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INTRODUCTION: Sodium‐glucose cotransporter 2 (SGLT2) inhibitors exhibit potential benefits in reducing dementia risk, yet the optimal beneficiary subgroups remain uncertain. METHODS: Individuals with type 2 diabetes (T2D) initiating either SGLT2 inhibitor or sulfonylurea were identified from OneFlorida+ Clinical Research Network (2016–2022). A doubly robust learning was deployed to estimate risk difference (RD) and 95% confidence interval (CI) of all‐cause dementia. RESULTS: Among 35,458 individuals with T2D, 1.8% in the SGLT2 inhibitor group and 4.7% in the sulfonylurea group developed all‐cause dementia over a 3.2‐year follow‐up, yielding a lower risk for SGLT2 inhibitors (RD, –2.5%; 95% CI, –3.0% to –2.1%). Hispanic ethnicity and chronic kidney disease were identified as the two important variables to define four subgroups in which RD ranged from –4.3% (–5.5 to –3.2) to –0.9% (–1.9 to 0.2). DISCUSSION: Compared to sulfonylureas, SGLT2 inhibitors were associated with a reduced risk of all‐cause dementia, but the association varied among different subgroups. Highlights: New users of sodium‐glucose cotransporter 2 (SGLT2) inhibitors were significantly associated with a lower risk of all‐cause dementia as compared to those of sulfonylureas.The association varied among different subgroups defined by Hispanic ethnicity and chronic kidney disease.A significantly lower risk of Alzheimer's disease and vascular dementia was observed among new users of SGLT2 inhibitors compared to those of sulfonylureas. [ABSTRACT FROM AUTHOR]

INTRODUCTION: Limited evidence exists on the associations of discontinuing versus continuing long‐term opioid therapy (LTOT) with pain intensity, physical function, and depression among patients with Alzheimer's disease and related dementias (ADRD). METHODS: A cohort study among 138,059 older residents with mild‐to‐moderate ADRD and receipt of LTOT was conducted using a 100% Medicare nursing home sample. Discontinuation of LTOT was defined as no opioid refills for ≥ 60 days. Outcomes were worsening pain, physical function, and depression from baseline to quarterly assessments during 1‐ and 2‐year follow‐ups. RESULTS: The adjusted odds of worsening pain and depressive symptoms were 29% and 5% lower at the 1‐year follow‐up and 35% and 9% lower at the 2‐year follow‐up for residents who discontinued versus continued LTOT, with no difference in physical function. DISCUSSION: Discontinuing LTOT was associated with lower short‐ and long‐term worsening pain and depressive symptoms than continuing LTOT among older residents with ADRD. Highlights: Discontinuing long‐term opioid therapy (LTOT) was associated with lower short‐ and long‐term worsening pain.Discontinuing LTOT was related to lower short‐ and long‐term worsening depression.Discontinuing LTOT was not associated with short‐ and long‐term physical function. [ABSTRACT FROM AUTHOR]

INTRODUCTION: Little is known about the heterogeneous treatment effects of metformin on dementia risk in people with type 2 diabetes (T2D). METHODS: Participants (≥ 50 years) with T2D and normal cognition at baseline were identified from the National Alzheimer's Coordinating Center database (2005–2021). We applied a doubly robust learning approach to estimate risk differences (RD) with a 95% confidence interval (CI) for dementia risk between metformin use and no use in the overall population and subgroups identified through a decision tree model. RESULTS: Among 1393 participants, 104 developed dementia over a 4‐year median follow‐up. Metformin was significantly associated with a lower risk of dementia in the overall population (RD, –3.2%; 95% CI, –6.2% to –0.2%). We identified four subgroups with varied risks for dementia, defined by neuropsychiatric disorders, non‐steroidal anti‐inflammatory drugs, and antidepressant use. DISCUSSION: Metformin use was significantly associated with a lower risk of dementia in individuals with T2D, with significant variability among subgroups. [ABSTRACT FROM AUTHOR]

INTRODUCTION: Alzheimer's disease studies often lack ethnic diversity. METHODS: We evaluated associations between plasma biomarkers commonly studied in Alzheimer's (p‐tau181, GFAP, and NfL), clinical diagnosis (clinically normal, amnestic MCI, amnestic dementia, or non‐amnestic MCI/dementia), and Aβ‐PET in Hispanic and non‐Hispanic older adults. Hispanics were predominantly of Cuban or South American ancestry. RESULTS: Three‐hundred seventy nine participants underwent blood draw (71.9 ± 7.8 years old, 60.2% female, 57% Hispanic of which 88% were Cuban or South American) and 240 completed Aβ‐PET. P‐tau181 was higher in amnestic MCI (p = 0.004, d = 0.53) and dementia (p < 0.001, d = 0.97) than in clinically normal participants and discriminated Aβ‐PET[+] and Aβ‐PET[‐] (AUC = 0.86). P‐tau181 outperformed GFAP and NfL. There were no significant interactions with ethnicity. Among amnestic MCI, Hispanics had lower odds of elevated p‐tau181 than non‐Hispanic (OR = 0.41, p = 0.006). DISCUSSION: Plasma p‐tau181 informs etiological diagnosis of cognitively impaired Hispanic and non‐Hispanic older adults. Hispanic ethnicity may relate to greater likelihood of non‐Alzheimer's contributions to memory loss. Highlights: Alzheimer's biomarkers were measured in Hispanic and non‐Hispanic older adults.Plasma p‐tau181 related to amnestic cognitive decline and brain amyloid burden.AD biomarker associations did not differ between Hispanic and non‐Hispanic ethnicity.Hispanic individuals may be more likely to have non‐Alzheimer causes of memory loss. [ABSTRACT FROM AUTHOR]

INTRODUCTION: Cognitive abilities have substantial heritability throughout life, as shown by twin‐ and population‐based studies. However, there is limited understanding of the genetic factors related to cognitive decline in aging across neurocognitive domains. METHODS: We conducted a meta‐analysis on 3045 individuals aged ≥65, derived from three population‐based cohorts, to identify genetic variants associated with the decline of five neurocognitive domains (attention, memory, executive function, language, visuospatial function) and global cognitive decline. We also conducted gene‐based and functional bioinformatics analyses. RESULTS: Apolipoprotein E (APOE)4 was significantly associated with decline of memory (p = 5.58E‐09) and global cognitive function (p = 1.84E‐08). We identified a novel association with attention decline on chromosome 9, rs6559700 (p = 2.69E‐08), near RASEF. Gene‐based analysis also identified a novel gene, TMPRSS11D, involved in the activation of SARS‐CoV‐2, to be associated with the decline in global cognitive function (p = 4.28E‐07). DISCUSSION: Domain‐specific genetic studies can aid in the identification of novel genes and pathways associated with decline across neurocognitive domains. Highlights: rs6559700 was associated with decline of attention.APOE4 was associated with decline of memory and global cognitive decline.TMPRSS11D, a gene involved in the activation of SARS‐CoV‐2, was implicated in global cognitive decline.Cognitive domain abilities had both unique and shared molecular pathways across the domains. [ABSTRACT FROM AUTHOR]

Background: Many complex traits and diseases show sex‐specific biases in clinical presentation and prevalence. For instance, two‐thirds of AD cases are female. Studies suggest that women might have higher cognitive reserve but steeper cognitive decline in older age. Cognitive traits have substantial genetic influence. Cognitive impairment could vary among sexes due to sex‐specific genetic factors. To understand the sex‐specific genetic architecture of cognitive decline, we performed genome‐wide association study (GWAS) on sex‐stratified data and assessed a SNP‐sex interaction. Method: We derived inter‐individual specific slopes using linear mixed effect model adjusting for age, education, and sex across five cognitive domains (attention, memory, executive function, language, visuospatial function) and global cognitive function in 3021 older adults aged ≥65 years (females = 1545, males = 1476) belonging to three prospective cohorts: Gingko Evaluation of Memory (GEM), Monongahela‐Youghiogheny Heathy Aging Team (MYHAT), and Monongahela Valley Independent Elders Survey (MoVIES). GWAS was conducted on each cognitive phenotype in each cohort adjusting for the first four genetic principal components. Gene‐based analysis was also conducted to discover genes specific to biological sexes. Result: We identified a novel genome‐wide significant (GWS) intergenic locus for decline of memory in males near RPS23P3 on chromosome 4 (top SNP: rs6851574; MAF = 0.39; Pmale = 4.10E‐08, bmale = ‐0.19; Pfemale = 6.13E‐01, bfemale = ‐0.017; Pinteraction = 3.76E‐04). This intergenic region has previously been associated with other cognitive related traits such as educational attainment, anatomical brain aging and brain shape. We also identified a subthreshold GWS locus for decline of executive function in females near NDUFA12 on chromosome 12 (top SNP: rs11107823; MAF = 0.12; Pfemale = 9.35E‐08, bfemale = 0.28; Pmale = 0.151, bmale = ‐0.077; Pinteraction = 7.42E‐06). NDUFA12/rs11107823 is cis‐eQTL for NDUFA12, NTN4 and VETZ in blood and brain tissues. NDUFA12 codes for a gene involved in oxidative phosphorylation in mitochondria and was also found to be suggestively associated with decline of executive function in gene‐based analysis in females (P = 1.40E‐04). Conclusion: In this sex‐stratified analysis of cognitive decline, we identified two novel loci affecting cognition. Our study illustrates that sex‐aware genetic studies can help in the identification of novel genetic loci and enhance sex‐specific understanding of cognitive aging. [ABSTRACT FROM AUTHOR]

Background: Dementia diagnoses are more common among Hispanic (HW) than non‐Hispanic white (NHW) older adults. Alzheimer's disease (AD) is the most common neuropathological finding in patients with dementia. Plasma AD biomarkers have accelerated efforts towards increasing access to timely diagnosis, but existing data often come from cohorts lacking ethnic diversity. Clinical translation of plasma AD biomarkers requires continued evaluation in study cohorts that reflect the growing ethnic diversity of the population. Method: We studied 379 older adults (age 71.9±7.8 years old, 60.2% female) from the 1Florida Alzheimer's Disease Research Center who underwent blood draw and analysis for P‐tau181 (Quanterix). Of these, 240 completed Aβ‐PET (converted to Centiloids). Over half (57%) self‐identified as HW (32% Cuba, 18% South American, 7% other). Analyses included 1) comparing plasma biomarker concentrations between clinically normal (CN), amnestic MCI (amnMCI), amnestic dementia (amnDEM), and nonamnestic MCI/dementia (ANCOVA controlling for age), 2) evaluating P‐tau181 correlations with Aβ burden (Spearman's rho), and 3) determining discriminability (AUC) of Aβ‐PET[+] from Aβ‐PET[‐]. Interactions between independent variables and ethnicity were evaluated to inform whether observed relationships differed between HW and non‐Hispanic white (NHW). Lastly, using a cutoff derived from the PET sub‐cohort, we investigated rates of P‐tau181‐defined "AD positivity" (plasmaAD[+]) between HW and NHW diagnosed with amnMCI. Additional data for plasma GFAP and NfL will also be presented. Results: Plasma P‐tau181 was higher in amnMCI (p =.004, d = 0.53) and amnDEM (p<.001, d = 0.97) than CN. Higher P‐tau181 related to greater Aβ burden (ρ =.59 [.50‐.67], p<.001) and had good discriminability between Aβ‐PET[+] and Aβ‐PET[‐] (AUC = 0.86 [0.81‐0.91], Youden's Index = 2.39 pg/mL). There were no significant interactions with ethnicity. Applying the P‐tau181 cutoff (2.39 pg/mL) to all amnMCI participants, HW diagnosed with amnMCI had lower odds of being plasmaAD[+] than NHW (36.5% vs. 58.5%; OR = 0.41 [0.21‐0.78], p =.006). Conclusion: Plasma P‐tau181 may aid etiological diagnosis of cognitively impaired older adults from Hispanic and non‐Hispanic ethnic origins. Hispanic ethnicity alone does not significantly influence the interpretation of how plasma P‐tau181 relates to Aβ‐PET, but may be linked to greater likelihood of non‐AD causes of memory loss. Blood‐based biomarkers could help reduce barriers to clinical diagnosis and research participation that disproportionately impact underrepresented groups. [ABSTRACT FROM AUTHOR]

Introduction: Growing evidence implicates air pollution as a risk factor for dementia, but prior work is limited by challenges in diagnostic accuracy and assessing exposures in the decades prior to disease development. We evaluated the impact of long‐term fine particulate matter (PM2.5) exposures on incident dementia (all‐cause, Alzheimer's disease [AD], and vascular dementia [VaD]) in older adults. Methods: A panel of neurologists adjudicated dementia cases based on extensive neuropsychological testing and magnetic resonance imaging. We applied validated fine‐scale air pollutant models to reconstructed residential histories to assess exposures. Results: An interquartile range increase in 20‐year PM2.5 was associated with a 20% higher risk of dementia (95% confidence interval [CI]: 5%, 37%) and an increased risk of mixed VaD/AD but not AD alone. Discussion: Our findings suggest that air pollutant exposures over decades contribute to dementia and that effects of current exposures may be experienced years into the future. [ABSTRACT FROM AUTHOR]

Background: Rapid declines in processing speed performance occur in aging and serve as a critical marker of cognitive abilities. Studies suggest that Useful Field of View (UFOV) training may ameliorate cognitive decline. The ACTIVE trial, consisting of over 2,800 participants, found a 29% reduction in ADRD risk 10 years following intervention. Recent clinical trials aimed at slowing cognitive decline in AD have focused on UFOV‐based interventions. Despite its efficacy, little is known about its neural correlates. The current study investigated blood‐oxygen level dependent (BOLD) activation patterns of the UFOV task. Method: 233 older adults completed the UFOV task while undergoing task‐based fMRI. The UFOV task requires participants to identify a central target, as well as a peripheral target amongst distractors, presented for a brief period of time. First‐level contrasts modeled hemodynamic response, while second‐level analyses assessed unique BOLD activation associated with encoding and recall components of the task. Age, education, sex and scanner were included as covariates. Significant clusters were defined as >10 voxels, and all clusters were corrected at a false discovery rate (FDR) of p<0.05. Result: Previous data have shown widespread bilateral whole‐brain activation associated with the encoding component, whereas discrete activation patterns were related to the recall component of the task. Additionally, numerous shared brain regions were critical to both the encoding and recall components of the UFOV task. We further investigated cortical activation patterns associated with age‐related differences in UFOV performance. Variability in performance was related to widespread patterns of activation during the encoding component of the UFOV task, namely the superior parietal lobule, insula, hippocampus and DLPFC. Assessing UFOV performance variability within recall, no significant clusters survived FDR correction. Furthermore, the inferior parietal lobule, cerebellum, and inferior frontal gyrus were critical in both encoding and recall in UFOV performance. Conclusion: The present study elucidates pivotal regions associated with UFOV task performance. Notably, we found that variability in UFOV performance is directly associated with neural activation during the presentation/apprehension of the stimuli, but not during recall. These findings suggest that variation in neural activation during speeded attentional processing is central to age‐related UFOV performance differences, and interventions targeting these neural processes may be of benefit. [ABSTRACT FROM AUTHOR]

Introduction: Apathy is common in neurocognitive disorders (NCD) but NCD‐specific diagnostic criteria are needed. Methods: The International Society for CNS Clinical Trials Methodology Apathy Work Group convened an expert group and sought input from academia, health‐care, industry, and regulatory bodies. A modified Delphi methodology was followed, and included an extensive literature review, two surveys, and two meetings at international conferences, culminating in a consensus meeting in 2019. Results: The final criteria reached consensus with more than 80% agreement on all parts and included: limited to people with NCD; symptoms persistent or frequently recurrent over at least 4 weeks, a change from the patient's usual behavior, and including one of the following: diminished initiative, diminished interest, or diminished emotional expression/responsiveness; causing significant functional impairment and not exclusively explained by other etiologies. Discussion: These criteria provide a framework for defining apathy as a unique clinical construct in NCD for diagnosis and further research. [ABSTRACT FROM AUTHOR]

Introduction: Amyloid beta (Aβ) oligomers are one of the most toxic structural forms of the Aβ protein and are hypothesized to cause synaptotoxicity and memory failure as they build up in Alzheimer's disease (AD) patients' brain tissue. We previously demonstrated that antagonists of the sigma‐2 receptor complex effectively block Aβ oligomer toxicity. CT1812 is an orally bioavailable, brain penetrant small molecule antagonist of the sigma‐2 receptor complex that appears safe and well tolerated in healthy elderly volunteers. We tested CT1812's effect on Aβ oligomer pathobiology in preclinical AD models and evaluated CT1812's impact on cerebrospinal fluid (CSF) protein biomarkers in mild to moderate AD patients in a clinical trial (ClinicalTrials.gov NCT02907567). Methods: Experiments were performed to measure the impact of CT1812 versus vehicle on Aβ oligomer binding to synapses in vitro, to human AD patient post mortem brain tissue ex vivo, and in living APPSwe/PS1dE9 transgenic mice in vivo. Additional experiments were performed to measure the impact of CT1812 versus vehicle on Aβ oligomer‐induced deficits in membrane trafficking rate, synapse number, and protein expression in mature hippocampal/cortical neurons in vitro. The impact of CT1812 on cognitive function was measured in transgenic Thy1 huAPPSwe/Lnd+ and wild‐type littermates. A multicenter, double‐blind, placebo‐controlled parallel group trial was performed to evaluate the safety, tolerability, and impact on protein biomarker expression of CT1812 or placebo given once daily for 28 days to AD patients (Mini‐Mental State Examination 18–26). CSF protein expression was measured by liquid chromatography with tandem mass spectrometry or enzyme‐linked immunosorbent assay in samples drawn prior to dosing (Day 0) and at end of dosing (Day 28) and compared within each patient and between pooled treated versus placebo‐treated dosing groups. Results: CT1812 significantly and dose‐dependently displaced Aβ oligomers bound to synaptic receptors in three independent preclinical models of AD, facilitated oligomer clearance into the CSF, increased synaptic number and protein expression in neurons, and improved cognitive performance in transgenic mice. CT1812 significantly increased CSF concentrations of Aβ oligomers in AD patient CSF, reduced concentrations of synaptic proteins and phosphorylated tau fragments, and reversed expression of many AD‐related proteins dysregulated in CSF. Discussion: These preclinical studies demonstrate the novel disease‐modifying mechanism of action of CT1812 against AD and Aβ oligomers. The clinical results are consistent with preclinical data and provide evidence of target engagement and impact on fundamental disease‐related signaling pathways in AD patients, supporting further development of CT1812. [ABSTRACT FROM AUTHOR]

Background: Previous studies have linked dietary fatty acids and antioxidants to dementia risk and cognitive decline. The relationships of objective markers of fatty acid and antioxidant intakes with brain imaging biomarkers remain uncertain. Method: We assessed the associations of antioxidants and phospholipids in plasma, collected in 2000‐2002, with brain amyloid‐ß deposition on PET scans and hippocampal and white matter lesion volume on MRIs in 2009 among 193 participants of the Ginkgo Evaluation of Memory Study who were free of clinical dementia. We used multivariable‐adjusted and inverse‐probability‐weighted robust linear regression models. We measured antioxidants by organic phase extraction followed by chromatographic analysis and individual plasma phospholipids (as a percentage of total plasma phospholipid fatty acids) by gas chromatography with flame ionization detection. Result: A total of 20 participants (10%) had mild cognitive impairment at baseline and 134 participants (69%) used either multivitamin, vitamin A or β‐carotene, or vitamin E supplements (Table 1). Higher plasma retinol,α‐tocopherol, and total vitamin E were related to higher future amyloid‐ß deposition (Table 2). Higher α‐tocopherol and total vitamin E were also related to less white matter lesion volume. Carotenoids were not significantly related to any of the brain imaging biomarkers. Higher concentrations of the saturated fatty acid margaric acid (17:0) were associated with more amyloid‐ß deposition (adjusted difference per 1 SD higher margaric acid: 0.10 standardized uptake value ratio; 95% CI: 0.02, 0.19) and smaller hippocampal volume (Table 3). In contrast, higher concentrations of the saturated fatty acid behenic acid (22:0) were associated with less white matter lesion volume. Higher oleic acid (18:1n‐9c, a major monounsaturated fatty acid), was related to more hippocampal volume. Higher concentrations of the n‐3 polyunsaturated fatty acid docosahexaenoic acid (22:6n‐3c) were associated with more amyloid‐ß deposition, while higher concentrations of linoleic acid (18:2n‐6cc; a major n‐6 polyunsaturated fatty acid) were associated with less amyloid‐ß deposition (adjusted difference per 1 SD higher linoleic acid: ‐0.10 standardized uptake value ratio; 95% CI:‐0.19, ‐0.01). Conclusion: Specific antioxidants and phospholipids may be associated with brain imaging biomarkers, a hypothesis that requires formal testing in long‐term intervention studies and that represents a possible preventive intervention, [ABSTRACT FROM AUTHOR]

Background: Engagement in lifestyle activities may be neuroprotective, but longitudinal data is needed to best inform health interventions. Characterizing the prospective impact of shared lifestyle activities among older adults may both identify subgroups who could benefit most from intervention and reveal contextual/motivational differences in lifestyle that are relevant to group‐level intervention design. We used latent class analysis to characterize qualitatively distinct lifestyle engagement groups and examined whether they had differential declines in global and domain‐specific cognition. Method: Participants were 3068 individuals from the Ginkgo Evaluation of Memory (GEM) Study who completed neuropsychological testing up to 8 years (M=5.0, SD=2.4). We assessed 18 physical, intellectual, and social activities using the Lifestyle Activity Questionnaire. Linear mixed effects models adjusted for demographic and health covariates were used to examine lifestyle engagement group differences in cognitive level and changes over time. Result: The four‐class model fit best (Figure 1). The Variety lifestyle group (22%) had high engagement in both intellectual (e.g., taking classes) and social activities (e.g., concerts, church, social clubs). The Intellectual (18%) group had high engagement in intellectual and some social leisure activities (e.g., concerts). The Social (32%) group had high engagement in social institutional activities (e.g., church). Compared to the Least Active (28%) group, the Variety (B's=.14‐.25, p's<.05) and Intellectual (B's=.10‐.29, p's<.05) groups had greater levels of cognitive performance across all domains, whereas the Social group was only higher in memory (B=.11, SE=.04, p=.013; Table 1). The Variety group also had attenuated declines in memory (B=.02, SE=.01, p=.035) and attention (B=.02, SE=.01, p=.023) over time. Conclusion: Higher lifestyle engagement, especially in intellectual activities, was associated with higher levels of cognition later in life. Yet, only those with the greatest diversity of activities (Variety group) were protected against subsequent declines in memory and attention. These results extend prior findings that these lifestyle groups differ in risk of incident dementia, by suggesting that memory and attention (vs. visuospatial construction) drive this protective relationship. Our findings also highlight subgroup differences in activity types (e.g., primarily social vs. intellectual) that may lead to more targeted interventions to reduce cognitive declines with age. [ABSTRACT FROM AUTHOR]

Background: Neurogranin (Ng) is a post‐synaptic protein involved in formation of long‐term potentials, and thus plays an important role in learning and memory. The concentration of Ng is increased in the cerebrospinal fluid (CSF) of people with Alzheimer's disease (AD), and CSF Ng is considered to be a biomarker for synaptic dysfunction in AD. The expression of Ng protein in the human brain and its association with AD pathology, however, are less well studied. Method: Using immunohistochemical detection methods we investigated the protein expression of Ng, beta‐amyloid (Aβ) and hyperphosphorylated paired helical filament tau (phospho‐tau; ptau) in the post‐mortem hippocampus from 12 AD patients and 12 cognitively unaffected controls (NC). We compared the number of positively stained cells (Ng, ptau) or plaques (Aβ) in the hippocampal sub‐regions (dentate gyrus, Cornu Ammonis (CA) fields 1‐3) from the 2 groups. Donor samples with intermediate AD (i.e., Braak stage III‐IV) or NC (Braak 0‐I/II) were analyzed using Image Pro Premier automated image analysis software (version 10.01). The data were normalized to the number of cells or clusters/mm2 and analyzed using a one‐way ANOVA. Using a test of circularity (Cir = (4*A)/Pi*MaxFeret2), we further investigated morphological differences in the Ng positive neurons by measuring the Ng expression in the apical dendrite of pyramidal neurons. Result: There was a 40% reduction of Ng immunopositive neurons in AD compared to NC in the CA3(N = 24;p = 0.0003) and in the CA1(N = 24;p = 0.014) hippocampal sub‐regions. Ng positive cells did not change significantly in AD compared to NC in the other hippocampal regions. Additionally, we showed that CA1 region, Ng was localized mainly in the neuronal cell soma of AD donors, while its expression extended into the apical dendrites of NC donors (N = 24;p = 0.006). In AD, Ng immunostaining negatively correlated with ptau immunopositive neurofibrillary tangles (r = ‐0.70;p = 0.04) Conclusion: Selective loss of Ng immunostaining in certain subregions of the hippocampus suggests that synaptic damage in AD maybe a region‐specific event. The mechanism underlying such regional synaptic damage and the changes in Ng expression will be key in understanding the selective vulnerability of brain regions to AD. [ABSTRACT FROM AUTHOR]

Background: Effective non‐pharmacological interventions to remediate age‐related cognitive decline and alter trajectories toward dementia are limited. The Augmenting Cognitive Training in Older Adults trial (ACT) was the first phase III randomized clinical trial initiated for transcranial direct current stimulation. Method: This NIA funded trial sought to evaluate whether 3 months of cognitive training paired with bilateral 2mA tDCS to the frontal lobes could produce clinically meaningful improvement in a composite measure of cognitive function in healthy older adults: the NIH Toolbox Fluid Cognition Composite score. The ACT trial will be unblinded April 30, 2022. Further still, over the past 5 years, it has become increasingly evident that fixed dosing approaches to tDCS, like those used in the ACT and every other trial to date, are insufficient for addressing individual differences and maximizing clinical outcomes. Results: We will present, for the first time, the primary outcome results from the ACT trial. In addition, we will present initial findings from related secondary neuroimaging and cognitive indices. In this talk, we will also present preliminary findings from our ongoing work to refine dosing technology for tDCS in older adults using computational modeling, artificial intelligence and multimodal imaging, paired with tDCS outcomes from the ACT trial. Conclusion: We will present new analyses, available only upon unblinding of ACT. These data use person‐specific computational models of tDCS current flow paired with machine learning and clinical outcomes to identify critical characteristics of tDCS current in the brain (e.g., intensity, direction of current flow) most strongly associated with response vs. non‐response. These data will provide initial insight into which regions of the brain and what characteristics of current were strongly associated with treatment response in the ACT trial. In addition, these data also provide critical insight into how stimulation dosing (electrode positioning, stimulation intensity) can be modified at a person‐specific level to potentially enhance clinical outcomes. Thus, the proposed talk will provide state of the art trial findings from the first completed tDCS Phase III clinical trial paired with next generation approaches to remediated age‐related cognitive decline using tDCS technology. [ABSTRACT FROM AUTHOR]

Background: Dementia broadly describes conditions that affect a person's memory, cognition, and behavior with Alzheimer's disease (AD) being the most common cause. AD affects millions of people in the U.S. and around the world causing a significant financial burden and placing significant stress on caretakers. AD is a complex disease influenced by both the environment and genetics, however, much of the genetic component remains unaccounted for. The purpose of this work was to use genome‐wide association analyses to detect genetic associations with incident AD in a sample of older adults age 75 and above. Method: We performed a genome‐wide association study (GWAS) on the genome‐wide genotyped and imputed data (14,113,004 variants) on the Gingko Evaluation of Memory (GEM) study sample consisting of 424 incident dementia cases (mean age ± sd = 84.64±3.95) and 2,206 non‐demented subjects (mean age ± sd = 84.55±3.23). Result: The established association of APOE*4 with AD was confirmed in this community‐based sample of older subjects (OR = 2.22; P = 9.36E‐14). In addition, a genome‐wide significant novel locus on chromosome 12 was observed near FAR2 and CCDC91 genes (OR = 3.31; P = 1.66E‐08). Sex‐stratified analyses showed a stronger association of APOE*4 with AD in females (P = 1.74E‐10) than in males (P = 2.43E‐05). In males, a novel SNP on chromosome 1 near LOC729987 and SNX7 genes reached genome‐wide significance (OR = 4.51; P = 3.72E‐08). Of the known AD genes, SNPs near or at TREM2, NME8/EPDR1, MS4A6A/MS4A4E, PICALM, APH1B, and PLCG2 showed nominal significance. Conclusion: The use of community‐based samples of older individuals and incident dementia as a phenotype may be a helpful approach for the identification of novel genes for AD, which may not be detected in standard case‐control studies. Replication of these signals and further study of these regions and genes will help to provide a clearer picture for their role in AD. [ABSTRACT FROM AUTHOR]

Background: A rare missense APOE variant (L28P; APOE*4Pittsburgh) has been reported to be a risk factor for Alzheimer's disease (AD). However, sinceL28P has been observed only among APOE*4 carriers, its independent genetic association is uncertain. In this study, we re‐evaluated this association in a large case‐control sample of 15,762 U.S. Whites aged ≥60 years and investigated its independent effect. Method: Samples were derived from three sources: University of Pittsburgh, Alzheimer's Disease Sequencing Project and the Gingko Evaluation Memory Study. Due to variation in the age distribution between cases and controls in the three studies, each study sample was analyzed separately, and the results then combined by meta‐analysis. To distinguish the independent effect of L28P from APOE*4, we restricted the analysis to subjects with the APOE 3/4 genotype, as L28P has been observed only in the heterozygous state in the APOE*4‐background and 3/4 is the most common genotype containing the APOE*4 allele. Result: A total of 80 L28P heterozygotes were observed in the combined case‐control sample, all in those containing only the APOE*4 allele, confirming the complete linkage disequilibrium between the two sites. The age‐ and sex‐adjusted meta‐analysis odds ratio (OR) was 2.87 (95% CI: 1.34 – 6.13; p = 0.0066). There were a total of 4,138 cases and controls with the 3/4 genotype. The age‐ and sex‐adjusted meta‐analysis OR was 1.53 (95% CI: 0.70 – 3.36; p = 0.28). The lack of significance is mainly due to the low power with the ∼4,100 sample size (12% power at α = 0.80), as compared to the required sample size of ∼151,000 to detect an OR of 1.5 at α = 0.80. Conclusion: Even with non‐significant p‐value, the OR of 1.53 among 3/4 subjects suggests that the effect of L28P on AD risk is independent of APOE*4. Our genetic finding is reinforced by an earlier experimental finding showing that this mutation leads to significant structural and conformational alterations in ApoE and can induce functional defects associated with neuronal Aβ42 accumulation and oxidative stress (J Biol Chem 2014; 289:12931). Additional studies in cell‐based systems and animal models will help to delineate its functional significance in the AD etiology. [ABSTRACT FROM AUTHOR]

Background: The APOE 2/3/4 polymorphism is the greatest risk factor for Alzheimer's disease (AD). This polymorphism is also associated with variation in plasma ApoE levels and explains about 20‐25% of its genetic variance; while APOE*4 lowers, APOE*2 increases ApoE levels. Lower plasma ApoE levels have also been reported to be a risk factor of future AD and all dementia, independent of the APOE 2/3/4 polymorphism (Ann Neurol 2015;77:301). To our knowledge, no genome‐wide association study (GWAS) has been reported on plasma ApoE levels. This study was aimed to identify novel genetic factors affecting plasma ApoE levels as well as to confirm if baseline plasma ApoE levels predict future AD dementia in an older and longitudinally followed cohort of the Ginkgo Evaluation of Memory (GEM) study. Method: Baseline plasma ApoE levels were measured using an immunoturbidimetric assay in 3,031 older subjects (aged 72 to 96 years; 94.1% White). Genome‐wide genotype was performed on the available 2,737 DNA samples (96% White). Due to the small number in other ethnicities, we only included the 2,852 White subjects (2,412 cognitively normal, 440 with incident AD dementia) for plasma ApoE analysis. GWAS analysis on plasma ApoE levels was performed on 2,580 White subjects where both genotype and ApoE level data were available. Result: As expected, the risk for AD increased from E2/2 through to E4/4 genotypes (p for trend =1.7E‐10). There was no significant difference in plasma ApoE levels between cognitively normal and AD dementia subjects (p=0.55). GWAS analysis revealed the expected associations of APOE*2 (β= 1.12; p= 3.57E‐79) and APOE*4 (β= ‐0.35; p= 2.21E‐11) with plasma ApoE levels. In addition, we observed 5 novel genome‐wide significant associations on chromosomes 1 (β= 0.921; p= 5.36E‐10), 4 (β= 0.796; p= 4.31E‐08;), 7 (β= 0.722; p= 9.64E‐09), 11 (β= 0.268; p= 2.58E‐08), and 20 (β= 1.379; p=8.25E‐09). Conclusion: We have identified multiple novel associations affecting plasma ApoE levels in addition to the established APOE association. However, we could not replicate the reported association of plasma ApoE levels with future AD, probably because of the older nature of our cohort. [ABSTRACT FROM AUTHOR]

Background: The Useful Field of View (UFOV) test assesses divided attention/speed of processing and relates to independent activities of daily living. Cognitive training utilizing UFOV improves speed‐of‐processing and reduces dementia risk by 29%. Neural correlates of UFOV include key regions of “higher‐order” resting state networks (RSNs) involved in attention processing and dementia risk: Frontoparietal control network (FPCN), Cingulo Opercular network (CON), Default Mode network (DMN), and Dorsal Attention network (DAN). Reduced anti‐correlation between the DMN and task positive RSNs (FPCN, CON, and DAN) is reported in dementia progression. Assessing the relationship of UFOV performance with within‐ and between‐ RSN connectivity may suggest neural mechanisms of cognitive training and potential pathways for reduced dementia risk. We hypothesize that FPCN, CON, and DAN within network connectivity will predict UFOV performance, as these networks are involved in attention processing. We also predict that DMN‐CON anti‐correlation will predict UFOV performance, as this anti‐correlation is related to dementia progression. Method: 279 healthy older adults (M = 71.6, SD = 5.1) from a larger multi‐site clinical trial were recruited. UFOV performance was measured via Double Decision (DD) task from Posit Science Brain HQ. Participants correctly identified a central target, while simultaneously specifying location of a peripheral target among distractors. Average within‐network connectivity of FPCN, CON, DAN, and DMN, and between‐network connectivity of DMN‐CON, DMN‐FPCN, and DMN‐DAN were extracted from resting‐state functional magnetic resonance imaging through the CONN Toolbox v18b via SPM 12. Multiple linear regressions predicted DD performance from within‐ and between‐network values, controlling for age, sex, education, and scanner. All between‐network values were included in the same regression model. Result: Reduced CON (β=‐.134, p=.023) and FPCN (β=‐.126, p=.029) connectivity was associated with poorer DD performance. Less DMN‐CON anticorrelation demonstrated a trend for predicting better DD performance (β=‐.126, p=.060). Conclusion: Consistent with previous research, faster DD performance is associated with RSNs involved in executive functioning, attention, and processing speed. Although only trending, reduced DMN‐CON anticorrelation may be related to DD performance. This suggests that within network connectivity may contribute more to DD performance than between‐network connectivity involved in dementia progression in healthy older adults. [ABSTRACT FROM AUTHOR]

Background: Plasma phospholipids are biomarkers of dietary fat intake and metabolism which have been linked to several cardiometabolic disorders. Few prospective studies have assessed plasma phospholipids in relation to adjudicated dementia risk and cognitive decline. Method: We measured plasma phospholipids in a case‐cohort study nested within the Ginkgo Evaluation of Memory Study. We included 911 randomly selected participants and 498 participants who developed dementia during a mean [SD] of 5.0 [1.8] years of follow‐up. We measured individual plasma phospholipids (as a percentage of total plasma phospholipid fatty acids) by gas chromatography with flame ionization detection. These were evaluated in association with the Modified Mini‐Mental State Examination (3MSE) scores at baseline and neurologist‐adjudicated risks of all‐cause dementia and Alzheimer's disease (AD), adjusting for sociodemographic and clinical characteristics. Result: When compared with saturated fatty acids (SFA), we found no associations of total mono‐unsaturated (MUFA), polyunsaturated (PUFA), or trans‐fatty acids (TFA) with risk of dementia or AD. However, higher docosahexaenoic acid was associated with a lower risk of dementia (hazard ratio 0.80 per 1% of docosahexaenoic acid instead of SFA; 95% confidence interval: 0.71‐0.91). Similarly, higher PUFA was associated with 0.04 point higher 3MSE score at baseline (per 1% PUFA instead of SFA; 95% confidence interval: 0.01, 0.08) signifying better cognitive function. Conclusions: Although we did not find strong associations of mono‐unsaturated or TFA with risk of dementia or AD when compared with SFA, replacement with PUFA was associated with better baseline cognitive function, and replacement with the marine n‐3 fatty acid docosahexaenoic acid was associated with lower risk of dementia. This prospective study highlights the potential of dietary improvement to prevent dementia. [ABSTRACT FROM AUTHOR]