Longitudinal Cognitive Trajectories Research Articles

Hypothesis: cerebrospinal fluid protein markers suggest a pathway toward symptomatic resilience to AD pathology

IntroductionWe sought biological pathways that explained discordance between Alzheimer's disease (AD) pathology and symptoms. MethodsIn 306 Alzheimer's Disease Neuroimaging Initiative (ADNI)-1 participants across the AD clinical spectrum, we investigated association between cognitive outcomes and 23 cerebrospinal fluid (CSF) analytes associated with abnormalities in the AD biomarkers amyloid β1-42 and total-tau. In a 200-person “training” set, Least Absolute Shrinkage and Selection Operator regression estimated model weights for the 23 proteins, and for the AD biomarkers themselves, as predictors of ADAS-Cog11 scores. In the remaining 106 participants (“validation” set), fully adjusted regression models then tested the Least Absolute Shrinkage and Selection Operator–derived models and a related protein marker summary score as predictors of ADAS-Cog11, ADNI diagnostic category, and longitudinal cognitive trajectory. ResultsAD biomarkers alone explained 26% of the variance in validation set cognitive scores. Surprisingly, the 23 AD-related proteins explained 31% of this variance. The biomarkers and protein markers appeared independent in this respect, jointly explaining 42% of test score variance. The composite protein marker score also predicted ADNI diagnosis and subsequent cognitive trajectory. Cognitive outcome prediction redounded principally to ten markers related to lipid or vascular functions or to microglial activation or chemotaxis. In each analysis, apoE protein and four markers in the latter immune-activation group portended better outcomes. DiscussionCSF markers of vascular, lipid-metabolic and immune-related functions may explain much of the disjunction between AD biomarker abnormality and symptom severity. In particular, our results suggest the hypothesis that innate immune activation improves cognitive outcomes in persons with AD pathology. This hypothesis should be tested by further study of cognitive outcomes related to CSF markers of innate immune activation.

Association Between Critical Care Admissions and Cognitive Trajectories in Older Adults.

Patients requiring admission to an ICU may subsequently experience cognitive decline. Our objective was to investigate longitudinal cognitive trajectories in older adults hospitalized in ICUs. We hypothesized that individuals hospitalized for critical illness develop greater cognitive decline compared with those who do not require ICU admission. A retrospective cohort study using prospectively collected cognitive scores of participants enrolled in the Mayo Clinic Study of Aging and ICU admissions retrospectively ascertained from electronic medical records. A covariate-adjusted linear mixed effects model with random intercepts and slopes assessed the relationship between ICU admissions and the slope of global cognitive z scores and domains scores (memory, attention/executive, visuospatial, and language). ICU admissions and cognitive scores in the Mayo Clinic Study of Aging from October 1, 2004, to September 11, 2017. Nondemented participants age 50 through 91 at enrollment in the Mayo Clinic Study of Aging with an initial cognitive assessment and at least one follow-up visit. None. Of 3,673 participants, 372 had at least one ICU admission with median (25-75th percentile) follow-up after first ICU admission of 2.5 years (1.2-4.4 yr). For global cognitive z score, admission to an ICU was associated with greater decline in scores over time compared with participants not requiring ICU admission (difference in annual slope = -0.028; 95% CI, -0.044 to -0.012; p < 0.001). ICU admission was associated with greater declines in memory (-0.029; 95% CI, -0.047 to -0.011; p = 0.002), attention/executive (-0.020; 95% CI, -0.037 to -0.004; p = 0.016), and visuospatial (-0.013; 95% CI, -0.026 to -0.001; p = 0.041) domains. ICU admissions with delirium were associated with greater declines in memory (interaction p = 0.006) and language (interaction p = 0.002) domains than ICU admissions without delirium. In older adults, ICU admission was associated with greater long-term cognitive decline compared with patients without ICU admission. These findings were more pronounced in those who develop delirium while in the ICU.

APOLIPOPROTEIN ε4 ALLELE EFFECTS ON LONGITUDINAL COGNITIVE TRAJECTORIES ARE SEX- AND AGE-DEPENDENT

The apolipoprotein E (APOE) ε4 allele is the most robust genetic risk factor for late-onset Alzheimer's disease (AD). However, the impact of APOE-ε4 status on cognitive trajectories in cognitively normal adults is not as well understood. Questions remain about whether APOE-ε4 status effects on cognitive decline are similar in men and women, and how APOE-ε4 status and age interact to influence decline in different cognitive domains. 1192 cognitively normal adults from the Baltimore Longitudinal Study on Aging (631 men, 561 women, baseline age 50-93) underwent serial assessments using a comprehensive cognitive test battery. Composite cognitive scores were calculated for six cognitive domains including: verbal memory, executive function, attention, language, visual-spatial ability and processing speed. In sex stratified analysis, linear mixed effects models were used to explore age-dependent associations between APOE-ε4 status and longitudinal cognitive trajectories. Where age-dependent relationships were found, the earliest age of divergence in trajectories was estimated. In men, APOE-ε4 status had significant age-dependent effects on longitudinal decline in verbal memory and executive function with APOE-ε4 carriers showing faster rates of decline compared to non-carriers. This divergence in trajectories was detectible from baseline age of 65 and 68, respectively. In women, APOE-ε4 status had a significant age-dependent effect on longitudinal decline in attention with APOE-ε4 carriers showing faster rates of decline compared to non-carriers. This divergence in trajectories was detectible at a baseline age of 66. No significant APOE-ε4 status effects were found for language, visual-spatial ability and processing speed. Results highlight the importance of considering sex and age when assessing APOE-ε4 associated vulnerability to cognitive decline. Understanding these potential interactions is crucial for clinical trials, especially as APOE-ε4 is increasingly used for screening and identifying individuals who may benefit from early interventions to promote successful cognitive aging.

RETROSPECTIVE COGNITIVE DECLINE IS ASSOCIATED WITH NEUROFIBRILLARY TANGLES AND BETA-AMYLOID PLAQUES MEASURED BY [F-18]MK-6240 AND [C-11]PIB IN LATE-MIDDLE AGED PERSONS CLINICALLY UNIMPAIRED AT BASELINE

Characterizing contributions of neurofibrillary tangles (NFTs) and beta-amyloid (AB) plaques to cognitive decline, and relationships with other biomarkers during the preclinical phase of Alzheimer's disease (AD) may improve diagnostic and clinical trial outcomes. This work investigated if NFTs and AB plaques measured by PET explained differences in retrospective longitudinal cognitive trajectories of persons recruited from the Wisconsin Registry for Alzheimer's Prevention (WRAP) who were clinically unimpaired at their baseline cognitive assessment. Individuals (N=159; 59±6 years at baseline composite) recruited from WRAP underwent longitudinal cognitive assessments and T1-weighted MR, MK-6240 and PiB PET imaging. A preclinical Alzheimer's cognitive composite (PACC-3: RAVLT Total, WMS-R Logical Memory Delayed Recall, and WAIS-R Digit Symbol) was calculated (mean of Z-scored tests) for each assessment. Four biomarker groups (A+/-, T+/-) were established based on PiB (Global DVR >1.19; Reference Logan, cerebellum GM) and MK-6240 (Entorhinal cortex SUVR>1.27, mean+2SD of PIB(-) group; cerebellum GM, 70–90 min) PET. Differences in PACC-3 trajectories by group were interrogated using a linear mixed effects model with random person-level slopes and intercepts (model in Figure 1). Group differences in demographics, select neuropsychological tests, and biomarkers (PET, hippocampal volume, systolic blood pressure) were also investigated. The linear model indicated a significant group×time interaction (Figure 1); post-hoc pairwise comparisons (Tukey-adjusted) indicated the A+/T+ group had steeper PACC-3 decline compared to all other groups, but other groups did not differ significantly. Groups did not differ by sex, race, or family history of dementia, but did differ in the frequency of APOE-e4 carriers (Table 1). Systolic blood pressure and hippocampal volume did not differ by group at baseline or last assessments. RAVLT Total, WMS-R Logical Memory Delayed Recall, self-reported severity of memory problems, PACC-3 and the frequency of MCI differed by group at last assessment, but MMSE, self- and informant-reported memory problems, and WAIS-R Digit Symbol did not (Table 2).

Defining Cognitive Reserve and Implications for Cognitive Aging.

The aim of this review is to summarize current conceptual models of cognitive reserve (CR) and related concepts and to discuss evidence for these concepts within the context of aging and Alzheimer's disease. Evidence to date supports the notion that higher levels of CR, as measured by proxy variables reflective of lifetime experiences, are associated with better cognitive performance, and with a reduced risk of incident mild cognitive impairment/dementia. However, the impact of CR on longitudinal cognitive trajectories is unclear and may be influenced by a number of factors. Although there is promising evidence that some proxy measures of CR may influence structural brain measures, more research is needed. The protective effects of CR may provide an important mechanism for preserving cognitive function and cognitive well-being with age, in part because it can be enhanced throughout the lifespan. However, more research on the mechanisms by which CR is protective is needed.

Self-reported Lifestyle Activities in Relation to Longitudinal Cognitive Trajectories

Few studies have examined the relationship between lifestyle activity engagement and cognitive trajectories among individuals who were cognitively normal at baseline. To examine the relationship of current engagement in lifestyle activities to previous cognitive performance among individuals who were cognitively normal at baseline, and whether this relationship differed for individuals who subsequently developed mild cognitive impairment (MCI), or by APOE-4 genotype, age, and level of cognitive reserve. Participants (N=189) were primarily middle-aged (M=56.6 y) at baseline and have been prospectively followed with annual assessments (M follow-up=14.3 y). Engagement in physical, cognitive, and social activities was measured by the CHAMPS activity questionnaire. Longitudinal cognitive performance was measured by a global composite score. Among individuals who progressed to MCI (n=27), higher lifestyle activity engagement was associated with less decline in prior cognitive performance. In contrast, among individuals who remained cognitively normal, lifestyle activity engagement was not associated with prior cognitive trajectories. These effects were largely independent of APOE-4 genotype, age, and cognitive reserve. Greater engagement in lifestyle activities may modify the rate of cognitive decline among those who develop symptoms of MCI, but these findings need to be confirmed in prospective studies.

Association between exposure to anaesthesia and surgery and long-term cognitive trajectories in older adults: report from the Mayo Clinic Study of Aging

The link between exposure to general anaesthesia and surgery (exposure) and cognitive decline in older adults is debated. We hypothesised that it is associated with cognitive decline. We analysed the longitudinal cognitive function trajectory in a cohort of older adults. Models assessed the rate of change in cognition over time, and its association with exposure to anaesthesia and surgery. Analyses assessed whether exposure in the 20 yr before enrolment is associated with cognitive decline when compared with those unexposed, and whether post-enrolment exposure is associated with a change in cognition in those unexposed before enrolment. We included 1819 subjects with median (25th and 75th percentiles) follow-up of 5.1 (2.7-7.6) yr and 4 (3-6) cognitive assessments. Exposure in the previous 20 yr was associated with a greater negative slope compared with not exposed (slope: -0.077 vs -0.059; difference: -0.018; 95% confidence interval: -0.032, -0.003; P=0.015). Post-enrolment exposure in those previously unexposed was associated with a change in slope after exposure (slope: -0.100 vs -0.059 for post-exposure vs pre-exposure, respectively; difference: -0.041; 95% confidence interval: -0.074, -0.008; P=0.016). Cognitive impairment could be attributed to declines in memory and attention/executive cognitive domains. In older adults, exposure to general anaesthesia and surgery was associated with a subtle decline in cognitive z-scores. For an individual with no prior exposure and with exposure after enrolment, the decline in cognitive function over a 5 yr period after the exposure would be 0.2 standard deviations more than the expected decline as a result of ageing. This small cognitive decline could be meaningful for individuals with already low baseline cognition.

Pre‐ and postsurgical cognitive trajectories and quantitative MRI changes in Rasmussen syndrome

To quantify the longitudinal cognitive trajectory, before and after surgery, of Rasmussen syndrome (RS), a rare disease characterized by focal epilepsy and progressive atrophy of one cerebral hemisphere. Thirty-two patients (mean age = 6.7 years; 17 male, 16 left hemispheres affected) were identified from hospital records. The changes in intelligence scores during 2 important phases in the patients' journey to treatment were investigated: (1) during the preoperative period (n = 28, mean follow-up 3.4 years) and (2) from before to after surgery (n = 21 patients, mean time to follow-up 1.5 years). A volumetric magnetic resonance imaging (MRI) analysis of longitudinal changes in gray matter volume was conducted in a subsample of 18 patients. (1) IQ during the preoperative period: At baseline assessment (on average 2.4 years after seizure onset), the left RS group had lower verbal than nonverbal intellectual abilities, whereas the right group exhibited more difficulties in nonverbal than verbal intellect. Verbal and nonverbal scores declined during the follow-up in both groups, irrespective of the affected side. Hemispheric gray matter volumes declined over time in both groups in affected as well as unaffected hemispheres. (2) Postoperative IQ change: The left surgery group declined further in verbal and nonverbal intellect. The right group's nonverbal intellect declined after surgery, whereas verbal abilities did not. Patients with higher abilities preoperatively experienced large declines, whereas those with poorer abilities showed little change. Postoperative seizures negatively impacted on cognitive abilities. During the chronic phase of the disease, parallel decline of verbal and nonverbal abilities suggest progressive bilateral hemispheric involvement, supported by evidence from MRI morphometry. Postsurgical cognitive losses are predicted by greater presurgical ability and continuing seizures. A shorter duration from seizure onset to surgery could reduce the postoperative cognitive burden by minimizing the decline in functions supported by the unaffected hemisphere.

Brain volume change and cognitive trajectories in aging.

Examine how longitudinal cognitive trajectories relate to brain baseline measures and change in lobar volumes in a racially/ethnically and cognitively diverse sample of older adults. Participants were 460 older adults enrolled in a longitudinal aging study. Cognitive outcomes were measures of episodic memory, semantic memory, executive function, and spatial ability derived from the Spanish and English Neuropsychological Assessment Scales (SENAS). Latent variable multilevel modeling of the four cognitive outcomes as parallel longitudinal processes identified intercepts for each outcome and a second order global change factor explaining covariance among the highly correlated slopes. We examined how baseline brain volumes (lobar gray matter, hippocampus, and white matter hyperintensity) and change in brain volumes (lobar gray matter) were associated with cognitive intercepts and global cognitive change. Lobar volumes were dissociated into global and specific components using latent variable methods. Cognitive change was most strongly associated with brain gray matter volume change, with strong independent effects of global gray matter change and specific temporal lobe gray matter change. Baseline white matter hyperintensity and hippocampal volumes had significant incremental effects on cognitive decline beyond gray matter change. Baseline lobar gray matter was related to cognitive decline, but did not contribute beyond gray matter change. Cognitive decline was strongly influenced by gray matter volume change and, especially, temporal lobe change. The strong influence of temporal lobe gray matter change on cognitive decline may reflect involvement of temporal lobe structures that are critical for late life cognitive health but also are vulnerable to diseases of aging. (PsycINFO Database Record

Longitudinal cognitive trajectories and associated clinical variables in youth with bipolar disorder.

There is substantial interest in delineating the course of cognitive functioning in bipolar (BP) youth. However, there are no longitudinal studies aimed at defining subgroups of BP youth based on their distinctive cognitive trajectories and their associated clinical variables. Cognitive functioning was measured in 135 participants from the Course and Outcome of BP Youth (COBY) study using several subtests of the Cambridge Neuropsychological Test Automated Battery (CANTAB). Youth were prospectively evaluated three times on average every 13.75months over 2.5years. Clinical and functional outcomes were assessed using the Longitudinal Interval Follow-Up Evaluation (LIFE). Latent class growth analysis identified three longitudinal patterns of cognitive functioning based on a general cognitive index: class 1, "persistently high" (N=21; 15.6%); class 2, "persistently moderate" (N=82; 60.74%); and class 3, "persistently low" (N=32; 23.7%). All classes showed normal cognitive functioning when compared with the CANTAB normative data. After adjustment for confounders, youth from class 3 had a significantly greater percentage of time with overall, manic, and depressive syndromal symptoms than youth in the other two classes. Also, after adjustment for confounders, youth from class 3 had significantly poorer global, academic, and social functioning than youth from class 1. BP youth showed normal overall cognitive functioning that remained stable during the follow-up within each class. However, 24% of BP youth showed poorer cognitive functioning than the other BP youth. This subgroup had poorer mood course and functioning, and may benefit from cognitive remediation and early management with evidence-based pharmacological treatments.

BDNF Val66Met predicts cognitive decline in the Wisconsin Registry for Alzheimer's Prevention.

To examine the influence of the brain-derived neurotrophic factor (BDNF) Val66Met polymorphism on longitudinal cognitive trajectories in a large, cognitively healthy cohort enriched for Alzheimer disease (AD) risk and to understand whether β-amyloid (Aβ) burden plays a moderating role in this relationship. One thousand twenty-three adults (baseline age 54.94 ± 6.41 years) enrolled in the Wisconsin Registry for Alzheimer's Prevention underwent BDNF genotyping and cognitive assessment at up to 5 time points (average follow-up 6.92 ± 3.22 years). A subset (n = 140) underwent 11C-Pittsburgh compound B (PiB) scanning. Covariate-adjusted mixed-effects regression models were used to elucidate the effect of BDNF on cognitive trajectories in 4 cognitive domains, including verbal learning and memory, speed and flexibility, working memory, and immediate memory. Secondary mixed-effects regression models were conducted to examine whether Aβ burden, indexed by composite PiB load, modified any observed BDNF-related cognitive trajectories. Compared to BDNF Val/Val homozygotes, Met carriers showed steeper decline in verbal learning and memory (p = 0.002) and speed and flexibility (p = 0.017). In addition, Aβ burden moderated the relationship between BDNF and verbal learning and memory such that Met carriers with greater Aβ burden showed even steeper cognitive decline (p = 0.033). In a middle-aged cohort with AD risk, carriage of the BDNF Met allele was associated with steeper decline in episodic memory and executive function. This decline was exacerbated by greater Aβ burden. These results suggest that the BDNF Val66Met polymorphism may play an important role in cognitive decline and could be considered as a target for novel AD therapeutics.

Klotho, APOEε4, cognitive ability, brain size, atrophy, and survival: a study in the Aberdeen Birth Cohort of 1936

A single copy of klotho allele KL-VS is associated with longevity, better health, increased cognition, and bigger regional brain volume. However, its longitudinal effects on cognition and brain volumes, both global and regional, in late life are unclear. In this study we show that, relative to noncarriers, KL-VS heterozygotes had (1) shorter survival; (2) smaller white matter volumes; (3) slower cognitive decline; and (4) greater right frontal lobe volumes. The KL-VS heterozygote survival and white matter volume disadvantages were unexpected. A possible explanation for these results in the context of the literature is a potential interaction between the environment and/or age of the participants, leading to a heterozygote disadvantage. The longitudinal cognitive trajectories indicate that heterozygotes would have an advantage in very late life. Collectively these results suggest that the genotype-survival advantage of the KL-VS allele is age-dependent and possibly mediated through differential cognition and brain volume.

PREVALENCE OF AUTISTIC TRAITS IN A COGNITIVELY NORMAL AGING COHORT

1.5% of young children have an autism spectrum disorder (ASD) but not included in such prevalence estimates are individuals with a subclinical “broad autism phenotype” (BAP), which has been found in approximately 4% among adults without a family history of ASD. Individuals with BAP are therefore likely present in most studies of cognitive aging, yet the impact of this is unknown. The Autism Spectrum Quotient (AQ) (Baron-Cohen et al), a validated screening questionnaire, was given to members of a cognitive aging cohort to determine the prevalence of individuals scoring in the BAP range, and to characterize their cognitive, behavioral, and personality profiles. The AQ was given during 428 consecutive member visits of the Arizona APOE cohort beginning January 2013, and was completed by 343 members. AQ scores were treated as a dichotomous variable with scores of 23 and higher defining high AQ. Cross-sectional characteristics were compared among groups by using the two-sample t-test / analysis of variance (ANOVA) F-test or Pearson chi-square test. 35 subjects scored in the BAP range of 23 or higher (AQ+) and included a higher proportion of men, reported history of depression and sleep disturbance but no difference in education, marital status, or estimated income (based on zip code) (Table 1). After adjusting for age, sex and education, the AQ+ group performed less well on most measures of mental speed, working memory and arithmetic (Table 2). Though behavioral measures remained within a normal range, mean scores on multiple measures including somatization, anxiety, and depression were higher and a measure of personal warmth was lower in the AQ+ group (Table 3). On the NEO-PI-R five factor personality inventory the AQ+ group exhibited higher neuroticism, and lower extraversion and agreeableness (Table 4). In our cognitively normal aging cohort, approximately 10% of subjects completing the AQ scored in the BAP range, and differ from AQ- subjects on multiple cognitive, psychological and personality measures. The impact of the broad autism phenotype on longitudinal cognitive trajectories and outcomes awaits further study.

Temporal course of neurodegenerative effects on cognition in old age.

To test the hypothesis that different forms of neurodegeneration are differentially related to longitudinal cognitive trajectories in old age. Participants are 420 older persons from 2 clinical-pathologic studies without cognitive impairment at study onset. They completed a battery of 17 cognitive tests annually for a minimum of 5 years, died, and underwent a neuropathologic examination to quantify neuronal neurofibrillary tangles and transactive response DNA-binding protein 43 (TDP-43) pathology and to identify Lewy bodies and hippocampal sclerosis. The authors used sigmoid mixed models based on the 4-parameter logistic distribution to decompose nonlinear global cognitive trajectories into components and assess the relation of each neuropathologic marker to each trajectory component. Cognitive function was assessed for a mean of 10.5 years before death. In the absence of pathology, global cognition was relatively stable before declining moderately in the last 3 to 4 years of life. Tangles were related to all trajectory components except initial level. TDP-43 pathology was the only marker related to initial level of function. It was also associated with an earlier midpoint of decline but not to slope of decline. Hippocampal sclerosis was related to an earlier midpoint of decline and more rapid slope of decline. Lewy bodies were associated with faster slope of decline and lower level of function proximate to death. Neurodegenerative processes are differentially related to cognitive trajectories, with TDP-43 pathology most potently impacting incipient cognitive decline, AD pathology and hippocampal sclerosis affecting the progression of cognitive decline, and Lewy bodies impacting terminal decline. (PsycINFO Database Record

Longitudinal Cognitive Trajectories of Women Veterans from the Women's Health Initiative Memory Study.

A comparison of longitudinal global cognitive functioning in women Veteran and non-Veteran participants in the Women's Health Initiative (WHI). We studied 7,330 women aged 65-79 at baseline who participated in the WHI Hormone Therapy Trial and its ancillary Memory Study (WHIMS). Global cognitive functioning (Modified Mini-Mental State Examination [3MSE]) in Veterans (n = 279) and non-Veterans (n = 7,051) was compared at baseline and annually for 8 years using generalized linear modeling methods. Compared with non-Veterans, Veteran women were older, more likely to be Caucasian, unmarried, and had higher rates of educational and occupational attainment. Results of unadjusted baseline analyses suggest 3MSE scores were similar between groups. Longitudinal analyses, adjusted for age, education, ethnicity, and WHI trial assignment revealed differences in the rate of cognitive decline between groups over time, such that scores decreased more in Veterans relative to non-Veterans. This relative difference was more pronounced among Veterans who were older, had higher educational/occupational attainment and greater baseline prevalence of cardiovascular risk factors (e.g., smoking) and cardiovascular disease (e.g., angina, stroke). Veteran status was associated with higher prevalence of protective factors that may have helped initially preserve cognitive functioning. However, findings ultimately revealed more pronounced cognitive decline among Veteran relative to non-Veteran participants, likely suggesting the presence of risks that may impact neuropathology and the effects of which were initially masked by Veterans' greater cognitive reserve.

Vascular and amyloid pathologies are independent predictors of cognitive decline in normal elderly.

Our primary objective was to investigate a biomarker driven model for the interrelationships between vascular disease pathology, amyloid pathology, and longitudinal cognitive decline in cognitively normal elderly subjects between 70 and 90 years of age. Our secondary objective was to investigate the beneficial effect of cognitive reserve on these interrelationships. We used brain amyloid-β load measured using Pittsburgh compound B positron emission tomography as a marker for amyloid pathology. White matter hyperintensities and brain infarcts were measured using fluid-attenuated inversion recovery magnetic resonance imaging as a marker for vascular pathology. We studied 393 cognitively normal elderly participants in the population-based Mayo Clinic Study of Aging who had a baseline 3 T fluid-attenuated inversion recovery magnetic resonance imaging assessment, Pittsburgh compound B positron emission tomography scan, baseline cognitive assessment, lifestyle measures, and at least one additional clinical follow-up. We classified subjects as being on the amyloid pathway if they had a global cortical amyloid-β load of ≥1.5 standard uptake value ratio and those on the vascular pathway if they had a brain infarct and/or white matter hyperintensities load ≥1.11% of total intracranial volume (which corresponds to the top 25% of white matter hyperintensities in an independent non-demented sample). We used a global cognitive z-score as a measure of cognition. We found no evidence that the presence or absence of vascular pathology influenced the presence or absence of amyloid pathology and vice versa, suggesting that the two processes seem to be independent. Baseline cognitive performance was lower in older individuals, in males, those with lower education/occupation, and those on the amyloid pathway. The rate of cognitive decline was higher in older individuals (P < 0.001) and those with amyloid (P = 0.0003) or vascular (P = 0.0037) pathologies. In those subjects with both vascular and amyloid pathologies, the effect of both pathologies on cognition was additive and not synergistic. For a 79-year-old subject, the predicted annual rate of global z-score decline was -0.02 if on neither pathway, -0.07 if on the vascular pathway, -0.08 if on the amyloid pathway and -0.13 if on both pathways. The main conclusions of this study were: (i) amyloid and vascular pathologies seem to be at least partly independent processes that both affect longitudinal cognitive trajectories adversely and are major drivers of cognitive decline in the elderly; and (ii) cognitive reserve seems to offset the deleterious effect of both pathologies on the cognitive trajectories.

The Statistical Modeling of Aging and Risk of Transition Project: Data Collection and Harmonization Across 11 Longitudinal Cohort Studies of Aging, Cognition, and Dementia

Longitudinal cognitive trajectories and other factors associated with mixed neuropathologies (such as Alzheimer's disease with co-occurring cerebrovascular disease) remain incompletely understood, despite being the rule and not the exception in older populations. The Statistical Modeling of Aging and Risk of Transition study (SMART) is a consortium of 11 different high-quality longitudinal studies of aging and cognition (N=11,541 participants) established for the purpose of characterizing risk and protective factors associated with subtypes of age-associated mixed neuropathologies (N=3,001 autopsies). While brain donation was not required for participation in all SMART cohorts, most achieved substantial autopsy rates (i.e., > 50%). Moreover, the studies comprising SMART have large numbers of participants who were followed from intact cognition and transitioned to cognitive impairment and dementia, as well as participants who remained cognitively intact until death. These data provide an exciting opportunity to apply sophisticated statistical methods, like Markov processes, that require large, well-characterized samples. Thus, SMART will serve as an important resource for the field of mixed dementia epidemiology and neuropathology.

Life experience and demographic influences on cognitive function in older adults.

We examined the influence of a broad spectrum of life experiences on longitudinal cognitive trajectories in a demographically diverse sample of older adults. Participants were 333 educationally, ethnically, and cognitively diverse older adults enrolled in a longitudinal aging study. Mixed-effects regression was used to measure baseline status in episodic memory, executive functioning, and semantic memory and change in a global cognition factor defined by change in these 3 domain-specific measures. We examined effects of life experience variables (literacy, childhood socioeconomic status, morphometric measures of physical development, life course physical and recreational activity) on longitudinal cognitive trajectories, covarying for age, apolipoprotein E (APOE) genotype and demographics (education, ethnicity, language). Non-Latino Whites had higher baseline cognition, but life experience variables attenuated ethnic differences in cognitive scores. Age, literacy, childhood socioeconomic status, and physical activity significantly influenced baseline cognition. Age, APOE ε4, and decline in intellectually and socially stimulating recreational activity from mid to late life were independently associated with increased late life cognitive decline. Higher literacy and late life recreational activity were associated with less decline. Literacy had similar effects for English and Spanish readers/speakers. Bilingual English and Spanish speakers did not differ from English Speakers in cognitive performance. Life experience variables, especially literacy level, were strongly related to baseline cognition and substantially attenuated effects of race/ethnicity and education. Cognitive change was best explained by age, APOE ε4, literacy, and current recreational activities. Literacy had robust associations with baseline cognition and cognitive change in both English and Spanish speakers.

Biological heterogeneity in ADNI amnestic mild cognitive impairment

BackgroundPrevious work examining normal controls from the Alzheimer's Disease Neuroimaging Initiative (ADNI) identified substantial biological heterogeneity. We hypothesized that ADNI mild cognitive impairment (MCI) subjects would also exhibit heterogeneity with possible clinical implications. MethodsADNI subjects diagnosed with amnestic MCI (n = 138) were clustered based on baseline magnetic resonance imaging, cerebrospinal fluid, and serum biomarkers. The clusters were compared with respect to longitudinal atrophy, cognitive trajectory, and time to conversion. ResultsFour clusters emerged with distinct biomarker patterns: The first cluster was biologically similar to normal controls and rarely converted to Alzheimer's disease (AD) during follow-up. The second cluster had characteristics of early Alzheimer's pathology. The third cluster showed the most severe atrophy but barely abnormal tau levels and a substantial proportion converted to clinical AD. The fourth cluster appeared to be pre-AD and nearly all converted to AD. ConclusionsSubjects with MCI who were clinically similar showed substantial heterogeneity in biomarkers.