Longitudinal Memory Research Articles

Medial Temporal Tau Predicts Memory Decline in Cognitively Unimpaired Elderly (P5-6.011)

<h3>Objective:</h3> Here, we assess the prognostic accuracy of baseline [18F]-MK-6420 tau PET for predicting longitudinal memory decline in asymptomatic elderly individuals. <h3>Background:</h3> Alzheimer’s disease (AD) can be detected in living people using in vivo biomarkers of amyloid-β (Aβ) and tau, even in the absence of cognitive impairment during the preclinical phase. [18F]-MK-6420 is a high affinity positron emission tomography (PET) tracer that quantifies tau neurofibrillary tangles, but its ability to predict cognitive changes associated with early AD symptoms, such as memory decline, is unclear. <h3>Design/Methods:</h3> In a longitudinal observational study, we evaluated a cohort of cognitively normal elderly participants from the Translational Biomarkers in Aging and Dementia (TRIAD) study (October 2017-July 2020, follow-up period of 12 months). All participants underwent tau PET with [18F]-MK-6420 and Aβ PET with [18F]-AZD-4694. <h3>Results:</h3> There were 111 eligible participants who were chosen based on the availability of Aβ PET, tau PET, magnetic resonance imaging (MRI), and APOEɛ4 genotyping. Among these participants, the mean (SD) age was 70.1 (8.6) years; 20 (18%) were tau PET positive and 71 of 111 (63.9%) were women. A significant association between baseline Braak I-II [18F]-MK-6240 SUVR positivity and change in composite memory score was observed at the 12 month follow-up, after correcting for age, sex, and years of education (Logical Memory and RAVLT, standardized beta = −0.52 (−0.82−0.21), p &lt; 0.001, for dichotomized tau PET and −1.22 (−1.84−(−0.61)), p &lt; 0.0001, for continuous tau PET). Moderate cognitive decline was observed for A+T+ over the follow-up period, whereas no significant change was observed for A-T+, A+T- and A-T−, though it should be noted that the A-T+ group was small. Our results indicate that baseline tau neurofibrillary tangle pathology is associated with longitudinal changes in memory function. <h3>Conclusions:</h3> [18F]-MK-6420 PET is a promising tool for predicting memory decline in older adults without cognitive impairment at baseline. <b>Disclosure:</b> Miss Kwan has nothing to disclose. Mr. Arfaie has nothing to disclose. Mr. Therriault has nothing to disclose. Dr. Azizi has nothing to disclose. Miss Lussier has nothing to disclose. Mrs. Tissot has nothing to disclose. Dr. Chamoun has nothing to disclose. Dr. Bezgin has nothing to disclose. Dr. Servaes has nothing to disclose. Miss Stevenson has nothing to disclose. Ms. Rahmouni has nothing to disclose. Miss Pallen has nothing to disclose. The institution of Dr. Rosa Neto has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Novo Nordisk.

7T amygdala and hippocampus subfields in volumetry-based associations with memory: A 3-year follow-up study of early Alzheimer’s disease

IntroductionThe hippocampus is the most prominent single region of interest (ROI) for the diagnosis and prediction of Alzheimer’s disease (AD). However, its suitability in the earliest stages of cognitive decline, i.e., subjective cognitive decline (SCD), remains uncertain which warrants the pursuit of alternative or complementary regions. The amygdala might be a promising candidate, given its implication in memory as well as other psychiatric disorders, e.g. depression and anxiety, which are prevalent in SCD. In this 7 tesla (T) magnetic resonance imaging (MRI) study, we aimed to compare the contribution of volumetric measurements of the hippocampus, the amygdala, and their respective subfields, for early diagnosis and prediction in an AD-related study population. MethodsParticipants from a longitudinal study were grouped into SCD (n = 29), mild cognitive impairment (MCI, n = 23), AD (n = 22) and healthy control (HC, n = 31). All participants underwent 7T MRI at baseline and extensive neuropsychological testing at up to three visits (baseline n = 105, 1-year n = 78, 3-year n = 39). Analysis of covariance (ANCOVA) was used to assess group differences of baseline volumes of the amygdala and the hippocampus and their subfields. Linear mixed models were used to estimate the effects of baseline volumes on yearly changes of a z-scaled memory score. All models were adjusted to age, sex and education. ResultsCompared to the HC group, individuals with SCD showed smaller amygdala ROI volumes (range across subfields −11% to −1%), but not hippocampus ROI volumes (-2% to 1%) except for the hippocampus-amygdala-transition-area (-7%). However, cross-sectional associations between baseline memory and volumes were smaller for amygdala ROIs (std. ß [95% CI] ranging between 0.16 [0.08; 0.25] and 0.46 [0.31; 0.60]) than hippocampus ROIs (between 0.32 [0.19; 0.44] and 0.53 [0.40; 0.67]). Further, the association of baseline volumes with yearly memory change in the HC and SCD groups was similarly weak for amygdala ROIs and hippocampus ROIs. In the MCI group, volumes of amygdala ROIs were associated with a relevant yearly memory decline [95% CI] ranging between −0.12 [−0.24; 0.00] and −0.26 [−0.42; −0.09] for individuals with 20% smaller volumes than the HC group. However, effects were stronger for hippocampus ROIs with a corresponding yearly memory decline ranging between −0.21 [−0.35; −0.07] and −0.31 [−0.50; −0.13]. ConclusionVolumes of amygdala ROIs, as determined by 7T MRI, might contribute to objectively and non-invasively identify patients with SCD, and thus aid early diagnosis and treatment of individuals at risk to develop dementia due to AD, however associations with other psychiatric disorders should be evaluated in further studies. The amygdala’s value in the prediction of longitudinal memory changes in the SCD group remains questionable. Primarily in patients with MCI, memory decline over 3 years appears to be more strongly associated with volumes of hippocampus ROIs than amygdala ROIs.

Medial temporal tau predicts memory decline in cognitively unimpaired elderly.

Alzheimer's disease can be detected in living people using in vivo biomarkers of amyloid-β and tau, even in the absence of cognitive impairment during the preclinical phase. [18F]-MK-6420 is a high-affinity PET tracer that quantifies tau neurofibrillary tangles, but its ability to predict cognitive changes associated with early Alzheimer's disease symptoms, such as memory decline, is unclear. Here, we assess the prognostic accuracy of baseline [18F]-MK-6420 tau-PET for predicting longitudinal memory decline in asymptomatic elderly individuals. In a longitudinal observational study, we evaluated a cohort of cognitively normal elderly participants (n = 111) from the translational biomarkers in ageing and dementia study (data collected between October 2017 and July 2020, with a follow-up period of 12 months). All participants underwent tau-PET with [18F]-MK-6420 and amyloid-β PET with [18F]-AZD-4694. The exclusion criteria included the presence of head trauma, stroke or other neurological disorders. There were 111 eligible participants selected based on the availability of amyloid-β PET, tau-PET, MRI and APOEɛ4 genotyping. Among these participants, the mean standard deviation age was 70.1 (8.6) years; 20 (18%) were tau-PET-positive and 71 of 111 (63.9%) were women. A significant association between the baseline Braak Stages I-II [18F]-MK-6240 standardized uptake value ratio positivity and change in composite memory score were observed at the 12-month follow-up, after correcting for age, sex and years of education [logical memory and Rey Auditory Verbal Learning Test, standardized beta = -0.52 (-0.82-0.21), P < 0.001, for dichotomized tau-PET and -1.22 (-1.84-(-0.61)], P < 0.0001, for continuous tau-PET]. Moderate cognitive decline was observed for A + T + over the follow-up period, whereas no significant change was observed for A-T+, A + T- and A-T-, although it should be noted that the A-T + group was small. Our results indicate that baseline tau neurofibrillary tangle pathology is associated with longitudinal changes in memory function, supporting the use of [18F]-MK-6420 PET to predict the likelihood of asymptomatic elderly individuals experiencing future memory decline. Overall, [18F]-MK-6420 PET is a promising tool for predicting memory decline in older adults without cognitive impairment at baseline. This is of critical relevance as the field is shifting towards a biological model of Alzheimer's disease defined by the aggregation of pathologic tau. Therefore, early detection of tau pathology using [18F]-MK-6420 PET provides us with hope that living patients with Alzheimer's disease may be diagnosed during the preclinical phase before it is too late.

Cognitive resilience polygenic risk score sensitive to preclinical disease changes

AbstractBackgroundAlzheimer’s disease (AD) polygenic risk scores (PRS) are often derived from case/control GWAS, which are typically not sensitive to preclinical disease changes, limiting their clinical utility. To overcome this pitfall, we built and evaluated the performance of multiple PRS of AD‐related endophenotypes, including resilience to cognitive impairment in the presence of amyloid.MethodFour PRS were derived from GWAS of baseline memory, memory decline, cognitive resilience (Dumitrescu et al., 2021), and AD (Kunkle et al. 2019). PRS were built in an independent cohort that was free of dementia, the Vanderbilt Memory and Aging Project (N=255). We used linkage disequilibrium clumping on TOPMed‐imputed genotypes, and a threshold of P=0.01. We ran linear models with baseline memory score as the outcome, and baseline age, sex, and PRS as predictors. Linear mixed effects models, with identical predictors, were used when longitudinal memory was the outcome, letting individual slope and intercept vary. Finally, we tested a CSF Aβ42‐by‐PRS interaction term to assess if PRS modified associations between amyloid and cognition. Sensitivity analyses excluded APOE from PRS calculations.ResultAs expected, the baseline memory PRS related to baseline memory (β=0.12, P=0.04), and the memory decline PRS related to longitudinal memory (β=0.04, P=0.001). Without APOE, the baseline memory PRS and the memory decline PRS results attenuated. The AD PRS related to both baseline memory (β=‐0.19, P=0.002) and longitudinal memory (β=‐0.03, P=0.01), but results attenuated without APOE. The resilience PRS did not have a main effect on baseline or longitudinal memory. However, interestingly, the resilience PRS interacted with CSF Aβ42 on baseline memory (β=‐0.001, P=0.02; Figure 1), whereby the resilience PRS related to memory among amyloid‐positive individuals (β=0.44, P=0.01) but not amyloid‐negative individuals (β=0.06, P=0.46). No other PRS was predictive of memory among amyloid‐positive individuals, and resilience PRS results remained consistent without APOE.ConclusionOur results demonstrate that a resilience PRS appears to be predictive of individual cognitive performance downstream of amyloidosis. Future work is needed to replicate this finding, but our preliminary findings highlight the potential utility of resilience PRS for predicting individual risk for AD‐related cognitive impairment during the preclinical stages of disease.

Sex differences in the protective effects of APOE ε2 on longitudinal cognitive decline

AbstractBackgroundThe APOE ε2 allele confers protection against cognitive decline and Alzheimer’s disease. There is some suggestion that APOE ε2 may have sex‐specific effects on cognition. We investigated sex differences in associations between APOE ε2 and longitudinal cognitive trajectories in a large sample of older adults.MethodWe used data from the National Alzheimer’s Coordinating Centre (NACC) database. We included participants who were ≥ 50 years old, White, free from dementia at baseline, and completed at least one follow‐up cognitive assessment. We categorized participants as APOE ε2 carriers (combining heterozygous and homozygous ε2 carriers) or APOE ε3 homozygote carriers. APOE ε4 carriers (including ε2/ε4 carriers) were excluded. Cognition was assessed approximately annually. We computed composite scores for memory, language, attention, and executive function. We examined the interaction between APOE allele (ε2 vs ε3), sex, and time on longitudinal cognition in linear mixed models, adjusting for baseline age, baseline MMSE, education, number of follow‐up visits, NACC test version, and their interactions with time.ResultWe included 6,733 participants classified as cognitively normal at baseline (mean age=72.9±9.12 years, mean education=16.0±2.87 years, 62.5% female), and 1,932 participants classified as mild cognitive impairment (MCI) at baseline (mean age=75.2±8.91 years, mean education=15.6±3.28 years, 44% female). Among participants with normal cognition, we observed significant interactions between sex, genotype, and time on longitudinal memory (β=0.022, p=0.039) and language (β=0.015, p=0.038), but not attention (β=0.01, p=0.09) or executive function (β=0.006, p=0.30). In sex stratified analyses, relative to male APOE ε3 carriers, male APOE ε2 carriers showed slower rates of decline in domains of memory and language. This effect was not observed in females. No significant interactions between sex, genotype, and time were observed in participants with MCI (memory: β=‐0.04, p=0.1; language: β=‐0.02, p=0.4; attention: β=‐0.01, p=0.5; executive function: β=‐0.02, p=0.3).ConclusionAmong cognitively normal adults, APOE ε2 carriage protects males but not females against longitudinal memory and language decline. The sex‐specific effect of APOE ε2 may contribute to the lower incidence of Alzheimer’s disease in males compared to females. Future research is needed to elucidate the mechanisms behind the observed sex disparities in cognitive decline.

Lower novelty‐related locus coeruleus function is associated with entorhinal tau‐mediated memory decline in older individuals.

AbstractBackgroundThe locus coeruleus (LC) is considered one of the earliest regions accumulating hyperphosphorylated tau before this pathology emerges in the entorhinal cortex (EC). Recent animal work suggested that LC phasic activity, which can be induced with exposure to novelty, can protect the cognitive downstream effects of tauopathy. Here we investigate whether activity of the LC during novelty is associated with memory decline and whether this association is mediated by EC‐tau deposition.Method92 participants (51 F, mean age at imaging (baseline) = 69.55±10.17 years) from the Harvard Aging Brain Study underwent both longitudinal memory testing (mean follow‐up = 4.8±1.9 years) and PiB(Aβ)‐, FTP(tau)‐PET, and 3T task‐fMRI scans performed within 1 year of each other (mean time difference = 0.29±0.24 years). The fMRI‐task consisted of novel and repeated face‐name pairs that the participants were instructed to remember. Voxel‐wise mixed‐effects analyses were performed to detect regions exhibiting significant novelty‐related activation. Vertex‐wise linear regression analyses were used to detect significant associations between LC activity and cortical tau deposition. Both analyses were adjusted for age, sex and multiple comparisons (pcl&lt;0.05). The association between LC activity and memory decline (composite, Fig. 3 caption) was evaluated using linear regression adjusted for age, sex and education. Mediation analyses were performed using a quasi‐Bayesian bootstrap (n = 1000) approach to investigate whether EC‐tau mediates the association and whether this mediation effect is moderated by Aβ status.ResultWe observed greater novelty‐related activation within the bilateral LC, amygdala, hippocampus, and fusiform and insular cortices (Fig. 1). LC activation was associated with tau in the EC, inferior‐temporal and fusiform cortices (confirmed by EC‐ROI analyses‐Fig. 2). Lower LC activation was associated with steeper memory decline (p&lt;0.05‐Fig. 3a), and this association was found to be mediated by EC‐tau (p&lt;0.05‐Fig. 3b). This mediation effect was significantly stronger for the Aβ+ compared to the Aβ– group (p&lt;0.05‐Fig. 3c).ConclusionThis work demonstrates that lower LC activity is associated with tau deposition in the medial‐ and inferior‐temporal lobe, consistent with the spatial patterns of tau observed in preclinical Alzheimer’s disease. Moreover, our observation that EC‐tau mediates the relationship between LC activity and memory decline suggests that lower LC function may indicate risk associated with Alzheimer’s‐related processes.

Sex‐specific genetic predictors of memory, executive function, and language performance

AbstractBackgroundAlzheimer’s disease (AD) is more prevalent in women than men, and robust evidence shows sex differences in the biological response to the AD neuropathological cascade. However, there is a lack of large‐scale genetic studies on sex‐specific genetic predictors of AD‐related cognitive outcomes. Thus, we sought to elucidate the sex‐specific genetic etiology of memory, executive function, and language performance.MethodThis study included six cohorts of cognitive aging (Nmales=7,267, Nfemales=9,518). We applied psychometric approaches to build harmonized memory, executive function, and language composite scores. Next, for all domains, we calculated slopes from the cognitive scores (two or more timepoints) with linear mixed effects models. Then we performed sex‐stratified and sex‐interaction GWAS on these phenotypes, covarying for baseline age and the first three genetic principal components. We meta‐analyzed across cohorts with a fixed‐effects model. Sensitivity analyses for all models restricted the sample to cognitively unimpaired individuals.ResultIn addition to well‐established associations with cognition at the APOE locus, we identified three genetic loci that showed sex‐specific effects with cognition. A chromosome 16 locus (rs114106271), a splicing‐quantitative trait locus for RP11‐152O14.4 and LINC02180 in the testis (GTEx), associated with baseline memory performance in men (β=0.13, P=2.40×10‐8; PInteraction=8.96×10‐6; Figures 1‐2) but not in women (β=‐0.01, P=0.76). A chromosome 14 locus (rs34074573), an expression‐quantitative trait locus (GTEx) for HOMEZ (a homeobox gene), and for BCL2L2 (a previously reported AD risk gene), associated with longitudinal memory performance in men (β=‐0.01, P=4.15×10‐8; PInteraction=5.83×10‐7; Figures 3‐4) but not in women (β=0.001, P=0.09). Finally, a chromosome 6 locus (rs9382966) associated with longitudinal language performance in men with near genome‐wide significance (β=‐0.004, P=6.29×10‐8; PInteraction=2.01×10‐4) but not in women (β=‐0.0003, P=0.61).ConclusionOur results highlight some key sex differences in the genetic architecture of cognitive outcomes. Findings further suggest that some sex‐specific genetic predictors have domain‐specific associations, providing an exciting opportunity to better understand the molecular basis of memory, executive function, and language through genomic analysis. Although our findings need to be replicated, our GWAS analyses highlight the contribution of sex‐specific genetic predictors beyond the APOE locus in conferring risk for late‐life cognitive decline.

Deconvolving Cerebrospinal Fluid Soluble TREM2 Signal and Longitudinal Associations with Cognition

AbstractBackgroundCerebrospinal fluid (CSF) soluble triggering receptor expressed on myeloid cells‐2 (sTREM2) is an emerging biomarker of neuroinflammation in Alzheimer’s disease (AD). Yet, sTREM2 expression has not been systematically evaluated in relation to concomitant drivers of neuroinflammation. We previously found a novel association between high Aβ40 (but not Aβ42) and high sTREM2 levels at baseline and replicated additional associations between a fluid biomarker of blood‐brain barrier (BBB) integrity and CSF biomarkers of neurodegeneration. Therefore, we sought to determine the relative contributions of these biological correlates to CSF sTREM2 levels during the prodromal stages of AD. Additionally we investigated whether the residual variance in sTREM2 level correlated with each biomarker predicted future cognitive performance.MethodLeveraging 155 Vanderbilt Memory and Aging Project (VMAP) participants (mean±standard deviation age=72±6, male=67%, mild cognitive impairment=47%), previously established associations between baseline CSF sTREM2 concentrations and CSF AD biomarkers (Aβx‐40, total tau, phosphorylated tau, and neurofilament light) and BBB integrity (CSF/plasma albumin ratio) were examined via hierarchical linear regression using sTREM2 as an outcome variable. Models adjusted for age, sex, education, cognitive status, and APOE‐ε4 status. Baseline CSF sTREM2 levels and corresponding residual components when adjusting for other biomarker levels in independent models were used in longitudinal mixed effects models predicting an episodic memory composite calculated as a z‐score from independent tests. Participants had up to five visits (mean±sd=2.63±1.30 visits).ResultHigh baseline CSF sTREM2 levels predicted slower longitudinal memory decline in VMAP (β=1.442e‐05, p=0.035). Additionally, the component of sTREM2 signal correlated with Aβx‐40 best predicted future memory performance (β=2.217e‐05, p=0.007). Together, Aβx‐40, phosphorylated tau, and the CSF/plasma albumin ratio jointly explained 36% of variance in sTREM2 levels. Aβx‐40 levels and the CSF/plasma albumin ratio explained sTREM2 signal above and beyond established associations with tau (R2=0.21; R2=0.21; and R2=0.17, respectively).ConclusionWe highlight potential contributions of Aβ homeostasis and BBB integrity to elevations in CSF sTREM2, underscoring novel biomarker associations relevant to disease progression. Results suggest that the tight correlation between baseline CSF sTREM2 and Aβx‐40 levels may have notable importance to cognitive trajectory in an aged cohort enriched for mild cognitive impairment.

Synchronized sigmoidal mixed‐effects model for dynamics of cognitive decline relative to onset of Alzheimer’s disease in aging adults in the Alzheimer’s Disease Neuroimaging Initiative (ADNI) study.

AbstractBackgroundModeling the dynamics of Alzheimer’s disease (AD) biomarkers over the entire continuum of AD progression is important, yet challenging due to limited resources to collect longitudinal biomarkers from the aging population with fully observed clinical spectrum of AD. This study proposed and applied a synchronized sigmoidal mixed‐effects model to characterize dynamics of longitudinal memory performance using data from the Alzheimer’s Disease Neuroimaging Initiative (ADNI). The model leveraged time to AD onset as the time scale and additionally allowed inclusion of participants without AD onset, drastically expanding future applications.MethodADNI participants with observed mild cognitive impairment (MCI) and/or AD onset (n = 312, mean (SD) baseline age 74.9 (6.44) years) were included (Table 1). A memory composite previously built in ADNI was leveraged for all analyses. A synchronized sigmoidal mixed‐effects model was constructed for dynamics of memory performance with parameters for initial memory level, magnitude of decline, and half‐life of decline. For participants with observed MCI but not AD onset, an additional parameter (t0 ) quantifying the time from MCI onset to AD was incorporated (Figure 1). We considered random effects for all parameters and allowed t0 to vary by age at MCI onset (nonlinearly), sex, apolipoprotein E (APOE)‐ε4 status and their interactions.ResultThe mean initial harmonized memory score is 0.24 (95% CI: 0.17‐0.32). The mean decline in the harmonized memory score is 1.53 (95% CI: 1.43‐1.64). The mean time when the harmonized memory score declined by half is 0.57 years before AD onset (95% CI: 0.32‐0.82). Female is associated with faster progression from MCI onset to AD (p = 0.002). Age at MCI onset is nonlinearly associated with MCI‐to‐AD progression (p &lt; 0.001) and APOE‐ε4 status interacts with age at MCI onset on MCI‐to‐AD progression (p = 0.002) (Figure 2).ConclusionThe proposed synchronized sigmoidal mixed effect model can be used to characterize dynamics of AD biomarkers relative to AD onset using participants with and without AD onset. A model to estimate duration of MCI‐to‐AD progression can be simultaneously included for synchronization purpose, which identified gender, age at MCI onset and APOE‐ε4 status as factors associated with MCI‐to‐AD progression.

Preliminary findings of accelerated visual memory decline and baseline brain correlates in middle-age and older adults with autism: The case for hippocampal free-water.

Research aimed at understanding cognitive and brain aging in adults with autism spectrum disorder (ASD) is growing, but critical longitudinal work is scant. Adults with ASD struggle with tasks involving visual memory compared with neurotypical adults (NT). This may be related to differences in size or integrity of the hippocampus and its' primary structural connectivity pathway, the fornix. The aim of this study was to describe preliminary findings of longitudinal aging trajectories in short- and long-term visual memory abilities in middle-age and older adults with ASD, compared with matched NT adults. We then evaluated baseline multi-modal imaging metrics of the hippocampal system, including the relatively novel metric of free-water, as potential correlates of longitudinal memory change in the ASD group. Middle-age and older adults with ASD (n = 25) and matched NT adults (n = 25) between the ages of 40 and 70 years were followed longitudinally at ~2-year intervals (range 2-5 years). Participants completed the Wechsler Memory Scale III Visual Reproduction task. Longitudinal mixed models were utilized to detect group differences in memory change with baseline age and sex as covariates. Hippocampal volume was measured via T1-weighted MRI images with FreeSurfer. Fornix fractional anisotropy and hippocampal and fornix free-water were measured from diffusion tensor imaging scans. Exploratory correlations were run between individual hippocampal system metrics and longitudinal slopes of visual memory change. There was a significant group by time interaction for long-term visual memory, such that middle-age and older adults with ASD declined faster than matched NT adults. There was no group by time interaction for short-term visual memory. Baseline hippocampal free-water was the only hippocampal system metric that correlated with long-term visual memory change in the ASD group. As one of the first longitudinal cognitive and brain aging studies in middle-age and older adults with ASD, our findings suggest vulnerabilities for accelerated long-term visual memory decline, compared to matched NT adults. Further, baseline hippocampal free-water may be a predictor of visual memory change in middle-age and older adults with ASD. These preliminary findings lay the groundwork for future prognostic applications of MRI for cognitive aging in middle-age and older adults with ASD.

Associations of circadian rest/activity rhythms with cognition in middle-aged and older adults: Demographic and genetic interactions.

ObjectivesWrist actigraphs (accelerometers) can record motor activity over multiple days and nights. The resulting data can be used to quantify 24-h activity profiles, known as circadian rest-activity rhythms (CRARs). Actigraphic CRARs have been tied to cognitive performance and decline in older adults; however, little is known about links between CRARs and performance or change in specific cognitive domains, or how individual differences may influence these associations. We investigated associations of actigraphic CRARs with cognitive performance and change in middle-aged and older adults, and explored whether age, sex/gender, race, and apolipoprotein E (APOE) e4 carrier status moderated these associations.Materials and methodsParticipants (N = 422; 47% male) were cognitively healthy adults (i.e., without mild cognitive impairment or dementia) at baseline aged ≥ 50 years from the Baltimore Longitudinal Study of Aging who completed 5.6 ± 0.89 nights of wrist actigraphy and tests of memory, executive function, attention, language, and visuospatial ability at the same visit the actigraph was issued; 292 participants had repeat cognitive testing 3.12 (1.58) years later. Predictors included indices of rhythm strength [i.e., amplitude; relative amplitude (RA); interdaily stability (IS); mesor], delayed timing of the rhythm peak [i.e., later acrophase; midpoint of an individual’s least active 5 h (L5 time); midpoint of an individual’s most active 10 h (M10 time)], and fragmentation [i.e., intradaily variability (IV)].ResultsIn main effects, later L5 time was cross sectionally associated with poorer memory, and greater IS predicted slower longitudinal memory decline. Associations of CRARs with cognition differed as a function of age, sex/gender, race, and APOE e4 carrier status.ConclusionAmong middle-aged and older adults, delayed circadian phase is associated with poorer memory performance, and greater day-to-day rhythm stability is associated with slower declines in memory. Significant interactions suggest that CRARs are generally more strongly associated with cognitive performance and rate of cognitive decline among women, Black adults, older individuals, and APOE e4 carriers. Replication in independent samples is needed.

Sleep slow waves' negative-to-positive-phase transition: a marker of cognitive and apneic status in aging.

The sleep slow-wave (SW) transition between negative and positive phases is thought to mirror synaptic strength and likely depends on brain health. This transition shows significant age-related changes but has not been investigated in pathological aging. The present study aimed at comparing the transition speed and other characteristics of SW between older adults with amnestic mild cognitive impairment (aMCI) and cognitively normal (CN) controls with and without obstructive sleep apnea (OSA). We also examined the association of SW characteristics with the longitudinal changes of episodic memory and executive functions and the degree of subjective cognitive complaints. aMCI (no/mild OSA = 17; OSA = 15) and CN (no/mild OSA = 20; OSA = 17) participants underwent a night of polysomnography and a neuropsychological evaluation at baseline and 18 months later. Participants with aMCI had a significantly slower SW negative-to-positive-phase transition speed and a higher proportion of SW that are "slow-switchers" than CN participants. These SW measures in the frontal region were significantly correlated with memory decline and cognitive complaints in aMCI and cognitive improvements in CN participants. The transition speed of the SW that are "fast-switchers" was significantly slower in OSA compared to no or mild obstructive sleep apnea participants. The SW transition-related metrics showed opposite correlations with the longitudinal episodic memory changes depending on the participants' cognitive status. These relationships were particularly strong in participants with aMCI. As the changes of the SW transition-related metrics in pathological aging might reflect synaptic alterations, future studies should investigate whether these new metrics covary with biomarker levels of synaptic integrity in this population.

Networks of inflammation, depression, and cognition in aging males and females

BackgroundPrioritizing the maintenance of healthy cognitive aging and personalizing preventive interventions to enhance their effectiveness is crucial as the global population ages. Systemic inflammation and depression in older people have been associated with decreased levels of cognition but results have been inconsistent.AimsTo explore the interactive network of inflammation, depression and cognition by sex in older people.MethodsWe used novel network analysis to explore the unique associations between inflammatory biomarkers, depression, cognition, and somatic, genetic, and lifestyle risk factors in an older (aged 70–90 years), non-demented, community-dwelling sample from the longitudinal Sydney Memory and Aging Study (N = 916) at baseline and at a two-year follow-up.ResultsThe networks of biomarkers, depression, cognition, and relevant covariates were significantly different between males and females. A stable negative link between depression and cognition was found in females only; a stable positive association between biomarker interleukin-6 and depression was found in females only; and a stable positive association between biomarker interleukin-8 and alcohol was found in females only. For both males and females, a stable, positive relationship was found between the presence of APOE-ε4 gene and biomarker C-reactive protein; between education and cognition; and between biomarker interleukin-6 and all other biomarkers.ConclusionsThese findings suggest different psychophysiological mechanisms underlie the interactive network of biomarkers, depression and cognition in males and females that should be considered when designing personalized preventive interventions to maintain cognitively healthy aging.

Self- and Partner-Reported Subjective Memory Complaints: Association with Objective Cognitive Impairment and Risk of Decline.

Background:Episodic memory decline is a hallmark of Alzheimer’s disease (AD). Subjective memory complaints (SMCs) may represent one of the earliest signs of impending cognitive decline. The degree to which self- or partner-reported SMCs predict cognitive change remains unclear.Objective:We aimed to evaluate the relationship between self- and partner-reported SMCs, objective cognitive performance, AD biomarkers, and risk of future decline in a well-characterized longitudinal memory center cohort. We also evaluated whether study partner characteristics influence reports of SMCs.Methods:758 participants and 690 study partners were recruited from the Penn Alzheimer’s Disease Research Center Clinical Core. Participants included those with Normal Cognition, Mild Cognitive Impairment, and AD. SMCs were measured using the Prospective and Retrospective Memory Questionnaire (PRMQ), and were evaluated for their association with cognition, genetic, plasma, and neuroimaging biomarkers of AD, cognitive and functional decline, and diagnostic progression over an average of four years.Results:We found that partner-reported SMCs were more consistent with cognitive test performance and increasing symptom severity than self-reported SMCs. Partner-reported SMCs showed stronger correlations with AD-associated brain atrophy, plasma biomarkers of neurodegeneration, and longitudinal cognitive and functional decline. A 10-point increase on baseline PRMQ increased the annual risk of diagnostic progression by approximately 70%. Study partner demographics and relationship to participants influenced reports of SMCs in AD participants only.Conclusion:Partner-reported SMCs, using the PRMQ, have a stronger relationship with the neuroanatomic and cognitive changes associated with AD than patient-reported SMCs. Further work is needed to evaluate whether SMCs could be used to screen for future decline.

Timely coupling of sleep spindles and slow waves linked to early amyloid-β burden and predicts memory decline.

Sleep alteration is a hallmark of ageing and emerges as a risk factor for Alzheimer's disease (AD). While the fine-tuned coalescence of sleep microstructure elements may influence age-related cognitive trajectories, its association with AD processes is not fully established. Here, we investigated whether the coupling of spindles and slow waves (SW) is associated with early amyloid-β (Aβ) brain burden, a hallmark of AD neuropathology, and cognitive change over 2 years in 100 healthy individuals in late-midlife (50-70 years; 68 women). We found that, in contrast to other sleep metrics, earlier occurrence of spindles on slow-depolarisation SW is associated with higher medial prefrontal cortex Aβ burden (p=0.014, r²β*=0.06) and is predictive of greater longitudinal memory decline in a large subsample (p=0.032, r²β*=0.07, N=66). These findings unravel early links between sleep, AD-related processes, and cognition and suggest that altered coupling of sleep microstructure elements, key to its mnesic function, contributes to poorer brain and cognitive trajectories in ageing.

Modeling the underlying biological processes in Alzheimer's disease using a multivariate competing risk joint model

Many clinical trials repeatedly measure several longitudinal outcomes on patients. Patient follow‐up can discontinue due to an outcome‐dependent event, such as clinical diagnosis, death, or dropout. Joint modeling is a popular choice for the analysis of this type of data. Using example data from a prodromal Alzheimer's disease trial, we propose a new type of multivariate joint model in which longitudinal brain imaging outcomes and memory impairment ratings are allowed to be associated both with time to open‐label medication and dropout, and where the brain imaging outcomes may also directly affect the memory impairment ratings. Existing joint models for multivariate longitudinal outcomes account for the correlation between the longitudinal outcomes through the random effects, often by assuming a multivariate normal distribution. However, for these models, it is difficult to interpret how the longitudinal outcomes affect each other. We model the dependence between the longitudinal outcomes differently so that a first longitudinal outcome affects a second one. Specifically, for each longitudinal outcome, we use a linear mixed‐effects model to estimate its trajectory, where, for the second longitudinal outcome, we include the linear predictor of the first outcome as a time‐varying covariate. This facilitates an easy and direct interpretation of the association between the longitudinal outcomes and provides a framework for latent mediation analysis to understand the underlying biological processes. For the trial considered here, we found that part of the intervention effect is mediated through hippocampal brain atrophy. The proposed joint models are fitted using a Bayesian framework via MCMC simulation.

Resilience resources may buffer some middle-aged and older Black Americans from memory decline despite experiencing discrimination

RationaleExperiences of discrimination have been associated with poorer episodic memory in Black Americans. However, resilience resources at multiple levels (individual, social, and endowed) may act as a buffer to protect future memory decline, especially in the face of discrimination. ObjectiveUsing longitudinal data from the 2006–2016 Health and Retirement Study (N = 1862), we tested whether Black Americans aged 50 and older would show different trajectories of episodic memory depending on their reported experiences of discrimination (everyday and major lifetime) and resilience resources. MethodsAnalyses were conducted in three steps: (1) joint latent cluster mixed modeling (JLCMM) to estimate the number of classes, (2) barycentric discriminant analyses (BADA) to model the combined influence of discrimination and resilience resources between each memory class, and (3) multinomial regression analyses to explore interactions between discrimination and resilience resources. ResultsJLCMM resulted in three memory classes that differentiated baseline from longitudinal memory performance: “High Decliners,” “Low Decliners,” and “Low Stable.” Two independent patterns described the relationships between the three classes in the context of discrimination and resilience resources. First, compared with High Decliners, the two lower baseline memory classes (Low Decliners and Low Stable) reported more everyday discrimination and lower individual and endowed resilience resources. Second, although the Low Stable class did not report different levels of discrimination, they had more social resilience resources (greater social support and more social contact) than both declining classes. ConclusionsBlack Americans in later life have heterogeneous patterns of memory trajectories as demonstrated by the three memory classes identified. Those with lower baseline memory experienced more everyday discrimination and had fewer resilience resources compared to those with high baseline performance (High Decliners). Greater social resilience resources were associated with maintained episodic memory over time in Black Americans.

The role of cognitive and brain reserve in memory decline and atrophy rate in mid and late-life: The SMART-MR study

ObjectiveInvestigate associations of cognitive and brain reserve with trajectories of memory decline in mid-life and late-life, and whether the relationship of memory decline with atrophy differs as a function of reserve. MethodsParticipants were 989 Dutch middle-aged to older adults from the SMART-MR prospective cohort, followed up to 12 years with up to 3 measurements of memory and brain MRI. Education and Dutch National Adult Reading Test (DART) were used as proxies of cognitive reserve, and intracranial volume (ICV) and baseline brain parenchymal fraction (BPF) for brain reserve. Univariate growth curve models analyzed associations of reserve with memory decline, and multiple-group bivariate growth curve models tested the longitudinal brain–memory relationship as a function of reserve. Models were additionally stratified by mid-life and late-life. ResultsHigher DART, education, and BPF were related to a slower rate of memory decline, particularly in late-life, but ICV was not. A positive covariance indicated that an individual who undergoes atrophy also undergoes memory decline—this relationship did not differ across cognitive or brain reserve, but was not present in mid-life. Memory declined slower than brain volume, yet rates were more similar in the low DART, education, and BPF groups. DiscussionHigher cognitive (DART, education) and brain reserve (BPF) work protectively in longitudinal memory change. ICV is an inappropriate proxy of brain reserve, failing to show any association with memory performance at baseline or over time. Deconstructing relationships of reserve capacities with longitudinal cognitive and brain outcomes may identify focus areas with potential for intervention.

Self‐rated daily language use, more than self‐rated bilingual language competency, moderates the effects of brain on cognition in a Hispanic cohort

AbstractBackgroundSome studies suggest that bilingualism may be associated with better cognition but the impact of bilingualism versus language practice on cognition and brain integrity is not well understood. Here, bilingualism encodes the knowledge of one language or two while language use encodes daily language practice (predominantly English or Spanish, or daily use of both). In a Hispanic cohort, we the assess effects of language variables on cognitive outcomes of baseline and longitudinal executive function and episodic memory, incorporating brain measures, age, gender, and education, and also whether they moderate the relationships between cognition and the MRI markers of brain integrity.MethodA baseline Hispanic cohort (N = 100) with a single MRI scan and a longitudinal subset (N = 73) with serial scans were sampled from the UC Davis Aging and Diversity cohort (Table 1). Linguistic measures were based on self‐reports. They were bilingualism, and among bilingual participants, daily language use. Baseline and longitudinal executive and memory were modeled by regressions incorporating age, education level, brain signature regions, and language variable ‐ first for bilingualism in the entire cohort and then for language use restricted to the bilinguals.ResultBilingualism was not a significant predictor of baseline outcomes and there were no moderations with brain variables (Table 2). Among bilinguals, English‐only speakers showed significantly increased association of gray matter (Table 3) to memory compared to those who daily spoke Spanish or both languages. Longitudinally, bilingualism had no direct or moderating effects on cognitive change (Table 4). Bilinguals speaking primarily English had significantly increased association of atrophy signatures with both cognitive changes compared to Spanish or speakers of both languages (Table 5).ConclusionResults suggest a complex pattern of moderation of brain atrophy effects on cognitive decline in self‐reported bilinguals depending on whether daily language use is predominantly English, Spanish, or both. Bilinguals who spoke predominantly English were more susceptible to brain atrophy effects in comparison with those who used both languages or predominantly Spanish. These results have important implications for understanding how bilingualism relates to cognitive reserve but require replication in larger and different samples.

Meta‐analysis of the associations of biomarkers of amyloid and tau with cognition in cognitively normal older adults

AbstractBackgroundConflicting evidence exists on the in vivo relationship of amyloid and tau levels to cognition among cognitively normal older adults. We conducted a meta‐analysis of reported relationships of biomarkers of amyloid or tau levels with baseline and change in cognition in cognitively normal older adults.MethodWe performed a literature search that returned studies between 2005 and January 2021 for studies reporting a relationship between amyloid or tau biomarkers measured via PET ligands, CSF, or plasma assays, with episodic memory or global cognition. Effect sizes were obtained for each study and weighted by sample size. For studies examining the same cohort, we selected effect sizes from the largest sample size available for each relationship of interest.ResultOne hundred and seven studies (89% reporting cross sectional measures and 62% reporting longitudinal) representing 26968 adults (82% characterized with amyloid measures and 23% with tau) were included. Amyloid levels showed a significant correlation with baseline and longitudinal global cognition (r=0.05, p&lt;0001; r=0.05, p=0.021, respectively), and with baseline episodic memory (r=0.05, p=0.001). Tau was significantly correlated with baseline and longitudinal global cognition (r=0.08, p=0.004; r=0.08, p=0.01, respectively), and with longitudinal episodic memory (r=0.02, p=0.04), whereas the interaction of amyloid and tau was significantly correlated only with baseline global cognition (r=0.09, p=0.024). The overall estimated correlation between amyloid and tau was r=0.17.ConclusionIn older adults with normal cognition, there is a very small but significant relationship between baseline global cognition and amyloid, tau, and their interactive effect. Episodic memory had a very small but significant relationship with amyloid at baseline and with tau longitudinally. These findings could help determine power estimations for future clinical trials evaluating cognition in asymptomatic older adults. Effect size and power estimations from this meta‐analysis may be limited by unmeasured variability among studies in the timing of biomarker measurement, differences in cognitive assessments, or other cohort‐specific differences.