interaction effects of HI and VI on dementia incidence, adjusting for established risk factors of dementia and accumulated mortality. Results HI and VI at baseline were reported by 30.3% and 16.6% of individuals, respectively. Adjusting for baseline information on sociodemographics, substance use, cognitive functioning and morbidity, and controlling for accumulated mortality risk, HI (sHR 1.16, 95% CI 1.04–1.30, p = 0.011) but not VI (sHR 1.07, 95% CI 0.90–1.28, p = 0.462) was significantly associated with incident dementia. There was no interaction between HI and VI (sHR 1.09, 95% CI 0.81–1.46, p = 0.567). Conclusions Hearing impairment is associated with an increased incidence of all-cause dementia in older adults. There is no excess risk or risk compensation through the additional presence or absence of visual impairment. Early prevention measures for hearing impairment might help to reduce the long-term risk of dementia

New Insights into the Genetic Etiology of Alzheimer’s Disease and Related Dementias

Characterization of the genetic landscape of Alzheimer’s disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/‘proxy’ AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele

Age-specific risk factors of depression among the oldest-old - evidence from the multicenter AgeCoDe-AgeQualiDe study

PurposeThe present study aimed to investigate age-group-specific incidence rates and risk factors for depressive symptoms in the highest age groups.MethodsData were derived from a prospective multicenter cohort study conducted in primary care – the AgeCoDe/AgeQualiDe study. In total, 2,436 patients 75 years and older were followed from baseline to ninth follow-up. To assess depressive symptoms, the short version of the Geriatric Depression Scale (GDS-15, cutoff score 6) was used. Age-specific competing risk regressions were performed to analyze risk factors for incident depressive symptoms in different age groups (75 to 79, 80 to 84, 85+ years), taking into account the accumulated mortality.ResultsThe age-specific incidence rate of depression was 33 (95% CI 29-38), 46 (95% CI 40-52) and 63 (95% CI 45-87) per 1,000 person years for the initial age groups 75 to 79, 80 to 84 and 85+ years, respectively. In competing risk regression models, female sex, mobility as well as vision impairment, and subjective cognitive decline (SCD) were found to be risk factors for incident depression for age group 75 to 79, female sex, single/separated marital status, mobility as well as hearing impairment, and SCD for age group 80 to 84, and mobility impairment for age group 85+.ConclusionDepressive symptoms in latest life are common and the incidence increases with increasing age. Modifiable and differing risk factors across the highest age groups open up the possibility of specifically tailored prevention concepts

Prevalence of pain and its associated factors among the oldest-olds in different care settings – results of the AgeQualiDe study

Background; The prevalence of pain is very common in the oldest age group. Managing pain successfully is a key topic in primary care, especially within the ageing population. Different care settings might have an impact on the prevalence of pain and everyday life. Methods: Participants from the German longitudinal cohort 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) were asked to rate their severity of pain as well as the impairment with daily activities. Besides gender, age, education, BMI and use of analgesics we focused on the current housing situation and on cognitive state. Associations of the dependent measures were tested using four ordinal logistic regression models. Model 1 and 4 consisted of the overall sample, model 2 and 3 were divided according to no cognitive impairment (NCI) and mild cognitive impairment (MCI). Results: Results show a decline in pain at very old age but nonetheless a high prevalence among the 85+ year olds. Sixty-three per cent of the participants report mild to severe pain and 69% of the participants mild to extreme impairment due to pain with daily activities. Use of analgesics, depression and living at home with care support are significantly associated with higher and male gender with lower pain ratings. Conclusions: Sufficient pain management among the oldest age group is inevitable. Outpatient care settings are at risk of overlooking pain. Therefore focus should be set on pain management in these settings

Changes in Social Network Size Are Associated With Cognitive Changes in the Oldest-Old

Objectives:Social isolation is increasing in aging societies and several studies have shown a relation with worse cognition in old age. However, less is known about the association in the oldest-old (85+); the group that is at highest risk for both social isolation and dementia. Methods:Analyses were based on follow-up 5 to 9 of the longitudinal German study on aging, cognition, and dementia in primary care patients (AgeCoDe) and the study on needs, health service use, costs, and health-related quality of life in a large sample of oldest-old primary care patients (AgeQualiDe), a multi-center population-based prospective cohort study. Measurements included the Lubben Social Network Scale (LSNS-6), with a score below 12 indicating social isolation, as well as the Mini-Mental Status Examination (MMSE) as an indicator of cognitive function. Results:Dementia-free study participants (n = 942) were M = 86.4 (SD = 3.0) years old at observation onset, 68.2% were women. One third (32.3%) of them were socially isolated. Adjusted linear hybrid mixed effects models revealed significantly lower cognitive function in individuals with smaller social networks (β = 0.5, 95% CI = 0.3-0.7, p < .001). Moreover, changes in an individual's social network size were significantly associated with cognitive changes over time (β = 0.2, 95% CI = 0.1-0.4, p = .003), indicating worse cognitive function with shrinking social networks. Conclusion:Social isolation is highly prevalent among oldest-old individuals, being a risk factor for decreases in cognitive function. Consequently, it is important to maintain a socially active lifestyle into very old age. Likewise, this calls for effective ways to prevent social isolation

The Role of Social Isolation and the Development of Depression: A Comparison of the Widowed and Married Oldest Old in Germany

Widowhood is common in old age, can be accompanied by serious health consequences and is often linked to substantial changes in social network. Little is known about the impact of social isolation on the development of depressive symptoms over time taking widowhood into account. We provide results from the follow-up 5 to follow-up 9 from the longitudinal study AgeCoDe and its follow-up study AgeQualiDe. Depression was measured with GDS-15 and social isolation was assessed using the Lubben Social Network Scale (LSNS-6). The group was aligned of married and widowed people in old age and education through entropy balancing. Linear mixed models were used to examine the frequency of occurrence of depressive symptoms for widowed and married elderly people depending on the risk of social isolation. Our study shows that widowhood alone does not lead to an increased occurrence of depressive symptoms. However, "widowed oldest old", who are also at risk of social isolation, have significantly more depressive symptoms than those without risk. In the group of "married oldest old", women have significantly more depressive symptoms than men, but isolated and non-isolated do not differ. Especially for people who have lost a spouse, the social network changes significantly and increases the risk for social isolation. This represents a risk factor for the occurrence of depressive symptoms