Daria Gref

Background: The brain age gap (BAG), the difference between neuroimaging-predicted and chronological age, captures inter-individual variation in brain aging. Although sensitive to Alzheimer’s disease (AD) pathology, its longitudinal patterns across the clinical AD continuum and prognostic relevance remain unclear. Methods: 577 participants from the DELCODE cohort (>2,100 MRI scans) were analysed: healthy controls individuals (HC, N=202), and patients with subjective cognitive decline (SCD, N=248), mild cognitive impairment (N=93), and AD dementia (N=34). All underwent structural MRI, amyloid (Aβ _42/40 ) and phosphorylated tau181 assessment, and lifestyle-related dementia risk profiling (LIBRA). BAG was derived using brainageR. Associations with baseline cognition, cognitive decline, and clinical progression (up to eight years) were examined using mixed-effects and Cox models. Mediation analyses tested whether BAG accounted for LIBRA-cognition associations. Biomarker-related and clinical findings were replicated in ADNI (N=461). Findings: BAG showed excellent short-term reliability, increased stepwise across the clinical spectrum and was elevated in amyloid-positive SCD, but not in asymptomatic amyloid-positive HC. Longitudinal BAG increases were strongest in amyloid- and tau-positive participants (Aβ+T+). Higher BAG was associated with poorer baseline cognition and predicted cognitive decline, with strongest effects in Aβ+T+. All main findings replicated in ADNI. BAG was associated with LIBRA only in biomarker-negative participants and partly mediated associations with cognitive outcomes in DELCODE. Interpretation: BAG is a reliable non-invasive marker of structural brain health sensitive to AD pathology and to modifiable AD risk. Detectable divergence prior to objective cognitive impairment supports its relevance for early risk stratification and prevention-oriented research. Funding: Helmholtz AI Cooperation Unit (ZT-I-PF-5-163).

Brain maintenance – the preservation of brain structure or function relevant to cognitive performance – remains challenging to quantify. Here, we propose a domain-general brain maintenance index derived by jointly modelling the longitudinal co-evolution of ageing-related atrophy (via medial temporal lobe to ventricle ratio, MTLV-ratio), white matter hyperintensities (WMH), and global cognition assessed by the preclinical Alzheimer’s cognitive composite (PACC5) using latent growth curve modelling. We demonstrate its utility in 543 cognitively unimpaired older adults from the DELCODE cohort, followed annually over four years. We show that changes in MTLV-ratio and WMH additively predict cognitive change. We further show that higher neuroticism, depressive symptoms, lower openness, and faster biological ageing are related to unfavourable domain-specific trajectories and poorer brain maintenance. Our findings highlight the combined relevance of WMH and ageing-related atrophy dynamics for brain maintenance. Maintaining cerebrovascular and mental health alongside cognitive engagement could promote brain maintenance, delay cognitive decline and dementia.

Background: Low socioeconomic status is associated with a higher risk for a number of health conditions, including cognitive impairment. Objective: While the association with economic indicators has been well researched, aim of this paper was to investigate specifically the association between non-economic social deprivation and cognitive functioning later in life. Methods: Participants without objective cognitive impairment at baseline (n = 91 controls, n = 106 with subjective cognitive decline) of the multicenter DZNE-Longitudinal Cognitive Impairment and Dementia Study (DELCODE) filled out a posthoc survey on social deprivation. Factor analysis identified four non-economic domains of social deprivation (Residential area conditions, Accessibility, Neighborhood support, Household distress). Cognition was assessed via the CERAD neuropsychological battery. Analyses were conducted using linear regression models as well as maximum-likelihood mixed-effects models adjusted for age, gender, years of education, marital status, depression, BMI, heart disease, hypercholesterolemia, hypertension, and diabetes. Results: At the time of the survey, cognitive functioning was significantly lower among participants with high deprivation ( b = −0.21, p = 0.037). These participants also had a faster rate of cognitive decline ( b = −0.07, p = 0.006). Analyses of the deprivation sub-scores revealed statistically significant effects only for Accessibility ( b = −0.31, p = 0.001; rate of cognitive decline b = −0.07, p = 0.004). Conclusions: Our findings suggest that non-economic social deprivation, especially in terms of access to a grocery store, pharmacy, postal office, and bus stop, might be relevant for maintaining cognitive functioning in old age. Further research should explore potential mechanisms of how these environmental conditions affect brain aging and neurodegenerative processes.

Alzheimer’s disease (AD) is a major cause of dementia and cognitive decline. Here, we assessed how episodic memory (EM) network dysfunction, a hallmark of AD, is related to the longitudinal progression of AD biomarkers, neurodegeneration and cognition using data from the DZNE DELCODE study. This data set includes over 1000 longitudinal functional magnetic resonance imaging measurements of EM network function. We related activation and deactivation of EM to individual disease progression scores from a disease progression model. Voxel-wise analyses revealed widespread loss of deactivation and activation with disease progression. Trajectories for the loss of deactivation were nonlinear, associated with amyloid- and tau-positivity and visually preceded trajectories of cognitive decline. The relationship between deactivation and cognitive decline was partly independent of neurodegeneration. Our results provide evidence that synaptic dysfunction and neurodegeneration are independent drivers of cognitive decline, providing a rationale for targeting synaptic dysfunction along the AD cascade.

Background: Subjective cognitive decline (SCD) is common in older adults and may precede mild cognitive impairment (MCI). Whether longitudinal changes in self- or study partner (SP)-reported SCD improve early identification of individuals at risk for clinical progression, particularly along the Alzheimer’s disease (AD) biological continuum, remains unclear. Methods: We pooled data from two longitudinal observational cohorts (DELCODE and ADNI). Cognitively unimpaired (CU) participants were recruited through public advertisement or memory clinics and included if baseline amyloid status, ≥2 SCD assessments, and clinical follow-up were available. SCD was assessed using the Everyday Cognition questionnaire (self- and SP-report). Linear mixed-effects models examined longitudinal associations between SCD trajectories, baseline AD biomarkers, and progression to incident MCI. Multivariable Cox proportional hazards models tested whether one-year changes in SCD predicted subsequent progression. Findings: Among 770 participants (median age 69·9years [IQR 66·0–74·6]; 52·6% women; median follow-up 5·0years [4·0-7·0]), amyloid-positive individuals and those who progressed to MCI showed steeper longitudinal increases in both SCD reports. In amyloid-positive participants, only increases in SP-reported SCD differentiated progressors from non-progressors. One-year increases in SP-reported SCD predicted a higher risk of subsequent MCI compared with unchanged scores (hazard ratio 3·24 [95%CI 1·73-6·07]), with effects confined to amyloid-positive participants. Interpretation: Longitudinal increases in SP-reported cognitive difficulties, particularly over short intervals, are associated with near-term progression to MCI in amyloid-positive CU older adults. SP-based longitudinal monitoring may represent a low-burden approach to support earlier clinical surveillance in aging populations. Funding: German Center for Neurodegenerative Diseases, US National Institutes of Health.

The cognitive reserve (CR) hypothesis posits that individuals can differ in how their brain function is disrupted by pathology associated with aging and neurodegeneration. Here, we test this hypothesis in the continuum from cognitively normal to at-risk stages for Alzheimer’s Disease (AD) to AD dementia using longitudinal data from 490 participants of the DELCODE multicentric observational study. Brain function is measured using task fMRI of visual memory encoding. Using a multivariate moderation analysis, we identify a CR-related activity pattern underlying successful memory encoding that moderates the detrimental effect of AD pathological load on cognitive performance. CR is mainly represented by a more pronounced expression of the task-active network encompassing deactivation of the default mode network (DMN) and activation of inferior temporal regions including the fusiform gyrus. We devise personalized fMRI-based CR scores that moderate the impact of AD pathology on cognitive performance and are positively associated with years of education. Furthermore, higher CR scores attenuate the effect of AD pathology on cognitive decline over time. Our findings primarily provide evidence for the maintenance of core cognitive circuits including the DMN as the neural basis of CR. Individual brain activity levels of these areas during memory encoding have prognostic value for future cognitive decline.