Relationships of Cognitive Measures with Cerebrospinal Fluid but Not Imaging Biomarkers of Alzheimer Disease Vary between Black and White Individuals.

OBJECTIVE: Biomarkers of Alzheimer disease vary between groups of self-identified Black and White individuals in some studies. This study examined whether the relationships between biomarkers or between biomarkers and cognitive measures varied by racialized groups. METHODS: Cerebrospinal fluid (CSF), amyloid positron emission tomography (PET), and magnetic resonance imaging measures were harmonized across four studies of memory and aging. Spearman correlations between biomarkers and between biomarkers and cognitive measures were calculated within each racialized group, then compared between groups by standard normal tests after Fisher's Z-transformations. RESULTS: The harmonized dataset included at least one biomarker measurement from 495 Black and 2,600 White participants. The mean age was similar between racialized groups. However, Black participants were less likely to have cognitive impairment (28% vs 36%) and had less abnormality of some CSF biomarkers including CSF Aß42/40, total tau, p-tau181, and neurofilament light. CSF Aß42/40 was negatively correlated with total tau and p-tau181 in both groups, but at a smaller magnitude in Black individuals. CSF Aß42/40, total tau, and p-tau181 had weaker correlations with cognitive measures, especially episodic memory, in Black than White participants. Correlations of amyloid measures between CSF (Aß42/40, Aß42) and PET imaging were also weaker in Black than White participants. Importantly, no differences based on race were found in correlations between different imaging biomarkers, or in correlations between imaging biomarkers and cognitive measures. INTERPRETATION: Relationships between CSF biomarkers but not imaging biomarkers varied by racialized groups. Imaging biomarkers performed more consistently across racialized groups in associations with cognitive measures. ANN NEUROL 2024;95:495-506.

The influence of vector-borne disease on human history: socio-ecological mechanisms.

Vector-borne diseases (VBDs) are embedded within complex socio-ecological systems. While research has traditionally focused on the direct effects of VBDs on human morbidity and mortality, it is increasingly clear that their impacts are much more pervasive. VBDs are dynamically linked to feedbacks between environmental conditions, vector ecology, disease burden, and societal responses that drive transmission. As a result, VBDs have had profound influence on human history. Mechanisms include: (1) killing or debilitating large numbers of people, with demographic and population-level impacts; (2) differentially affecting populations based on prior history of disease exposure, immunity, and resistance; (3) being weaponised to promote or justify hierarchies of power, colonialism, racism, classism and sexism; (4) catalysing changes in ideas, institutions, infrastructure, technologies and social practices in efforts to control disease outbreaks; and (5) changing human relationships with the land and environment. We use historical and archaeological evidence interpreted through an ecological lens to illustrate how VBDs have shaped society and culture, focusing on case studies from four pertinent VBDs: plague, malaria, yellow fever and trypanosomiasis. By comparing across diseases, time periods and geographies, we highlight the enormous scope and variety of mechanisms by which VBDs have influenced human history.

Sex-related Differences in Tau Positron Emission Tomography (PET) and the Effects of Hormone Therapy (HT).

IMPORTANCE: Female sex is a major risk factor for late-onset Alzheimer disease (AD), and sex hormones have been implicated as a possible protective factor. Neuroimaging studies that evaluated the effects of sex hormones on brain integrity have primarily emphasized neurodegenerative measures rather than amyloid and tau burden. OBJECTIVE: We compared cortical amyloid and regional tau positron emission tomography (PET) deposition between cognitively normal males and females. We also compared preclinical AD pathology between females who have and have not used hormone therapy (HT). Finally, we compared the effects of amyloid and tau pathology on cognition, testing for both sex and HT effects. DESIGN, SETTING, AND PARTICIPANTS: We analyzed amyloid, tau, and cognition in a cognitively normal cross-sectional cohort of older individuals (n=148) followed at the Knight Alzheimer Disease Research Center. Amyloid and tau PET, medication history, and neuropsychological testing were obtained for each participant. RESULTS: Within cognitively normal individuals, there was no difference in amyloid burden by sex. Whether or not we controlled for amyloid burden, female participants had significantly higher tau PET levels than males in multiple regions, including the rostral middle frontal and superior and middle temporal regions. HT accounted for a small reduction in tau PET; however, males still had substantially lower tau PET compared with females. Amyloid PET and tau PET burden were negatively associated with cognitive performance, although increasing amyloid PET did not have a deleterious effect on cognitive performance for women with a history of HT. CONCLUSIONS AND RELEVANCE: Regional sex-related differences in tau PET burden may contribute to the disparities in AD prevalence between males and females. The observed decreases tau PET burden in HT users has important implications for clinical practice and trials and deserves future consideration in longitudinal studies.

Incident cognitive impairment: longitudinal changes in molecular, structural and cognitive biomarkers.

Longer periods are needed to examine how biomarker changes occur relative to incident sporadic cognitive impairment. We evaluated molecular (CSF and imaging), structural, and cognitive biomarkers to predict incident cognitive impairment and examined longitudinal biomarker changes before and after symptomatic onset. Data from participants who were cognitively normal, underwent amyloid imaging using Pittsburgh compound B and/or CSF studies, and at least two clinical assessments were used. Stepwise Cox proportional hazards models tested associations of molecular (Pittsburgh compound B; CSF amyloid-ß42, tau, ptau181, tau/amyloid-ß42, ptau181/amyloid-ß42), structural (normalized hippocampal volume, normalized whole brain volume), and cognitive (Animal Naming, Trail Making A, Trail Making B, Selective Reminding Test - Free Recall) biomarkers with time to Clinical Dementia Rating (CDR) > 0. Cognitively normal participants (n = 664), aged 42 to 90 years (mean ± standard deviation = 71.4 ± 9.2) were followed for up to 16.9 years (mean ± standard deviation = 6.2 ± 3.5 years). Of these, 145 (21.8%) participants developed a CDR > 0. At time of incident cognitive impairment, molecular, structural, and cognitive markers were abnormal for CDR > 0 compared to CDR = 0. Linear mixed models indicated rates of change in molecular biomarkers were similar for CDR = 0 and CDR > 0, suggesting that the separation in values between CDR = 0 and CDR > 0 must have occurred prior to the observation period. Rate of decline for structural and cognitive biomarkers was faster for CDR > 0 compared to CDR = 0 (P < 0.0001). Structural and cognitive biomarkers for CDR > 0 diverged from CDR 0 at 9 and 12 years before incident cognitive impairment, respectively. Within those who developed CDR > 0, a natural separation occurred for Pittsburgh compound B values. In particular, CDR > 0 who had at least one APOE ɛ4 allele had higher, and more rapid increase in Pittsburgh compound B, while APOE ɛ2 was observed to have slower increases in Pittsburgh compound B. Of molecular biomarker-positive participants followed for at least 10 years (n = 16-23), ∼70% remained CDR = 0 over the follow-up period. In conclusion, conversion from cognitively normal to CDR > 0 is characterized by not only the magnitude of molecular biomarkers but also rate of change in cognitive and structural biomarkers. Findings support theoretical models of biomarker changes seen during transition to cognitive impairment using longitudinal data and provide a potential time for changes seen during this transition. These findings support the use of molecular biomarkers for trial inclusion and cognitive/structural biomarkers for evaluating trial outcomes. Finally, results support a potential role for APOE ɛ in modulating amyloid accumulation in CDR > 0 with APOE ɛ4 being deleterious and APOE ɛ2 protective.

Driving cessation over a 24-year period: Dementia severity and cerebrospinal fluid biomarkers.

INTRODUCTION: With 36 million older adult U.S. drivers, safety is a critical concern, particularly among those with dementia. It is unclear at what stage of Alzheimer's disease (AD) older adults stop driving and whether preclinical AD affects driving cessation. METHODS: Time to driving cessation was examined based on Clinical Dementia Rating (CDR) and AD cerebrospinal fluid biomarkers. 1795 older adults followed up to 24 years received CDR ratings. A subset (591) had cerebrospinal fluid biomarker measurements and was followed up to 17 years. Differences in CDR and biomarker groups as predictors of time to driving cessation were analyzed using Kaplan-Meier curves and Cox proportional models. RESULTS: Higher CDR scores and more abnormal biomarker measurements predicted a shorter time to driving cessation. DISCUSSION: Higher levels of AD biomarkers, including among individuals with preclinical AD, lead to earlier driving cessation. Negative functional outcomes of preclinical AD show a nonbenign phase of the disease.

Amyloid Imaging, Cerebrospinal Fluid Biomarkers Predict Driving Performance Among Cognitively Normal Individuals.

Postmortem brain studies of older drivers killed in car accidents indicate that many had Alzheimer disease (AD) neuropathologic changes. We examined whether AD biomarkers are related to driving performance among cognitively normal older adults. Individuals with normal cognition, aged 65+ years, and driving at least once per week, were recruited. Participants (N=129) took part in clinical assessments, a driving test, and positron emission tomography imaging with Pittsburgh compound B (PIB) and/or cerebrospinal fluid (CSF) collection. General linear models tested whether the number of driving errors differed as a function of each of the biomarker variables (mean cortical binding potential for PIB, and CSF Aß42, tau, ptau181, tau/Aß42, ptau181/Aß42). Higher ratios of CSF tau/Aß42, ptau181/Aß42, and PIB mean cortical binding potential, were associated with more driving errors (P<0.05). Preclinical AD may have subtle cognitive and functional effects, which alone may go unnoticed. However, when combined, these changes may impact complex behaviors such as driving.

Assessment of Instrumental Activities of Daily Living in Preclinical Alzheimer Disease.

Questionnaires are used to assess instrumental activities of daily living (IADL) among individuals with preclinical Alzheimer disease (AD). They have indicated no functional impairment among this population. We aim to determine among cognitively normal (CN) older adults with and without preclinical AD whether: (a) performance-based IADL assessment measures a wider range of function than an IADL questionnaire and (b) biomarkers of AD are associated with IADL performance. In this cross-sectional analysis of 161 older adults, participants in studies of AD completed an IADL questionnaire, performance-based IADL assessment, cognitive assessments, and had biomarkers of AD (amyloid, hippocampal volume, brain network strength) assessed within 2 to 3 years. Performance-based IADL scores were more widely distributed compared with the IADL questionnaire. Smaller hippocampal volumes and reduced brain network connections were associated with worse IADL performance. A performance-based IADL assessment demonstrates functional impairment associated with neurodegeneration among CN older adults.

Falls Associate with Neurodegenerative Changes in ATN Framework of Alzheimer's Disease.

BACKGROUND: Behavioral markers for Alzheimer's disease (AD) are not included within the widely used amyloid-tau-neurodegeneration framework. OBJECTIVE: To determine when falls occur among cognitively normal (CN) individuals with and without preclinical AD. METHODS: This cross-sectional study recorded falls among CN participants (n = 83) over a 1-year period. Tailored calendar journals recorded falls. Biomarkers including amyloid positron emission tomography (PET) and structural and functional magnetic resonance imaging were acquired within 2 years of fall evaluations. CN participants were dichotomized by amyloid PET (using standard cutoffs). Differences in amyloid accumulation, global resting state functional connectivity (rs-fc) intra-network signature, and hippocampal volume were compared between individuals who did and did not fall using Wilcoxon rank sum tests. Among preclinical AD participants (amyloid-positive), the partial correlation between amyloid accumulation and global rs-fc intra-network signature was compared for those who did and did not fall. RESULTS: Participants who fell had smaller hippocampal volumes (p = 0.04). Among preclinical AD participants, those who fell had a negative correlation between amyloid uptake and global rs-fc intra-network signature (R = -0.75, p = 0.012). A trend level positive correlation was observed between amyloid uptake and global rs-fc intra-network signature (R = 0.70, p = 0.081) for preclinical AD participants who did not fall. CONCLUSION: Falls in CN older adults correlate with neurodegeneration biomarkers. Participants without falls had lower amyloid deposition and preserved global rs-fc intra-network signature. Falls most strongly correlated with presence of amyloid and loss of brain connectivity and occurred in later stages of preclinical AD.

Long-term cognitive decline in older subjects was not attributable to noncardiac surgery or major illness.

BACKGROUND: Persistent postoperative cognitive decline is thought to be a public health problem, but its severity may have been overestimated because of limitations in statistical methodology. This study assessed whether long-term cognitive decline occurred after surgery or illness by using an innovative approach and including participants with early Alzheimer disease to overcome some limitations. METHODS: In this retrospective cohort study, three groups were identified from participants tested annually at the Washington University Alzheimer's Disease Research Center in St. Louis, Missouri: those with noncardiac surgery, illness, or neither. This enabled long-term tracking of cognitive function before and after surgery and illness. The effect of surgery and illness on longitudinal cognitive course was analyzed using a general linear mixed effects model. For participants without initial dementia, time to dementia onset was analyzed using sequential Cox proportional hazards regression. RESULTS: Of the 575 participants, 214 were nondemented and 361 had very mild or mild dementia at enrollment. Cognitive trajectories did not differ among the three groups (surgery, illness, control), although demented participants declined more markedly than nondemented participants. Of the initially nondemented participants, 23% progressed to a clinical dementia rating greater than zero, but this was not more common after surgery or illness. CONCLUSIONS: The study did not detect long-term cognitive decline independently attributable to surgery or illness, nor were these events associated with accelerated progression to dementia. The decision to proceed with surgery in elderly people, including those with early Alzheimer disease, may be made without factoring in the specter of persistent cognitive deterioration.

Differentiating cognitive impairment due to corticobasal degeneration and Alzheimer disease.

OBJECTIVE: To identify clinical features that reliably differentiate individuals with cognitive impairment due to corticobasal degeneration (CBD) and Alzheimer disease (AD). METHODS: Clinical features were compared between individuals with autopsy-proven CBD (n = 17) and AD (n = 16). All individuals presented with prominent cognitive complaints and were evaluated annually with semistructured interviews, detailed neurologic examinations, and neuropsychological testing. RESULTS: Substantial overlap was observed between individuals with dementia due to CBD and AD concerning presenting complaints, median (range) duration of symptoms before assessment (CBD = 3.0 [0-5.0] years, AD = 2.5 [0-8.0] years; p = 0.96), and median (range) baseline dementia severity (Clinical Dementia Rating Sum of Boxes: CBD = 3.5 [0-12.0], AD = 4.25 [0.5-9.0], p = 0.49). Subsequent emergence of asymmetric motor/sensory signs, hyperreflexia, gait abnormalities, parkinsonism, falls, urinary incontinence, and extraocular movement abnormalities identified individuals with CBD, with ≥3 discriminating features detected in 80% of individuals within 3.1 years (95% confidence interval 2.9-3.3) of the initial assessment. Individuals with CBD exhibited accelerated worsening of illness severity and declines in episodic memory, executive functioning, and letter fluency. Semiquantitative pathologic assessment revealed prominent tau pathology within the frontal and parietal lobes of CBD cases. Comorbid AD neuropathologic change was present in 59% (10 of 17) of CBD cases but did not associate with the clinical phenotype, rate of dementia progression, or dementia duration. CONCLUSIONS: CBD may mimic AD dementia early in its disease course. Interval screening for discriminating clinical features may improve antemortem diagnosis in individuals with CBD and prominent cognitive symptoms.

Preclinical Alzheimer's disease and longitudinal driving decline.

INTRODUCTION: Links between preclinical AD and driving difficulty onset would support the use of driving performance as an outcome in primary and secondary prevention trials among older adults (OAs). We examined whether AD biomarkers predicted the onset of driving difficulties among OAs. METHODS: 104 OAs (65+ years) with normal cognition took part in biomarker measurements, a road test, clinical and psychometric batteries and self-reported their driving habits. RESULTS: Higher values of CSF tau/Aß42 and ptau181/Aß42 ratios, but not uptake on PIB amyloid imaging (p=.12), predicted time to a rating of Marginal or Fail on the driving test using Cox proportional hazards models. Hazards ratios (95% confidence interval) were 5.75 (1.70-19.53), p=.005 for CSF tau/Aß42; 6.19 (1.75-21.88) and p=.005 for CSF ptau181/Aß42. DISCUSSION: Preclinical AD predicted time to receiving a Marginal or Fail rating on an on-road driving test. Driving performance shows promise as a functional outcome in AD prevention trials.

The neuropathology of Alzheimer disease in African American and white individuals.

BACKGROUND: Data from neuropathologic studies of the frequency of Alzheimer disease (AD) among African American persons conflict as to whether the neuropathologic phenotype of AD is identical in African American and white persons. OBJECTIVES: To examine clinical and neuropathologic phenotypes of AD in African American individuals and to compare AD and vascular burdens between African American and white persons. DESIGN, SETTING, AND PATIENTS: Ten African American decedents who underwent brain autopsy at the Washington University Alzheimer's Disease Research Center were matched for age, sex, and Clinical Dementia Rating with 10 white decedents between January 1, 1990, and January 1, 2000. The presence and degree of neurofibrillary tangles, senile plaques, Lewy bodies, cerebral infarcts, and cerebral amyloid angiopathy were determined. RESULTS: All 20 individuals had a neuropathologic diagnosis of AD. There were no group differences in the presence or number of infarcts, plaques, tangles, Lewy bodies, or amyloid angiopathy. CONCLUSION: In this small sample, we found no substantive differences in the neuropathology of AD among African American and white individuals.

Cerebrospinal Fluid Biomarkers and Reserve Variables as Predictors of Future "Non-Cognitive" Outcomes of Alzheimer's Disease.

BACKGROUND: The influence of reserve variables and Alzheimer's disease (AD) biomarkers on cognitive test performance has been fairly well-characterized. However, less is known about the influence of these factors on "non-cognitive" outcomes, including functional abilities and mood. OBJECTIVE: We examined whether cognitive and brain reserve variables mediate how AD biomarker levels in cognitively normal persons predict future changes in function, mood, and neuropsychiatric behavior. METHODS: Non-cognitive outcomes were examined in 328 individuals 50 years and older enrolled in ongoing studies of aging and dementia at the Knight Alzheimer Disease Research Center (ADRC). All participants were cognitively normal at baseline (Clinical Dementia Rating [CDR] 0), completed cerebrospinal fluid (CSF) and structural neuroimaging studies within one year of baseline, and were followed for an average of 4.6 annual visits. Linear mixed effects models explored how cognitive reserve and brain reserve variables mediate the relationships between AD biomarker levels and changes in function, mood, and neuropsychiatric behavior in cognitively normal participants. RESULTS: Education levels did not have a significant effect on predicting non-cognitive decline. However, participants with smaller brain volumes exhibited the worst outcomes on measures of mood, functional abilities, and behavioral disturbance. This effect was most pronounced in individuals who also had abnormal CSF biomarkers. CONCLUSIONS: The findings suggest that brain reserve plays a stronger, or earlier, role than cognitive reserve in protecting against non-cognitive impairment in AD.

Neuropathologic criteria for diagnosing Alzheimer disease in persons with pure dementia of Alzheimer type.

Universally accepted neuropathologic criteria for differentiating Alzheimer disease (AD) from healthy brain aging do not exist. We tested the hypothesis that Bielschowsky silver stained total, cored, and neuritic senile plaques (TSPs, CSPs, and NSPs, respectively), rather than neurofibrillary tangles (NFTs), best discriminate between the 2 conditions using rigorously defined nondemented (n = 7) and AD (n = 35) subjects with no known co-morbidities. We compared lesions in 3 neocortical regions, in hippocampal CA1, and in entorhinal cortex in 19 men and 13 women between 74 and 86 years at death. The Clinical Dementia Rating (CDR) was used to assess degree of cognitive impairment within a year of demise. Neocortical TSP measures provided the highest correlation with expiration CDR: area under the curve (AUC) = 0.986 with 97.8% sensitivity at 90% specificity with an estimated cut-point of 6.0 TSP/ mm2. All SP measures yielded higher estimated AUC and sensitivity for 90% specificity compared to NFTs. Derived TSP cut-points applied to 149 persons with clinical AD regardless of their neuropathologic diagnosis yielded a sensitivity of 97% and specificity of 84% for TSPs in the 3 neocortical areas. Thus cut-points based on both diffuse and neuritic SP in neocortical regions distinguished nondemented and AD subjects with high sensitivity and specificity.

Absence of effect of depression on cognitive performance in early-stage Alzheimer disease.

BACKGROUND: Depression can interfere with the normal expression of cognitive abilities in adults of all ages, but it is unclear if depression in demented people, which is common, is associated with reduced cognitive performance beyond the effect of the dementia itself. OBJECTIVE: To determine if depression adds to the cognitive deficit in dementia. DESIGN: Performance on psychometric tests of memory and other cognitive function was correlated with the number of depressive features reported by the individual and by a knowledgeable collateral source, as well as the judgment of a research clinician as to whether the person was depressed. SETTING: An Alzheimer disease research center. PARTICIPANTS: The convenience sample included individuals with very mild (Clinical Dementia Rating, 0.5; n = 167 [mean age, 76.03 years]) or mild (Clinical Dementia Rating, 1; n = 155 [mean age, 78.41 years]) Alzheimer disease who were enrolled in ongoing longitudinal studies at the center. MAIN OUTCOME MEASURES: Psychometric measures of memory and cognition. RESULTS: Depression was present in 15% of the very mild and 24% of the mild dementia groups. There was no relation between the clinicians' diagnoses of depression and psychometric scores. Little relation was found between performance on the cognitive tests and the number of depressive features (maximum, 9) reported by the individual or collateral source. The few statistically significant (P<.05) correlations were modest (< or =0.21). CONCLUSION: Depression does not worsen cognitive test performance beyond the effect of dementia.

Rates of progression in mild cognitive impairment and early Alzheimer's disease.

OBJECTIVE: To compare rates of progression in the very mildest stages of AD, including the stage currently identified as mild cognitive impairment (MCI), and to identify predictors of those rates. METHODS: Demented (n = 289) and nondemented (n = 230) individuals enrolled in longitudinal studies at an Alzheimer Disease Research Center received annual clinical and psychometric examinations for up to 20 years. In order of increasing dementia severity, demented individuals were diagnosed with incipient, very mild, or mild dementia; the incipient stage is equivalent to MCI. Outcome measures included death, nursing home placement, and psychometric scores. RESULTS: Rate of progression increased with dementia severity as staged by the Clinical Dementia Rating at entry into the study. With respect to the dichotomous outcomes, the increase with dementia severity was more dramatic for the endpoint of nursing home entry than it was for the endpoint of death. Increased rates of cognitive decline with increased dementia severity were also obtained for psychometric scores. There was limited evidence of other predictors of progression. CONCLUSIONS: The lack of effective predictors of the rate of dementia progression extends to the very earliest stages of the disease, including what is often called MCI. A new approach to the identification of correlates of rates of progression is needed.

Accuracy of collateral source reports in very mild to mild dementia of the Alzheimer type.

OBJECTIVES: To examine the reporting accuracy of collateral sources (knowledgeable informants) regarding very mild and mild dementia of the Alzheimer type (DAT) and to identify characteristics associated with collateral source accuracy. DESIGN: Secondary data analysis of initial visits of individuals enrolled in a longitudinal study of healthy aging and Alzheimer disease. SETTING: Urban Alzheimer disease research center. PARTICIPANTS: Pairs of 515 individuals with very mild (n = 203) or mild (n = 312) DAT and their collateral sources. MEASUREMENTS: Collateral sources were asked separately during a semistructured interview by experienced clinicians to report current ability of the individual with DAT in memory, orientation, and judgment and problem solving. The clinical performance of the individuals with DAT in these domains was compared with these predictions. RESULTS: Collateral sources were consistently and significantly accurate in reporting the cognitive capabilities of individuals with very mild and mild DAT. Although all types of collateral sources performed significantly better than chance, individual variables that correlated with collateral source accuracy included spousal relationship; living with the individual with DAT; frequent exposure to the individual; and age, education level, sex and dementia severity of the individual with DAT. CONCLUSION: Collateral sources are accurate in reporting the cognitive capabilities of individuals with DAT, even in the very mild stage of dementia.

CSF biomarkers of Alzheimer disease: "noncognitive" outcomes.

OBJECTIVES: To test whether CSF Alzheimer disease biomarkers (ß-amyloid 42 [Aß42], tau, phosphorylated tau at threonine 181 [ptau181], tau/Aß42, and ptau181/Aß42) predict future decline in noncognitive outcomes among individuals cognitively normal at baseline. METHODS: Longitudinal data from participants (N = 430) who donated CSF within 1 year of a clinical assessment indicating normal cognition and were aged 50 years or older were analyzed. Mixed linear models were used to test whether baseline biomarker values predicted future decline in function (instrumental activities of daily living), weight, behavior, and mood. Clinical Dementia Rating Sum of Boxes and Mini-Mental State Examination scores were also examined. RESULTS: Abnormal levels of each biomarker were related to greater impairment with time in behavior (p < 0.035) and mood (p < 0.012) symptoms, and more difficulties with independent activities of daily living (p < 0.012). However, biomarker levels were unrelated to weight change with time (p > 0.115). As expected, abnormal biomarker values also predicted more rapidly changing Mini-Mental State Examination (p < 0.041) and Clinical Dementia Rating Sum of Boxes (p < 0.001) scores compared with normal values. CONCLUSIONS: CSF biomarkers among cognitively normal individuals are associated with future decline in some, but not all, noncognitive Alzheimer disease symptoms studied. Additional work is needed to determine the extent to which these findings generalize to other samples.

Preclinical Alzheimer disease and risk of falls.

OBJECTIVE: We determined the rate of falls among cognitively normal, community-dwelling older adults, some of whom had presumptive preclinical Alzheimer disease (AD) as detected by in vivo imaging of fibrillar amyloid plaques using Pittsburgh compound B (PiB) and PET and/or by assays of CSF to identify Aß42, tau, and phosphorylated tau. METHODS: We conducted a 12-month prospective cohort study to examine the cumulative incidence of falls. Participants were evaluated clinically and underwent PiB PET imaging and lumbar puncture. Falls were reported monthly using an individualized calendar journal returned by mail. A Cox proportional hazards model was used to test whether time to first fall was associated with each biomarker and the ratio of CSF tau/Aß42 and CSF phosphorylated tau/Aß42, after adjustment for common fall risk factors. RESULTS: The sample (n = 125) was predominately female (62.4%) and white (96%) with a mean age of 74.4 years. When controlled for ability to perform activities of daily living, higher levels of PiB retention (hazard ratio = 2.95 [95% confidence interval 1.01-6.45], p = 0.05) and of CSF biomarker ratios (p < 0.001) were associated with a faster time to first fall. CONCLUSIONS: Presumptive preclinical AD is a risk factor for falls in older adults. This study suggests that subtle noncognitive changes that predispose older adults to falls are associated with AD and may precede detectable cognitive changes.

Preclinical Alzheimer's disease and its outcome: a longitudinal cohort study.

BACKGROUND: New research criteria for preclinical Alzheimer's disease have been proposed, which include stages for cognitively normal individuals with abnormal amyloid markers (stage 1), abnormal amyloid and neuronal injury markers (stage 2), or abnormal amyloid and neuronal injury markers and subtle cognitive changes (stage 3). We aimed to investigate the prevalence and long-term outcome of preclinical Alzheimer's disease according to these criteria. METHODS: Participants were cognitively normal (clinical dementia rating [CDR]=0) community-dwelling volunteers aged at least 65 years who were enrolled between 1998 and 2011 at the Washington University School of Medicine (MO, USA). CSF amyloid-ß1-42 and tau concentrations and a memory composite score were used to classify participants as normal (both markers normal), preclinical Alzheimer's disease stage 1-3, or suspected non-Alzheimer pathophysiology (SNAP, abnormal injury marker without abnormal amyloid marker). The primary outcome was the proportion of participants in each preclinical AD stage. Secondary outcomes included progression to CDR at least 0·5, symptomatic Alzheimer's disease (score of at least 0·5 for memory and at least one other domain and cognitive impairments deemed to be due to Alzheimer's disease), and mortality. We undertook survival analyses using subdistribution and standard Cox hazards models and linear mixed models. FINDINGS: Of 311 participants, 129 (41%) were classed as normal, 47 (15%) as stage 1, 36 (12%) as stage 2, 13 (4%) as stage 3, 72 (23%) as SNAP, and 14 (5%) remained unclassified. The 5-year progression rate to CDR at least 0·5, symptomatic Alzheimer's disease was 2% for participants classed as normal, 11% for stage 1, 26% for stage 2, 56% for stage 3, and 5% for SNAP. Compared with individuals classed as normal, participants with preclinical Alzheimer's disease had an increased risk of death after adjusting for covariates (hazard ratio 6·2, 95% CI 1·1-35·0; p=0·040). INTERPRETATION: Preclinical Alzheimer's disease is common in cognitively normal elderly people and is associated with future cognitive decline and mortality. Thus, preclinical Alzheimer's disease could be an important target for therapeutic intervention. FUNDING: National Institute of Aging of the National Institutes of Health (P01-AG003991, P50-AG05681, P01-AG02676), Internationale Stichting Alzheimer Onderzoek, the Center for Translational Molecular Medicine project LeARN, the EU/EFPIA Innovative Medicines Initiative Joint Undertaking, and the Charles and Joanne Knight Alzheimer Research Initiative.