Introduction We investigated plasma proteomic markers of astrocytopathy, brain degeneration, plasticity, and inflammation in sporadic early-onset versus late-onset Alzheimer's disease (EOAD and LOAD). Methods Plasma was analyzed using ultra-sensitive immuno-based assays from 33 EOAD, 30 LOAD, and 36 functionally normal older adults. Results Principle component analyses identified 3 factors: trophic (BDNF, VEGF, TGFβ), degenerative (GFAP, NfL), and inflammatory (TNFα, IL-6, IP-10, IL-10). Trophic factor was elevated in both AD groups and associated with cognition and gray matter volumes. Degenerative factor was elevated in EOAD, with higher levels associated with worse functioning in this group. Biomarkers of inflammation were not significantly different between groups and were only associated with age. Disucssion Plasma proteomic biomarkers provide novel means of investigating molecular processes in vivo and their contributions to clinical outcomes. We present initial investigations of several of these fluid biomarkers, capturing aspects of astrocytopathy, neuronal injury, cellular plasticity, and inflammation in EOAD versus LOAD.

Introduction This clinical trial evaluates the efficacy and safety of a 6-week course of daily neuroAD™ therapy. Methods 131 subjects between 60 and 90 years old, unmedicated for Alzheimer's disease (AD), or on stable doses of an acetylcholinesterase inhibitor and/or memantine, with Mini–Mental State Examination scores between 18 and 26, clinical dementia rating scale scores of 1 or 2, enrolled for a prospective, randomized, double-blind, sham-controlled, multicenter clinical trial. Structural brain MRIs were obtained for transcranial magnetic stimulation targeting. Baseline Alzheimer's disease assessment scale—cognitive (ADAS-Cog) and Clinical Global Impression of Change were assessed. 129 participants were randomized to active treatment plus standard of care (SOC) or sham treatments plus SOC. Results Subjects with baseline ADAS-Cog ≤ 30 (~85% of study population) showed a statistically significant benefit favoring active over sham. Responder analysis showed 31.7% participants in the active group with ≤ −4 point improvement on ADAS-Cog versus 15.4% in the sham group. Discussion neuroAD™ Therapy System provides a low-risk therapeutic benefit for patients with milder AD (baseline ADAS-Cog ≤30) beyond pharmacologic SOC.

Introduction Blood-brain barrier (BBB) breakdown is an early independent biomarker of human cognitive dysfunction, as found using gadolinium (Gd) as a contrast agent. Whether Gd accumulates in brains of individuals with an age-dependent BBB breakdown and/or mild cognitive impairment remains unclear. Methods We analyzed T1-weighted magnetic resonance imaging (MRI) scans from 52 older participants with BBB breakdown in the hippocampus 19-28 months after either cyclic or linear Gd agent. Results There was no change in T1-weighted signal intensity between the baseline contrast MRI and unenhanced MRI on re-examination in any of the studied 10 brain regions with either Gd agent suggesting undetectable Gd brain retention. Discussion Gd does not accumulate in brains of older individuals with a BBB breakdown in the hippocampus. Thus, Gd agents can be used without risk of brain retention within a ∼2-year follow-up to study BBB in the aging human brain in relation to cognition and/or other pathologies.

Introduction Preventing dementia, or modifying disease course, requires identification of presymptomatic or minimally symptomatic high-risk individuals. Methods We used longitudinal electronic health records from two large academic medical centers and applied a validated natural language processing tool to estimate cognitive symptomatology. We used survival analysis to examine the association of cognitive symptoms with incident dementia diagnosis during up to 8 years of follow-up. Results Among 267,855 hospitalized patients with 1,251,858 patient years of follow-up data, 6516 (2.4%) received a new diagnosis of dementia. In competing risk regression, an increasing cognitive symptom score was associated with earlier dementia diagnosis (HR 1.63; 1.54–1.72). Similar results were observed in the second hospital system and in subgroup analysis of younger and older patients. Discussion A cognitive symptom measure identified in discharge notes facilitated stratification of risk for dementia up to 8 years before diagnosis.

Introduction We previously characterized associations between brain imaging measurements of amyloid-β (Aβ) plaque burden and apolipoprotein E (APOE) ϵ4 gene dose in a small number of cognitively unimpaired late-middle-aged APOE ϵ4 homozygotes (HMs), heterozygotes (HTs), and noncarriers (NCs). We now characterize cross-sectional Aβ plaque, tau tangle, and cortical atrophy (neurodegeneration) measurements, classifications, and associations with age in a larger number of unimpaired HMs, HTs, and NCs over a wider age range. Methods We analyzed 11C Pittsburgh compound B (Aβ) positron emission tomography (PET), flortaucipir (tau) PET, and volumetric magnetic resonance imaging data from 164 study participants of age 47–86 years, including 26 APOE ϵ4 HMs, 48 HTs, and 90 NCs matched for age and sex. Results Aβ PET measurements rose, plateaued at the respective ages of 68 and 76, and then declined with age in unimpaired HM and HT groups. Compared with NCs, these two groups began to have significantly higher Aβ PET measurements at ages 62 and 70, respectively, and no longer had significantly higher measurements by ages 71 and 78, respectively. They began to have significantly higher entorhinal cortex tau PET measurements at ages 66 and 70, respectively, and no longer had significantly higher measurements by ages 74 and 78, respectively. Brain atrophy measurements tended to decline slowly with age in all three genetic groups. Their elevated tau PET measurements were attributable to those with positive Aβ PET scans. 41.0%, 18.0%, and 5.0% of the 47- to 70-year-old HMs, HTs, and NCs and 25.0%, 79.0%, and 38.0% of the 71- to 86-year-old HMs, HTs, and NCs had positive Aβ PET scans, and the long-term recall memory scores are significantly higher in the older HMs than in HT and NC groups, suggesting resistance to Aβ deposition in those HMs who remained unimpaired at older ages. Conclusions This study provides information about Aβ plaque burden, tau tangle burden, and neurodegeneration in cognitively unimpaired persons at three levels of genetic risk for AD. Unimpaired APOE ϵ4 HMs can be studied before their 70s to evaluate the understanding of factors, processes, and interventions involved in the predisposition to and prevention of AD, and after their 70s, to discover factors, processes, and interventions involved in the resilience or resistance to and prevention of AD.

Introduction Some Alzheimer's disease biomarker studies found amyloid changes 20 years or more in advance of expected symptoms, while cognitive changes lagged for more than a decade, but this apparent lag might reflect the sensitivities of the biomarker and cognitive assays used. How far in advance of incident amnestic mild cognitive impairment (MCI) does cognition begin to decline? Methods Longitudinal neuropsychological study of an apolipoprotein E e4 enriched cohort of cognitively normal individuals at entry. Linear mixed models for MCI converters (n = 65) and nonconverters (n = 719) fitted for each neuropsychological measure; annual changes compared between groups before and after linear model intersections (inflection points). Results 34 of 35 cognitive measures and 9 of 18 behavioral measures declined faster post-inflection in the MCI converters; the earliest cognitive inflection point was nearly 20 years in advance of MCI diagnosis. Discussion The preclinical duration of cognitive and behavioral changes approaches the earliest reported biomarker changes.

Introduction Relationship between age and dementia at extreme old ages is still an open question, yet population-based studies in this high-risk age segment are rare. Methods The Monzino 80-plus is a population-based study among residents 80 years and older in the Varese province, Italy. Of 1371 eligible individuals, 1294 (94.4%), of whom 64 are centenarians, were included in the incidence study. Results Since 2002, 584 new cases of all-cause dementia were identified over 15 years. The overall incidence rate was 7.9 per 100 person-years. Dementia risk rose with age (IRR: 1.06), with the cubic model providing the best fit (R2 = 0.91–0.96). Cumulative incidences of dementia unadjusted and adjusted for competing mortality risk progressively diverged with age. Conclusion Dementia incidence also keeps rising in nonagenarians and centenarians. Slowing down in growing risk of developing dementia with age is mainly attributable to increasing competing risk of death and resulting selective survival of individuals at lower risk of dementia.

Introduction Observational studies have suggested that light-to-moderate alcohol consumption decreases the risk of Alzheimer's disease, but it is unclear if this association is causal. Methods Two-sample Mendelian randomization (MR) analysis was used to examine whether alcohol consumption, alcohol dependence, or Alcohol Use Disorder Identification Test (AUDIT) scores were causally associated with the risk of Late-Onset Alzheimer's disease (LOAD) or Alzheimer's disease age of onset survival (AAOS). Additionally, γ-glutamyltransferase levels were included as a positive control. Results There was no evidence of a causal association between alcohol consumption, alcohol dependence, or AUDIT, and LOAD. Alcohol consumption was associated with an earlier AAOS and increased γ-glutamyltransferase blood concentrations. Alcohol dependence was associated with a delayed AAOS. Discussion MR found robust evidence of a causal association between alcohol consumption and an earlier AAOS, but not alcohol intake and LOAD risk. The protective effect of alcohol dependence is potentially due to survivor bias.

Introduction To date, the clinical relevance of comorbid amyloid-β (Aβ) pathology in patients with vascular cognitive disorders (VCD) is largely unknown. Methods We included 218 VCD patients with available cerebrospinal fluid Aβ42 levels. Patients were divided into Aβ+ mild-VCD (n = 84), Aβ− mild-VCD (n = 68), Aβ+ major-VCD (n = 31), and Aβ− major-VCD (n = 35). We measured depression with the Geriatric Depression Scale, cognition with a neuropsychological test battery and derived white matter hyperintensities (WMH) and gray matter atrophy from MRI. Results Aβ− patients showed more depressive symptoms than Aβ+. In the major-VCD group, Aβ− patients performed worse on attention (P = .02) and executive functioning (P = .008) than Aβ+. We found no cognitive differences in patients with mild VCD. In the mild-VCD group, Aβ− patients had more WMH than Aβ+ patients, whereas conversely, in the major-VCD group, Aβ+ patients had more WMH. Atrophy patterns did not differ between Aβ+ and Aβ− VCD group. Discussion Comorbid Aβ pathology affects the manifestation of VCD, but effects differ by severity of VCD.

Introduction The ROADMAP project aimed to provide an integrated overview of European real-world data on Alzheimer's disease (AD) across the disease spectrum. Methods Metadata were identified from data sources in catalogs of European AD projects. Priority outcomes for different stakeholders were identified through systematic literature review, patient and public consultations, and stakeholder surveys. Results Information about 66 data sources and 13 outcome domains were integrated into a Data Cube. Gap analysis identified cognitive ability, functional ability/independence, behavioral/neuropsychiatric symptoms, treatment, comorbidities, and mortality as the outcomes collected most. Data were most lacking in caregiver-related outcomes. In general, electronic health records covered a broader, less detailed data spectrum than research cohorts. Discussion This integrated real-world AD data overview provides an intuitive visual model that facilitates initial assessment and identification of gaps in relevant outcomes data to inform future prospective data collection and matching of data sources and outcomes against research protocols.

Introduction Comparison of tau (flortaucipir) positron emission tomography (FTP-PET) to autopsy is important to demonstrate the relationship of FTP-PET to neuropathologic findings. Methods Autopsies were performed on 26 participants who had antemortem FTP-PET. FTP-PET standardized uptake value ratios (SUVRs) were compared to autopsy diagnoses and Braak tangle stage. Quantitative tau burden was compared to regional FTP-PET signal. Results Participants with Braak stages of IV or greater had elevated FTP-PET signal. FTP-PET was elevated in participants with Alzheimer's disease. An FTP-PET SUVR cut point of 1.29 was determined to be optimal. Quantitative measurements of hippocampal and temporal lobe tau burden were highly correlated to FTP-PET signal (rho's from 0.61 to 0.70, P ≤ .02). Discussion Elevated FTP-PET reflects Braak IV or greater neuropathology. Participants with primary age-related tauopathy and hippocampal sclerosis did not show elevated FTP-PET signal. Secondary neuropathologic diagnoses of Alzheimer's disease neuropathologic change can lead to borderline elevated FTP-PET signal.

Introduction The Advancing Research and Treatment in Frontotemporal Lobar Degeneration and Longitudinal Evaluation of Familial Frontotemporal Dementia Subjects longitudinal studies were designed to describe the natural history of familial-frontotemporal lobar degeneration due to autosomal dominant mutations. Methods We examined cognitive performance, behavioral ratings, and brain volumes from the first time point in 320 MAPT, GRN, and C9orf72 family members, including 102 non–mutation carriers, 103 asymptomatic carriers, 43 mildly/questionably symptomatic carriers, and 72 carriers with dementia. Results Asymptomatic carriers showed similar scores on all clinical measures compared with noncarriers but reduced frontal and temporal volumes. Those with mild/questionable impairment showed decreased verbal recall, fluency, and Trail Making Test performance and impaired mood and self-monitoring. Dementia was associated with impairment in all measures. All MAPT carriers with dementia showed temporal atrophy, but otherwise, there was no single cognitive test or brain region that was abnormal in all subjects. Discussion Imaging changes appear to precede clinical changes in familial-frontotemporal lobar degeneration, but specific early clinical and imaging changes vary across individuals.

Introduction Frontotemporal dementia disorders (FTDs) are heterogeneous phenotypical behavioral and language disorders usually associated with frontal and/or temporal lobe degeneration. We investigated their incidence in a population-based cohort. Methods Using a records-linkage system, we identified all patients with a diagnostic code for dementia in Olmsted County, MN, 1995–2010, and confirmed the diagnosis of FTD. A behavioral neurologist verified the clinical diagnosis and determined phenotypes. Results We identified 35 FTDs cases. Overall, the incidence of FTDs was 4.3/100,000/year (95% CI: 2.9, 5.7). Incidence was higher in men (6.3/100,000, 95% CI 3.6, 9.0) than women (2.9/100,000; 95% CI: 1.3, 4.5); we observed an increased trend over time (B = 0.83, 95% CI: 0.54, 1.11, P < .001). At autopsy, clinical diagnosis was confirmed in eight (72.7%) cases. Discussion We observed an increased incidence and trends of FTDs over time. This may reflect a better recognition by clinicians and improvement of clinical criteria and diagnostic tools.

Introduction Apolipoprotein E (APOE) status may modify the risk of postoperative delirium conferred by inflammation. Methods We tested whether APOE modifies the established association between C-reactive protein (CRP) and delirium incidence, severity, and duration in 553 noncardiac surgical patients aged 70 and older. High postoperative plasma CRP (≥234.12 mg/L) was defined by the highest sample-based quartile. Delirium was determined using the Confusion Assessment Method and chart review, and severity was determined by the Confusion Assessment Method––Severity score. Results APOE ε4 carrier prevalence was 19%, and postoperative delirium occurred in 24%. The relationship between CRP and delirium incidence, severity, and duration differed by ε4 status. Among ε4 carriers, there was a strong relationship between high CRP (vs. low CRP) and delirium incidence (relative risk [95% confidence interval], 3.0 [1.4–6.7]); however, no significant association was observed among non-ε4 carriers (relative risk [95% CI], 1.2 [0.8–1.7]). Discussion Our findings raise the possibility that APOE ε4 carrier status may modify the relationship between postoperative day 2 CRP levels and postoperative delirium.

Introduction Demonstrating the “clinical meaningfulness” of slowing early cognitive decline in clinically normal (CN) older adults with elevated amyloid-β (Aβ+) is critical for Alzheimer's disease secondary prevention trials and for understanding early cognitive progression. Methods Cox regression analyses were used to determine whether 3-year slopes on the preclinical Alzheimer's cognitive composite predicted MCI diagnosis and global Clinical Dementia Rating>0 in 267 Aβ+ CN individuals participating in the Harvard Aging Brain Study, Australian Imaging, Biomarker and Lifestyle Study, and Alzheimer's Disease Neuroimaging Initiative. Results Steeper preclinical Alzheimer's cognitive composite decline over 3 years was associated with increased risk for MCI diagnosis and global Clinical Dementia Rating>0 in the following years across all cohorts. Hazard ratios using meta-analytic estimates were 5.47 (95% CI: 3.25–9.18) for MCI diagnosis and 4.49 (95% CI: 2.84–7.09) for Clinical Dementia Rating>0 in those with subtle decline (>−.14 to −.26 preclinical Alzheimer's cognitive composite standard deviations/year) on longitudinal cognitive testing. Discussion Early “subtle cognitive decline” among Aβ+ CN on a sensitive cognitive composite demonstrably increases risk for imminent clinical disease progression and functional impairment.

Hispanics/Latinos are the largest ethnic/racial group in the United States and at high risk for Alzheimer's disease and related dementia (ADRD). Yet, ADRD among diverse Latinos is poorly understood and disparately understudied or unstudied compared to other ethnic/racial groups that leave the nation ill-prepared for major demographic shifts that lay ahead in coming decades. The primary purpose of this Perspectives article was to provide a new research framework for advancing Latino ADRD knowledge, encompassing the unique sociocultural, cardiometabolic, and genomic aspects of Latino health, aging, and ADRD. In addition, we describe some of the research challenges to progress in Latino ADRD research. Finally, we present the Study of Latinos – Investigation of Neurocognitive Aging (SOL-INCA) as an example of implementing this new framework for advancing Latino ADRD research.

Introduction Detecting cognitive impairment in diverse, health disparities communities is an urgent health care priority. Methods The Brooklyn Cognitive Impairments in Health Disparities Pilot Study investigated quantitative aspects and liking of a computerized cognitive performance assessment, Cognigram, among individuals ≥ 40 years in traditional and nontraditional primary care settings. Results Cognigram was piloted in the Emergency Department, Family Medicine, and Geriatric Psychiatry clinics: 58 adults (23 men, 35 women), 67.9 ± 9.8 years (range 43–91), completed the Cognigram and 5-item liking survey. The observed liking range was 2 to maximum score 5 (67% scored 4–5; no sex or age differences). Discussion The Cognigram was well liked in waiting rooms of primary care settings. Assistance from a trained adult and clinic endorsement were keys to success. How the Cognigram performs in a geographically compact, population-dense global setting, such as Brooklyn with high vascular disease risk and a plethora of health disparities, is being tested.

Introduction We estimated the prevalence and correlates of mild cognitive impairment (MCI) among middle-aged and older diverse Hispanics/Latinos. Methods Middle-aged and older diverse Hispanics/Latinos enrolled (n = 6377; 50–86 years) in this multisite prospective cohort study were evaluated for MCI using the National Institute on Aging–Alzheimer's Association diagnostic criteria. Results The overall MCI prevalence was 9.8%, which varied between Hispanic/Latino groups. Older age, high cardiovascular disease (CVD) risk, and elevated depressive symptoms were significant correlates of MCI prevalence. Apolipoprotein E4 (APOE) and APOE2 were not significantly associated with MCI. Discussion MCI prevalence varied among Hispanic/Latino backgrounds, but not as widely as reported in the previous studies. CVD risk and depressive symptoms were associated with increased MCI, whereas APOE4 was not, suggesting alternative etiologies for MCI among diverse Hispanics/Latinos. Our findings suggest that mitigating CVD risk factors may offer important pathways to understanding and reducing MCI and possibly dementia among diverse Hispanics/Latinos.

Introduction Some models of therapy for neurodegenerative diseases envision starting treatment before symptoms develop. Demonstrating that such treatments are effective requires accurate knowledge of when symptoms would have started without treatment. Familial frontotemporal lobar degeneration offers a unique opportunity to develop predictors of symptom onset. Methods We created dementia risk scores in 268 familial frontotemporal lobar degeneration family members by entering covariate-adjusted standardized estimates of brain atrophy into a logistic regression to classify asymptomatic versus demented participants. The score's predictive value was tested in a separate group who were followed up longitudinally (stable vs. converted to dementia) using Cox proportional regressions with dementia risk score as the predictor. Results Cross-validated logistic regression achieved good separation of asymptomatic versus demented (accuracy = 90%, SE = 0.06). Atrophy scores predicted conversion from asymptomatic or mildly/questionably symptomatic to dementia (HR = 1.51, 95% CI: [1.16,1.98]). Discussion Individualized quantification of baseline brain atrophy is a promising predictor of progression in asymptomatic familial frontotemporal lobar degeneration mutation carriers.

Introduction Identifying clinical measures that track disease in the earliest stages of frontotemporal lobar degeneration (FTLD) is important for clinical trials. Familial FTLD provides a unique paradigm to study early FTLD. Executive dysfunction is a clinically relevant hallmark of FTLD and may be a marker of disease progression. Methods Ninety-three mutation carriers with no symptoms or minimal/questionable symptoms (MAPT, n = 31; GRN, n = 28; C9orf72, n = 34; Clinical Dementia Rating scale plus NACC FTLD Module < 1) and 78 noncarriers enrolled through Advancing Research and Treatment in Frontotemporal Lobar Degeneration/Longitudinal Evaluation of Familial Frontotemporal Dementia Subjects studies completed the Executive Abilities: Measures and Instruments for Neurobehavioral Evaluation and Research (NIH-EXAMINER) and the UDS neuropsychological battery. Linear mixed-effects models were used to identify group differences in cognition at baseline and longitudinally. We examined associations between cognition, clinical functioning, and magnetic resonance imaging volumes. Results NIH-EXAMINER scores detected baseline and differences in slopes between carriers and noncarriers, even in carriers with a baseline Clinical Dementia Rating scale plus NACC FTLD Module = 0. NIH-EXAMINER declines were associated with worsening clinical symptoms and brain volume loss. Discussion The NIH-EXAMINER is sensitive to cognitive changes in presymptomatic familial FTLD and is a promising surrogate endpoint.

Several concepts, which in the aggregate get might be used to account for “resilience” against age- and disease-related changes, have been the subject of much research. These include brain reserve, cognitive reserve, and brain maintenance. However, different investigators have use these terms in different ways, and there has never been an attempt to arrive at consensus on the definition of these concepts. Furthermore, there has been confusion regarding the measurement of these constructs and the appropriate ways to apply them to research. Therefore the reserve, resilience, and protective factors professional interest area, established under the auspices of the Alzheimer's Association, established a whitepaper workgroup to develop consensus definitions for cognitive reserve, brain reserve, and brain maintenance. The workgroup also evaluated measures that have been used to implement these concepts in research settings and developed guidelines for research that explores or utilizes these concepts. The workgroup hopes that this whitepaper will form a reference point for researchers in this area and facilitate research by supplying a common language.

Introduction The effect of comorbid cardiometabolic diseases (CMDs), including diabetes, heart diseases, and stroke, on dementia remains unclear. Methods A cohort of 2648 dementia-free adults aged ≥60 years was followed up for 12 years. An active lifestyle was defined in accordance with the engagement in leisure activities and/or a social network. Cox models were used in data analysis. Results The multiadjusted hazard ratio (HR, 95% confidence interval) of dementia was 1.41 (1.07–1.86) for one, 2.38 (1.58–3.59) for two, and 4.76 (2.04–11.13) for three CMDs. In joint exposure analysis, the HR of dementia was 3.36 (2.14–5.30) for participants with CMDs plus an inactive lifestyle and 1.32 (0.95–1.84) for those with CMDs plus an active lifestyle (reference: no CMDs plus active lifestyle). An active lifestyle delayed dementia onset by 3.50 years in people with CMDs. Discussion CMDs, especially when comorbid, are associated with increased dementia risk; however, leisure activities and social integration mitigate this risk.

Development of disease-modifying treatments for Alzheimer's disease (AD) has been challenging, with no drugs approved to date. The failures of several amyloid-targeted programs have led many to dismiss the amyloid beta (Aβ) hypothesis of AD. An antiamyloid antibody aducanumab recently showed modest but significant efficacy in a phase 3 trial, providing important validation of amyloid as a therapeutic target. However, the inconsistent results observed with aducanumab may be explained by the limited brain penetration and lack of selectivity for the soluble Aβ oligomers, which are implicated as upstream drivers of neurodegeneration by multiple studies. Development of agents that can effectively inhibit Aβ oligomer formation or block their toxicity is therefore warranted. An ideal drug would cross the blood-brain barrier efficiently and achieve sustained brain levels that can continuously prevent oligomer formation or inhibit their toxicity. A late-stage candidate with these attributes is ALZ-801, an oral drug with a favorable safety profile and high brain penetration that can robustly inhibit Aβ oligomer formation. An upcoming phase 3 trial with ALZ-801 in APOE4/4 homozygous patients with early AD will effectively test this amyloid oligomer hypothesis.

Introduction The levels and distribution of amyloid deposits in the brain does not correlate well with Alzheimer's disease (AD) progression. Therefore, it is likely that amyloid precursor protein and its proteolytic fragments other than amyloid β (Aβ) contribute to the onset of AD. Methods We developed a sensitive assay adapted to the detection of C99, the direct precursor of β-amyloid. Three postmortem groups were studied: control with normal and stable cognition; patients with moderate AD, and individuals with severe AD. The amount of C99 and Aβ was quantified and correlated with the severity of AD. Results C99 accumulates in vulnerable neurons, and its levels correlate with the degree of cognitive impairment in patients suffering from AD. In contrast, Aβ levels are increased in both vulnerable and resistant brain areas. Discussion These results raise the possibility that C99, rather than Aβ plaques, is responsible for the death of nerve cells in AD.

Introduction Multidomain intervention for Alzheimer's disease (AD) risk reduction is an emerging therapeutic paradigm. Methods Patients were prescribed individually tailored interventions (education/pharmacologic/nonpharmacologic) and rated on compliance. Normal cognition/subjective cognitive decline/preclinical AD was classified as Prevention. Mild cognitive impairment due to AD/mild-AD was classified as Early Treatment. Change from baseline to 18 months on the modified Alzheimer's Prevention Cognitive Composite (primary outcome) was compared against matched historical control cohorts. Cognitive aging composite (CogAging), AD/cardiovascular risk scales, and serum biomarkers were secondary outcomes. Results One hundred seventy-four were assigned interventions (age 25–86). Higher-compliance Prevention improved more than both historical cohorts (P = .0012, P < .0001). Lower-compliance Prevention also improved more than both historical cohorts (P = .0088, P < .0055). Higher-compliance Early Treatment improved more than lower compliance (P = .0007). Higher-compliance Early Treatment improved more than historical cohorts (P < .0001, P = .0428). Lower-compliance Early Treatment did not differ (P = .9820, P = .1115). Similar effects occurred for CogAging. AD/cardiovascular risk scales and serum biomarkers improved. Discussion Individualized multidomain interventions may improve cognition and reduce AD/cardiovascular risk scores in patients at-risk for AD dementia.

Introduction Odor identification deficits characterize Alzheimer's disease and other dementias. We examined if intact performance on brief cognitive and odor identification tests predicts lack of transition to dementia. Methods In an urban community, 1037 older adults without dementia completed the 40-item University of Pennsylvania Smell Identification Test, which includes the 12-item Brief Smell Identification Test (B-SIT). Data from 749 participants followed up for 4 years were analyzed. Results In covariate-adjusted survival analyses, impairment on the Blessed Orientation Memory Concentration Test and B-SIT each predicted dementia (n = 109), primarily Alzheimer's disease (n = 101). Among participants with intact olfactory (B-SIT ≥ 11/12 correct) and cognitive (Blessed Orientation Memory Concentration Test ≤ 5/28 incorrect) ability, 3.4% (4/117) transitioned to dementia during follow-up with no transitions in the 70–75 and 81–83 years age group quartiles. Discussion Odor identification testing adds value to global cognitive testing, and together can identify individuals who rarely transition to dementia, thereby avoiding unnecessary diagnostic investigation.

Introduction This study aimed to determine if later birth year influences trajectory of age-related cognitive decline across racial/ethnic groups and to test whether years of school, childhood socioeconomic status, and cardiovascular disease burden explain such secular trends. Methods We compared cognitive trajectories of global cognition and subdomains in two successive racially/ethnically and educationally diverse birth cohorts of a prospective cohort study. Results Later birth year was associated with higher initial cognitive levels for Whites and Blacks, but not Hispanics. Later birth year was also associated with less rapid rate of decline in all three racial/ethnic groups. More years of education, higher childhood socioeconomic status, and, to a smaller extent, greater cardiovascular disease burden accounted for higher intercepts in the later-born cohort, but did not account for attenuated slope of cognitive decline. Discussion Later birth year is related to a slower rate of age-related decline in some cognitive domains in some racial/ethnic groups. Our analyses suggest that racial/ethnic and social inequalities are part of the mechanisms driving secular trends in cognitive aging and dementia.

Introduction Differential patterns of brain atrophy on structural magnetic resonance imaging (MRI) revealed four reproducible subtypes of Alzheimer's disease (AD): (1) “typical”, (2) “limbic-predominant”, (3) “hippocampal-sparing”, and (4) “mild atrophy”. We examined the neurobiological characteristics and clinical progression of these atrophy-defined subtypes. Methods The four subtypes were replicated using a clustering method on MRI data in 260 amyloid-β–positive patients with mild cognitive impairment or AD dementia, and we subsequently tested whether the subtypes differed on [18F]flortaucipir (tau) positron emission tomography, white matter hyperintensity burden, and rate of global cognitive decline. Results Voxel-wise and region-of-interest analyses revealed the greatest neocortical tau load in hippocampal-sparing (frontoparietal-predominant) and typical (temporal-predominant) patients, while limbic-predominant patients showed particularly high entorhinal tau. Typical patients with AD had the most pronounced white matter hyperintensity load, and hippocampal-sparing patients showed the most rapid global cognitive decline. Discussion Our data suggest that structural MRI can be used to identify biologically and clinically meaningful subtypes of AD.

Introduction Synaptic damage, axonal neurodegeneration, and neuroinflammation are common features in Alzheimer's disease (AD), frontotemporal dementia (FTD), and Creutzfeldt-Jakob disease (CJD). Methods Unicentric cohort of 353 participants included healthy control (HC) subjects, AD continuum stages, genetic AD and FTD, and FTD and CJD. We measured cerebrospinal fluid neurofilament light (NF-L), neurogranin (Ng), 14-3-3, and YKL-40 proteins. Results Biomarkers showed differences in HC subjects versus AD, FTD, and CJD. Disease groups differed between them except AD versus FTD for YKL-40. Only NF-L differed between all stages within the AD continuum. AD and FTD symptomatic mutation carriers presented differences with respect to HC subjects. Applying the AT(N) system, 96% subjects were positive for neurodegeneration if 14-3-3 was used, 94% if NF-L was used, 62% if Ng was used, and 53% if YKL-40 was used. Discussion Biomarkers of synapse and neurodegeneration differentiate HC subjects from neurodegenerative dementias and between AD, FTD, and CJD. NF-L and 14-3-3 performed similar to total tau when AT(N) system was applied.

Introduction Alzheimer's disease (AD) is linked to neuronal calcium dyshomeostasis, which is associated with network hyperexcitability. Decreased expression of the calcium-binding protein calbindin-D28K (CB) might be a susceptibility factor for AD. The subiculum is affected early in AD, for unknown reasons. Methods In AD, CB knock-out and control mice fluorescence Ca2+ imaging combined with patch clamp were used to characterize Ca2+ dynamics, resting Ca2+, and Ca2+-buffering capacity in subicular neurons. CB expression levels in wild-type and AD mice were also analyzed. Results The subiculum and dentate gyrus of wild-type mice showed age-related decline in CB expression not observed in AD mice. Resting Ca2+ and Ca2+-buffering capacity was increased in aged AD mice subicular dendrites. Modeling suggests that AD calcium changes can be explained by alterations of Ca2+ extrusion pumps rather than by buffers. Discussion Overall, abnormal Ca2+ homeostasis in AD has an age dependency that comprises multiple mechanisms, including compensatory processes.

Introduction Sensor-based assessment of challenging behaviors in dementia may be useful to support caregivers. Here, we investigated accelerometry as tool for identification and prediction of challenging behaviors. Methods We set up a complex data recording study in two nursing homes with 17 persons in advanced stages of dementia. Study included four-week observation of behaviors. In parallel, subjects wore sensors 24 h/7 d. Participants underwent neuropsychological assessment including Mini–Mental State Examination and Cohen-Mansfield Agitation Inventory. Results We calculated the accelerometric motion score (AMS) from accelerometers. The AMS was associated with several types of agitated behaviors and could predict subject's Cohen-Mansfield Agitation Inventory values. Beyond the mechanistic association between AMS and behavior on the group level, the AMS provided an added value for prediction of behaviors on an individual level. Discussion We confirm that accelerometry can provide relevant information about challenging behaviors. We extended previous studies by differentiating various types of agitated behaviors and applying long-term measurements in a real-world setting.

Introduction Three cerebrospinal fluid (CSF) markers of neurodegeneration (N) (neurofilament light [NfL], total-tau [T-tau], and neurogranin [Ng]) have been proposed under the AT(N) scheme of the National Institute on Aging–Alzheimer's Association Research Framework. Methods We examined, in a community-based population (N = 777, aged 50–95) (1) what variables were associated with each of the CSF (N) markers, and (2) whether the variables associated with each marker differed by increased brain amyloid. CSF T-tau was measured with an automated electrochemiluminescence Elecsys immunoassay; NfL and Ng were measured with in-house enzyme-linked immunosorbent assays. Results Multiple variables were differentially associated with CSF NfL and T-tau levels, but not Ng. Most associations were attenuated after adjustment for age and sex. T-tau had the strongest association with cognition in the presence of amyloidosis, followed by Ng. Variables associations with NfL did not differ by amyloid status. Discussion Understanding factors that influence CSF (N) markers will assist in the interpretation and utility of these markers in clinical practice.

Introduction Frontotemporal lobar degeneration (FTLD) is the most common form of dementia for those under 60 years of age. Increasing numbers of therapeutics targeting FTLD syndromes are being developed. Methods In March 2018, the Association for Frontotemporal Degeneration convened the Frontotemporal Degeneration Study Group meeting in Washington, DC, to discuss advances in the clinical science of FTLD. Results Challenges exist for conducting clinical trials in FTLD. Two of the greatest challenges are (1) the heterogeneity of FTLD syndromes leading to difficulties in efficiently measuring treatment effects and (2) the rarity of FTLD disorders leading to recruitment challenges. Discussion New personalized endpoints that are clinically meaningful to individuals and their families should be developed. Personalized approaches to analyzing MRI data, development of new fluid biomarkers and wearable technologies will help to improve the power to detect treatment effects in FTLD clinical trials and enable new, clinical trial designs, possibly leveraged from the experience of oncology trials. A computational visualization and analysis platform that can support novel analyses of combined clinical, genetic, imaging, biomarker data with other novel modalities will be critical to the success of these endeavors.

Objective Understanding the heterogeneous pathology in Alzheimer's disease and related tauopathies is one of the most urgent and fundamental challenges facing the discovery of novel disease-modifying therapies. Through monitoring ensembles of toxic and nontoxic tau oligomers spontaneously formed in cells, our biosensor technology can identify tool compounds that modulate tau oligomer structure and toxicity, providing much needed insight into the nature and properties of toxic tau oligomers. Background Tauopathies are a group of neurodegenerative disorders characterized by pathologic aggregation of the microtubule binding protein tau. Recent studies suggest that tau oligomers are the primary toxic species in tauopathies. New/Updated Hypothesis We hypothesize that tau biosensors capable of monitoring tau oligomer conformation are able to identify tool compounds that modulate the structure and conformation of these tau assemblies, providing key insight into the unique structural fingerprints of toxic tau oligomers. These fingerprints will provide gravely needed biomarker profiles to improve staging of early tauopathy pathology and generate lead compounds for potential new therapeutics. Our time-resolved fluorescence resonance energy transfer biosensors provide us an exquisitely sensitive technique to monitor minute structural changes in monomer and oligomer conformation. In this proof-of-concept study, we identified a novel tool compound, MK-886, which directly binds tau, perturbs the conformation of toxic tau oligomers, and rescues tau-induced cytotoxicity. Furthermore, we show that MK-886 alters the conformation of tau monomer at the proline-rich and microtubule binding regions, stabilizing an on-pathway oligomer. Major Challenges for the Hypothesis Our approach monitors changes in the ensemble of assemblies that are spontaneously formed in cells but does not specifically isolate or enrich unique toxic tau species. However, time-resolved fluorescence resonance energy transfer does not provide high-resolution, atomic scale information, requiring additional experimental techniques to resolve the structural features stabilized by different tool compounds. Linkage to Other Major Theories Our biosensor technology is broadly applicable to other areas of tauopathy therapeutic development. These biosensors can be readily modified for different isoforms of tau, specific post-translational modifications, and familial Alzheimer's disease–associated mutations. We are eager to explore tau interactions with chaperone proteins, monitor cross-reactivity with other intrinsically disordered proteins, and target seeded oligomer pathology.

Introduction It is important to establish the natural history of familial frontotemporal lobar degeneration (f-FTLD) and provide clinical and biomarker data for planning these studies, particularly in the asymptomatic phase. Methods The Longitudinal Evaluation of Familial Frontotemporal Dementia Subjects protocol was designed to enroll and follow at least 300 subjects for more than at least three annual visits who are members of kindreds with a mutation in one of the three most common f-FTLD genes—microtubule-associated protein tau, progranulin, or chromosome 9 open reading frame 72. Results We present the theoretical considerations of f-FTLD and the aims/objectives of this protocol. We also describe the design and methodology for evaluating and rating subjects, in which detailed clinical and neuropsychological assessments are performed, biofluid samples are collected, and magnetic resonance imaging scans are performed using a standard protocol. Discussion These data and samples, which are available to interested investigators worldwide, will facilitate planning for upcoming disease-modifying therapeutic trials in f-FTLD.

Introduction Multiple immunity biomarkers have been suggested as tracers of neuroinflammation in neurodegeneration. This study aimed to verify findings in cerebrospinal fluid (CSF) samples of Alzheimer's disease (AD) and Parkinson's disease (PD) subjects from the network of the European, Innovative Medicines Initiative–funded project AETIONOMY. Methods A total of 227 samples from the studies/centres AETIONOMY, ICEBERG, and IDIBAPS were used to analyse 21 selected immunity biomarkers in CSF. Results were compared to data of an independent cohort of 399 subjects previously published. Results Immunity markers were predominantly and reproducibly associated with pathological levels of tau isoforms, but also with amyloid levels, aging, sex, APOE genotype, and center-specific factors. Discussion Immunity biomarker levels in CSF reflect molecular and cellular pathology rather than diagnosis in neurodegenerative disorders. Assay standardization and stratification for age and other covariates could improve the power of such markers in clinical applications or intervention studies targeting immune responses in neurodegeneration.

Introduction Successful development of effective β-site amyloid precursor protein cleaving enzyme 1 (BACE1)–targeted therapies for early stages of Alzheimer's disease requires biomarker-guided intervention strategies. Methods We investigated whether key biological factors such as sex, apolipoprotein E (APOE ε4) allele, and age affect longitudinal plasma BACE1 concentrations in a large monocenter cohort of individuals at risk for Alzheimer's disease. We explored the relationship between plasma BACE1 concentrations and levels of brain amyloid-β (Aβ) deposition, using positron emission tomography global standard uptake value ratios. Results Baseline and longitudinal mean concentrations of plasma BACE1 were significantly higher in women than men. We also found a positive significant impact of plasma BACE1 on baseline Aβ–positron emission tomography global standard uptake value ratios. Discussion Our results suggest a sexual dimorphism in BACE1-related upstream mechanisms of brain Aβ production and deposition. We argue that plasma BACE1 should be considered in further biomarker validation and qualification studies as well as in BACE1 clinical trials.

Introduction We investigated the relation between self-reported hearing loss and risk of subjective cognitive function (SCF) decline among women. Methods We conducted a longitudinal study of 20,193 women in the Nurses' Health Study aged ≥66 years who reported their hearing status and had no subjective cognitive concerns in 2012. SCF scores were assessed by a 7-item questionnaire in 2012 and 2014. SCF decline was defined as a new report of at least one cognitive concern during follow-up. Results Self-reported hearing loss was associated with higher risk of SCF decline. Compared with women with no hearing loss, the multivariable-adjusted odds ratios (95% confidence interval) for incident SCF score ≥1 were 1.35 (1.25, 1.47), 1.39 (1.24, 1.56), and 1.40 (1.21, 1.75) among women with mild, moderate, and severe hearing loss, respectively. Recent progression of hearing loss was associated with even higher risk. Discussion Self-reported hearing loss was associated with higher risk of incident subjective cognitive function decline in women.

Introduction Prospective studies reporting associations between cognitive performance and subsequent incident dementia have been subject to attrition bias. Furthermore, the extent to which established risk factors account for such associations requires further elucidation. Methods We used UK Biobank baseline cognitive data (n ≤ 488,130) and electronically linked hospital inpatient and death records during three- to eight-year follow-up, to estimate risk of total dementia (n = 1051), Alzheimer's disease (n = 352), and vascular dementia (n = 169) according to four brief cognitive tasks, with/without adjustment for constitutional and modifiable risk factors. Results We found associations of cognitive task performance with all-cause and cause-specific dementia (P < .01); these were not accounted for by established risk factors. Cognitive data added up to 5% to the discriminative accuracy of receiver operating characteristic curve models; areas under the curve ranged from 82% to 86%. Discussion This study offers robust evidence that brief cognitive testing could be a valuable addition to dementia prediction models.

Introduction Alzheimer's disease (AD) has a long prodromal stage and identifying high-risk individuals is critical. We aimed to investigate the ability of Aβ misfolding in blood plasma, APOE4 status, and dementia risk factors to predict diagnosis of AD. Methods Within a community-based cohort, Aβ misfolding in plasma measured by immuno-infrared sensor and APOE genotype were determined at baseline in 770 participants followed over 14 years. Associations between Aβ misfolding, APOE4, and other predictors with clinical AD, vascular dementia, and mixed dementia diagnoses were assessed. Results Aβ misfolding was associated with a 23-fold increased odds of clinical AD diagnosis within 14 years. No association was observed with vascular dementia/mixed dementia diagnoses. APOE4-positive participants had a 2.4-fold increased odds of clinical AD diagnosis within 14 years. Discussion Aβ misfolding in blood plasma was a strong, specific risk prediction marker for clinical AD even many years before diagnosis in a community-based setting.

Introduction To determine if sleep-disordered breathing (SDB), daytime sleepiness, insomnia, and sleep duration predict seven-year neurocognitive decline in US Hispanics/Latinos (N = 5247). Methods The exposures were baseline SDB, daytime sleepiness, insomnia, and sleep duration. The outcomes were change in episodic learning and memory (B-SEVLT-Sum and SEVLT-Recall), language (word fluency [WF]), processing speed (Digit Symbol Substitution), and a cognitive impairment screener (Six-item Screener [SIS]). Results Mean age was 63 ± 8 years, with 55% of the population being female with 7.0% Central American, 24.5% Cuban, 9.3% Dominican, 35.9% Mexican, 14.4% Puerto Rican, and 5.1% South American background. Long sleep (>9 hours), but not short sleep (<6 hours), was associated with decline (standard deviation units) in episodic learning and memory (βSEVLT-Sum = −0.22 [se = 0.06]; P < .001; βSEVLT-Recall = −0.13 [se = 0.06]; P < .05), WF (βWF = −0.20 [se = 0.06]; P < .01), and SIS (βSIS = −0.16 [se = 0.06]; P < .01), but not processing speed, after adjusting for covariates. SDB, sleepiness, and insomnia were not associated with neurocognitive decline. Conclusion Long sleep duration predicted seven-year cognitive decline.

Introduction The present study sought to determine whether cognitive trajectories differ between men and women across and within racial/ethnic groups. Methods Participants were 5258 non-Hispanic White (NHW), Black, and Hispanic men and women in the Washington/Hamilton Heights-Inwood Columbia Aging Project who were administered neuropsychological tests of memory, language, and visuospatial abilities at 18- to 24-month intervals for up to 25 years. Multiple-group latent growth curve modeling examined trajectories across sex/gender by race/ethnicity. Results After adjusting for age and education, the largest baseline differences were between NHW men and Hispanic women on visuospatial and language, and between NHW women and Black men on memory. Memory and visuospatial decline was steeper for Black women compared with Hispanic men and NHW women, respectively. Discussion This study takes an important first step in understanding interactions between race/ethnicity and sex/gender on cognitive trajectories by demonstrating variability in sex/gender differences across race/ethnicity.

Introduction Although the relationship between APOE and Alzheimer's disease (AD) is well established in populations of European descent, the effects of APOE and ancestry on AD risk in diverse populations is not well understood. Methods Logistic mixed model regression and survival analyses were performed in a sample of 3067 Caribbean Hispanics and 3028 individuals of European descent to assess the effects of APOE genotype, local ancestry, and genome-wide ancestry on AD risk and age at onset. Results Among the Caribbean Hispanics, individuals with African-derived ancestry at APOE had 39% lower odds of AD than individuals with European-derived APOE, after adjusting for APOE genotype, age, and genome-wide ancestry. While APOE E2 and E4 effects on AD risk and age at onset were significant in the Caribbean Hispanics, they were substantially attenuated compared with those in European ancestry individuals. Discussion These results suggest that additional genetic variation in the APOE region influences AD risk beyond APOE E2/E3/E4.

Introduction We examined the influence of enrollment factors demonstrated to differ by race on incident mild cognitive impairment and dementia using Alzheimer's Disease Center data. Methods Differences in rates of incident impairment between non-Latino Whites and Blacks (n = 12,242) were examined with age-at-progression survival models. Models included race, sex, education, source of recruitment, health factors, and family history of dementia. Results No significant race differences in progression were observed in cognitively unimpaired participants. In those with mild cognitive impairment at baseline, Whites evidenced greater risk for progression than Blacks. Enrollment factors, for example, referral source, were significantly related to progression. Discussion The finding that Blacks demonstrated lower rate of progression than Whites is contrary to the extant literature. Nested-regression analyses suggested that selection-related factors, differing by race, may account for these findings and influence our ability to accurately estimate risk for progression. It is potentially problematic to make racial comparisons using Alzheimer's Disease Center data sets.

Introduction The objective of this study was to assess the usefulness of the appropriate use criteria (AUC) for amyloid imaging in an unselected cohort. Methods We calculated sensitivity and specificity of appropriate use (increased confidence and management change), as defined by Amyloid Imaging Taskforce in the AUC, and other clinical utility outcomes. Furthermore, we compared differences in post–positron emission tomography diagnosis and management change between “AUC-consistent” and “AUC-inconsistent” patients. Results Almost half (250/507) of patients were AUC-consistent. In both AUC-consistent and AUC-inconsistent patients, post–positron emission tomography diagnosis (28%–21%) and management (32%–17%) change was substantial. The Amyloid Imaging Taskforce's definition of appropriate use occurred in 55/507 (13%) patients, detected by the AUC with a sensitivity of 93%, and a specificity of 56%. Diagnostic changes occurred independently of AUC status (sensitivity: 57%, specificity: 53%). Discussion The current AUC are not sufficiently able to discriminate between patients who will benefit from amyloid positron emission tomography and those who will not.

Introduction The associations between self-reported current and past leisure time physical activity (LTPA) and Alzheimer's disease (AD) incidence were determined using data from the multiethnic Washington/Hamilton Heights-Inwood Columbia Aging Project (WHICAP) study. Methods The metabolic equivalent of LTPA energy expenditure was calculated for self-reported current and past LTPA for 1345 older adults. A Cox proportional hazard model was conducted to estimate the association between LTPA (low, middle, and high) and incident AD risk. Results Comparing high to low level, current and past LTPA were both associated with reduced AD risk, with hazard ratio (95% confidence interval) = 0.39 (0.20–0.75) and 0.37 (0.18–0.75), respectively. Compared with “always low,” “increased” and “always high” LTPA throughout life were associated with reduced AD risk, with hazard ratio (95% confidence interval) = 0.60 (0.36–0.99) and 0.28 (0.08–0.94), respectively. Light- and moderate-intensity LTPA were associated with lower AD risk. Discussion LTPA both throughout life and later in life are associated with lower risk of AD.

Introduction Alzheimer's disease (AD) is a disabling, common cause of dementia, and agitation is one of the most common and distressing symptoms for patients with AD. Escitalopram for agitation in Alzheimer's disease (S-CitAD) tests a novel, clinically derived therapeutic approach to treat agitation in patients with AD. Methods S-CitAD is a NIH-funded, investigator-initiated, randomized, multicenter clinical trial. Participants receive a structured psychosocial intervention (PSI) as standard of care. Participants without sufficient response to PSI are randomized to receive 15 mg escitalopram/day or a matching placebo in addition to PSI. Primary outcome is the Modified Alzheimer's Disease Cooperative Study - Clinical Global Impression of Change (mADCS-CGIC). Discussion S-CitAD will provide information about a practical, immediately available approach to treating agitation in patients with AD. S-CitAD may become a model of how to evaluate and predict treatment response in patients with AD and agitation as a neuropsychiatric symptom (ClinicalTrials.gov Identifier: NCT03108846).

Introduction The aim of this study was to investigate the registry-based national time trends in incidence and prevalence rates of dementia from 1996 to 2015. Methods We assessed annual incidence and prevalence using longitudinal data from nationwide registries on dementia status and demographics on all residents ≥ 65 years old in Denmark. Results Our population comprised 2 million people, of whom 152,761 were diagnosed with dementia. The age- and sex-adjusted incidence rate increased, on average, by 9% annually from 1996 to 2003, followed by a 2% annual decline, while total prevalence increased during the whole period. Discussion This is the first study to report continuous time trends of incidence and prevalence in an entire national population. The incidence rate has declined steadily since 2003, while the total prevalence is still increasing. Future health care planning on prevention and treatment of dementia should take these findings into account.

The 2018 National Institute on Aging and the Alzheimer's Association (NIA-AA) research framework recently redefined Alzheimer's disease (AD) as a biological construct, based on in vivo biomarkers reflecting key neuropathologic features. Combinations of normal/abnormal levels of three biomarker categories, based on single thresholds, form the AD signature profile that defines the biological disease state as a continuum, independent of clinical symptomatology. While single thresholds may be useful in defining the biological signature profile, we provide evidence that their use in studies with cognitive outcomes merits further consideration. Using data from the Alzheimer's Disease Neuroimaging Initiative with a focus on cortical amyloid binding, we discuss the limitations of applying the biological definition of disease status as a tool to define the increased likelihood of the onset of the Alzheimer's clinical syndrome and the effects that this may have on trial study design. We also suggest potential research objectives going forward and what the related data requirements would be.

Introduction The prevalence, mortality, and healthcare impact of Alaska Native and American Indian (ANAI) people with Alzheimer's disease and related dementias (ADRD) are unknown. Methods We conducted a cohort study of electronic health record data that compared healthcare service utilization in patients with and without an ADRD diagnosis. Zero-inflated negative binomial regression with robust standard errors was used to estimate utilization rates. Results Compared with patients without ADRD, utilization rates were similar before but higher after ADRD diagnosis. For those with diagnosed ADRD, utilization increased gradually over time with sharp upward change during the year of diagnosis. Discussion This is the only study quantifying changes in healthcare service utilization before and after ADRD diagnosis among ANAI people, which is crucial for tailoring geriatric care for ANAI populations.

Introduction Questions remain about whether apolipoprotein E (APOE)-ε4 effects on cognitive decline are similar in men and women and how APOE-ε4 and age interact to influence decline in different cognitive domains. Methods In sex-stratified analyses, baseline age-dependent associations between APOE-ε4 status and longitudinal cognitive trajectories were examined in cognitively normal Caucasian older adults (631 men, 561 women, baseline age range: 50–93, 6733 assessments). Results In men, older baseline age was associated with greater effects of APOE-ε4 on longitudinal decline in memory and executive function, detectible from baseline age of 64 and 68, respectively. In women, older baseline age was associated with greater APOE-ε4 effects on longitudinal decline in attention, detectible at baseline age of 66. No significant APOE-ε4 effects were found for language, visual-spatial ability, or processing speed. Discussion Results highlight the importance of considering sex and age when assessing APOE-ε4–associated vulnerability to cognitive decline.

Introduction The Multidomain Alzheimer Preventive Trial (MAPT) assessed the efficacy of omega-3 fatty acid supplementation, a multidomain intervention (MI), or a combination of both on cognition. Impact according to cerebral amyloid status was evaluated by PET scan. Methods Participants were nondemented and had memory complaints, limitation in one instrumental activity of daily living, or slow gait. The primary outcome was a change from baseline in 36 months measured with a cognitive composite Z score. Results No effect was observed on cognition in the negative amyloid group (n = 167). In the positive amyloid group (n = 102), we observed a difference of 0.708 and 0.471 in the cognitive composite score between the MI plus omega-3 fatty acid group, the MI alone group, and the placebo group, respectively. Discussion MI alone or in combination with omega-3 fatty acids was associated with improved primary cognitive outcome in subjects with positive amyloid status. Trial Registration ClinicalTrials.gov Identifier: NCT01513252.

Objective We aimed to refine the hypothesis that dementia has a unique signature of gait impairment reflective of underlying pathology by considering two dementia subtypes, Alzheimer's disease (AD) and Lewy body disease (LBD), and exploring the role of cognition in disease-specific gait impairments. Background Accurately differentiating AD and LBD is important for treatment and disease management. Early evidence suggests gait could be a marker of dementia due to associations between discrete gait characteristics and cognitive domains. Updated Hypothesis We hypothesize that AD and LBD have unique signatures of gait, reflecting disease-specific cognitive profiles and underlying pathologies. An exploratory study included individuals with mild cognitive impairment or dementia due to LBD (n = 45) and AD (n = 36) and 29 older adult controls. An instrumented walkway quantified 16 gait characteristics reflecting five independent domains of locomotion (pace, rhythm, variability, asymmetry, and postural control). The LBD group demonstrated greater impairments in asymmetry and variability compared with AD; both groups were more impaired in pace and variability domains than controls. Executive dysfunction explained 11% of variance for gait variability in LBD, whereas global cognitive impairment explained 13.5% of variance in AD; therefore, gait impairments may reflect disease-specific cognitive profiles. With a refined hypothesis that AD- and LBD-specific signatures of gait reflect discrete pathologies, future studies must examine the relationship between a validated model of gait with neural networks, using recognized biomarkers and postmortem follow-up. Major Challenges for Hypothesis Differential diagnosis of AD and LBD used appropriate criteria and required consensus from an expert diagnostic panel to improve diagnostic accuracy. Future work should follow the framework set out in Parkinson's disease to establish unique signatures of gait as proxy measures of disease-specific pathology; that is, use a validated gait model to explore the progressive relationship between gait, cognition, and pathology. Linkage to Other Major Theories These exploratory findings support the theory of interacting cognitive-motor networks, as the gait-cognition relationship may reflect cognitive control over motor networks. Unique signatures of gait may reflect different temporal patterns of pathological burden in neural areas related to cognitive and motor function.

Introduction Environmental factors are poorly understood in the etiology of Alzheimer's disease (AD) and related dementias. The importance of environmental factors in gene environment interactions (GxE) is suggested by wide individual differences in cognitive loss, even for carriers of AD-risk genetic variants. Results and Discussion We propose the “AD exposome” to comprehensively assess the modifiable environmental factors relevant to genetic underpinnings of cognitive aging and AD. Analysis of endogenous and exogenous environmental factors requires multi-generational consideration of these interactions over age and time (GxExT). New computational approaches to the multi-level complexities may identify accessible interventions for individual brain aging. International collaborations on diverse populations are needed to identify the most relevant exposures over the life course for GxE interactions.

Introduction Poor gait has recently emerged as a potential prodromal feature of cognitive decline and dementia. We assessed to what extent various aspects of poor gait are independently associated with cognitive decline and incident dementia. Methods We leveraged detailed quantitative gait (GAITRite™) and cognitive assessments in 4258 dementia-free participants (median age 67 years, 55% women) of the population-based Rotterdam Study (baseline 2009–2013). We summarized 30 gait parameters into seven mutually independent gait domains and a Global Gait score. Participants underwent follow-up cognitive assessments between 2014 and 2016 and were followed up for incident dementia until 2016 (median 4 years). Results Three independent gait domains (Base of Support, Pace, and Rhythm) and Global Gait were associated with cognitive decline. Two independent gait domains (Pace and Variability) and Global Gait were associated with incident dementia. Associations of gait with cognitive decline and incident dementia were only present in individuals who had been cognitively unimpaired at baseline. Discussion Poor performance on several independent gait domains precedes cognitive decline and incident dementia.

Introduction Individuals with homozygosity for the apolipoprotein E (APOE) ε4 allele are in the highest risk category for late-onset Alzheimer's disease (LOAD). However, some individuals in this category do not develop LOAD beyond the age of 75 years, despite being at elevated genetic risk. These “resilient” individuals may carry protective genetic factors. Methods This study aimed to systematically review any previous studies that involved resilient APOE ε4 homozygotes and to identify possible modifying or protective genetic factors. Results Fifteen studies met our inclusion criteria and reported genetic factors contributing to reduced risk. We found that only two single nucleotide polymorphisms, CASP7 rs10553596 and SERPINA3 rs4934-A/A, had strong evidence. Discussion We found a paucity of studies adequately designed to discover protective genetic factors against LOAD. Many studies combined APOE ε4 homozygotes and heterozygotes together because of small sample sizes and used control populations too young to be clearly defined as controls for LOAD.

Introduction Large longitudinal biomarkers database focusing on middle age is needed for Alzheimer's disease (AD) prevention. Methods Data for cerebrospinal fluid analytes, molecular imaging of cerebral fibrillar β-amyloid with positron emission tomography, magnetic resonance imaging–based brain structures, and clinical/cognitive outcomes were harmonized across eight AD biomarker studies. Statistical power was estimated. Results The harmonized database included 7779 participants with clinical/cognitive data: 3542 were 18∼65 years at the baseline, 5865 had longitudinal cognitive data for a median of 4.7 years, 2473 participated in the cerebrospinal fluid studies (906 had longitudinal data), 2496 participated in the magnetic resonance imaging studies (1283 had longitudinal data), and 1498 participated in the positron emission tomography amyloid studies (849 had longitudinal data). The database provides adequate power for detecting early biomarker changes, and demonstrates the feasibility of AD prevention trials on middle-aged individuals. Discussion The harmonized database is an optimum resource to design AD prevention trials decades before symptomatic onset.

Introduction It is unclear the degree to which tau pathology in the medial temporal lobe (MTL) measured by 18F-flortaucipir positron emission tomography relates to MTL subregional atrophy and whether this relationship differs between amyloid-β–positive and amyloid-β–negative individuals. Methods We analyzed correlation of MTL 18F-flortaucipir uptake with MTL subregional atrophy measured with high-resolution magnetic resonance imaging in a region of interest and regional thickness analysis and determined the relationship between memory performance and positron emission tomography and magnetic resonance imaging measures. Results Both groups showed strong correlations between 18F-flortaucipir uptake and atrophy, with similar spatial patterns. Effects in the rhinal cortex recapitulated Braak staging. Correlations of memory recall with atrophy and tracer uptake were observed. Discussion Correlation patterns between tau burden and atrophy in the amyloid-β–negative group mimicking early Braak stages suggests that 18F-flortaucipir is sensitive to tau pathology in primary age-related tauopathy. Correlations of imaging measures with memory performance indicate that this pathology is associated with poorer cognition.

Introduction Several microRNAs (miRNAs) have been implicated in Alzheimer's disease pathogenesis, but the evidence from individual case-control studies remains inconclusive. Methods A systematic literature review was performed, followed by standardized multistage data extraction, quality control, and meta-analyses on eligible data for brain, blood, and cerebrospinal fluid specimens. Results were compared with miRNAs reported in the abstracts of eligible studies or recent qualitative reviews to assess novelty. Results Data from 147 independent data sets across 107 publications were quantitatively assessed in 461 meta-analyses. Twenty-five, five, and 32 miRNAs showed studywide significant differential expression (α < 1·08 × 10−4) in brain, cerebrospinal fluid, and blood-derived specimens, respectively, with 5 miRNAs showing differential expression in both brain and blood. Of these 57 miRNAs, 13 had not been reported in the abstracts of previous original or review articles. Discussion Our systematic assessment of differential miRNA expression is the first of its kind in Alzheimer's disease and highlights several miRNAs of potential relevance.

Introduction Plasma proteins have been widely studied as candidate biomarkers to predict brain amyloid deposition to increase recruitment efficiency in secondary prevention clinical trials for Alzheimer's disease. Most such biomarker studies are targeted to specific proteins or are biased toward high abundant proteins. Methods 4001 plasma proteins were measured in two groups of participants (discovery group = 516, replication group = 365) selected from the European Medical Information Framework for Alzheimer's disease Multimodal Biomarker Discovery study, all of whom had measures of amyloid. Results A panel of proteins (n = 44), along with age and apolipoprotein E (APOE) ε4, predicted brain amyloid deposition with good performance in both the discovery group (area under the curve = 0.78) and the replication group (area under the curve = 0.68). Furthermore, a causal relationship between amyloid and tau was confirmed by Mendelian randomization. Discussion The results suggest that high-dimensional plasma protein testing could be a useful and reproducible approach for measuring brain amyloid deposition.