Study Objectives Although short sleep could promote neurodegeneration, long sleep may be a marker of ongoing neurodegeneration, potentially as a result of neuroinflammation. The objective was to evaluate sleep patterns with age of expected Alzheimer's disease (AD) onset and neuroinflammation.Methods We tested 203 dementia-free participants (68.5 +/- 5.4 years old, 78M). The PREVENT-AD cohort includes older persons with a parental history of AD whose age was nearing their expected AD onset. We estimated expected years to AD onset by subtracting the participants' age from their parent's at AD dementia onset. We extracted actigraphy sleep variables of interest (times of sleep onset and morning awakening, time in bed, sleep efficiency, and sleep duration) and general profiles (sleep fragmentation, phase delay, and hypersomnia). Cerebrospinal fluid (CSF) inflammatory biomarkers were assessed with OLINK multiplex technology.Results Proximity to, or exceeding, expected age of onset was associated with a sleep profile suggestive of hypersomnia (longer sleep and later morning awakening time). This hypersomnia sleep profile was associated with higher CSF neuroinflammatory biomarkers (IL-6, MCP-1, and global score). Interaction analyses revealed that some of these sleep-neuroinflammation associations were present mostly in those closer/exceeding the age of expected AD onset, APOE4 carriers, and those with better memory performance.Conclusions Proximity to, or exceeding, parental AD dementia onset was associated with a longer sleep pattern, which was related to elevated proinflammatory CSF biomarkers. We speculate that longer sleep may serve a compensatory purpose potentially triggered by neuroinflammation as individuals are approaching AD onset. Further studies should investigate whether neuroinflammatory-triggered long sleep duration could mitigate cognitive deficits. Graphical Abstract

AbstractBackgroundBlood‐biomarkers of Alzheimer’s disease (AD) pathology have been investigated cross‐sectionally in heterogenous AD cohorts and have been shown to detect underlying AD pathology, even at preclinical stages. However, longitudinal studies, including serial blood‐biomarker measurements, are needed to better understand whether these markers could help monitor disease progression. We aimed to assess blood‐biomarkers temporal trajectories in cognitively unimpaired older adults at different pathological stages as assessed by positron emission tomography (PET). This may provide insight into dynamic changes of these biomarkers beginning prior to abnormality on PET.MethodWe included a subset of 126 cognitively unimpaired older adults from the Prevent‐AD cohort. Blood was drawn from baseline up to four‐year follow‐up visits. We measured Aβ42/Aβ40 ratio, pTau181 and pTau231 using novel single molecular array (Simoa). All participants completed Aβ (18F‐NAV4694) and tau (18F‐flortaucipir) PET scans, which were mostly performed at the latest blood collection timepoint. Aβ positivity was defined by global neocortical Aβ‐PET retention (SUVR cut‐off = 1.29), and tau‐PET positivity by entorhinal cortex flortaucipir binding (SUVR cut‐off = 1.23). Using these thresholds, 82 subjects were classified as A‐T‐, 29 as A+T‐, and 15 as A+T+. Linear mixed effects models were used to assess differences in the longitudinal rate of change in plasma biomarkers between the groups.ResultAmyloid‐PET‐positive individuals showed elevated levels of pTau181, and pTau231 and lower levels of Aβ42/40 when compared with amyloid‐PET‐negative participants. Plasma pTau181 levels showed a greater increase over time in the A+T+ group when compared with the A‐T‐ group (p = 0.01; Figure 1). Overall, the A+T‐ and A+T+ groups had lower levels of plasma Aβ42/40 compared with the A‐T‐ group (p = 0.05, p = 0.0189; Figure 2), and the A+T‐ group had higher pTau231 compared with A‐T‐ participants (p = 0.0006; Figure 3). Longitudinal rate of change in Aβ42/40 and pTau231 did not differ between the groups.ConclusionWe observed increased pTau181 levels and rate of change in those with both amyloid and tau pathology on PET. The slopes between PET groups did not differ across time when using pTau231 and Aβ biomarkers despite group differences in the overall level of pathology.

Importance Preventive trials of anti-amyloid agents might preferably recruit persons showing earliest biologically relevant β-amyloid (Aβ) binding on positron emission tomography (PET). Objective To investigate the timing at which Aβ-PET binding starts showing associations with other markers of Alzheimer disease. Design, Setting, and Participants This longitudinal multicentric cohort study included 3 independent cohorts: Presymptomatic Evaluation of Experimental or Novel Treatments for Alzheimer Disease (PREVENT-AD) (data collected from 2012-2020), Alzheimer Disease Neuroimaging Initiative (ADNI) (data collected from 2005-2019), and Harvard Aging Brain Study (HABS) (data collected from 2011-2019). In a 3-tiered categorization of Aβ-PET binding spatial extent, individuals were assigned as having widespread Aβ deposition if they showed positive signal throughout a designated set of brain regions prone to early Aβ accumulation. Those with binding in some but not all were categorized as having regional deposition, while those who failed to show any criterion Aβ signal were considered Aβ-negative. All participants who were cognitively unimpaired at their first Aβ PET scan. Main Outcomes and Measures Differences in cerebrospinal fluid (CSF), genetics, tau-PET burden, and cognitive decline. Results A total of 817 participants were included, including 129 from the PREVENT-AD cohort (mean [SD] age, 63.5 [4.7] years; 33 [26%] male; 126 [98%] White), 400 from ADNI (mean [SD] age, 73.6 [5.8] years; 190 [47%] male; 10 [5%] Hispanic, 338 [91%] White), and 288 from HABS (mean [SD] age, 73.7 [6.2] years; 117 [40%] male; 234 [81%] White). Compared with Aβ-negative persons, those with regional Aβ binding showed proportionately more APOE ε4 carriers (18 [64%] vs 22 [27%] in PREVENT-AD and 34 [31%] vs 38 [19%] in ADNI), reduced CSF Aβ1-42 levels (F = 24 and 71), and greater longitudinal Aβ-PET accumulation (significant β = 0.019 to 0.056). Participants with widespread amyloid binding further exhibited notable cognitive decline (significant β = -0.014 to -0.08), greater CSF phosphorylated tau181 (F = 5 and 27), and tau-PET binding (all F > 7.55). Using each cohort's specified dichotomous threshold for Aβ positivity or a visual read classification, most participants (56% to 100%, depending on classification method and cohort) with regional Aβ would have been classified Aβ-negative. Conclusions and Relevance Regional Aβ binding appears to be biologically relevant and participants at this stage remain relatively free from CSF phosphorylated tau181, tau-PET binding, and related cognitive decline, making them ideal targets for anti-amyloid agents. Most of these individuals would be classified as negative based on classical thresholds of Aβ positivity.

OBJECTIVE:The objective of this study was to evaluate novel plasma p-tau231 and p-tau181, as well as Aβ40 and Aβ42 assays as indicators of tau and Aβ pathologies measured with positron emission tomography (PET), and their association with cognitive change, in cognitively unimpaired older adults.METHODS:In a cohort of 244 older adults at risk of Alzheimer's disease (AD) owing to a family history of AD dementia, we measured single molecule array (Simoa)-based plasma tau biomarkers (p-tau231 and p-tau181), Aβ40 and Aβ42 with immunoprecipitation mass spectrometry, and Simoa neurofilament light (NfL). A subset of 129 participants underwent amyloid-β (18 F-NAV4694) and tau (18 F-flortaucipir) PET assessments. We investigated plasma biomarker associations with Aβ and tau PET at the global and voxel level and tested plasma biomarker combinations for improved detection of Aβ-PET positivity. We also investigated associations with 8-year cognitive change.RESULTS:Plasma p-tau biomarkers correlated with flortaucipir binding in medial temporal, parietal, and inferior temporal regions. P-tau231 showed further associations in lateral parietal and occipital cortices. Plasma Aβ42/40 explained more variance in global Aβ-PET binding than Aβ42 alone. P-tau231 also showed strong and widespread associations with cortical Aβ-PET binding. Combining Aβ42/40 with p-tau231 or p-tau181 allowed for good distinction between Aβ-negative and -positive participants (area under the receiver operating characteristic curve [AUC] range = 0.81-0.86). Individuals with low plasma Aβ42/40 and high p-tau experienced faster cognitive decline.INTERPRETATION:Plasma p-tau231 showed more robust associations with PET biomarkers than p-tau181 in presymptomatic individuals. The combination of p-tau and Aβ42/40 biomarkers detected early AD pathology and cognitive decline. Such markers could be used as prescreening tools to reduce the cost of prevention trials. ANN NEUROL 2022;91:548-560.

Blood-biomarkers of Alzheimer’s disease (AD) pathology have been investigated cross-sectionally in heterogenous AD cohorts and have been shown to detect underlying AD pathology, even at preclinical stages. However, longitudinal studies, including serial blood-biomarker measurements, are needed to better understand whether these markers could help monitor disease progression. We aimed to assess blood-biomarkers temporal trajectories in cognitively unimpaired older adults at different pathological stages as assessed by positron emission tomography (PET). This may provide insight into dynamic changes of these biomarkers beginning prior to abnormality on PET. We included a subset of 126 cognitively unimpaired older adults from the Prevent-AD cohort. Blood was drawn from baseline up to four-year follow-up visits. We measured Aβ 42 /Aβ 40 ratio, pTau181 and pTau231 using novel single molecular array (Simoa). All participants completed Aβ ( 18 F-NAV4694) and tau ( 18 F-flortaucipir) PET scans, which were mostly performed at the latest blood collection timepoint. Aβ positivity was defined by global neocortical Aβ-PET retention (SUVR cut-off = 1.29), and tau-PET positivity by entorhinal cortex flortaucipir binding (SUVR cut-off = 1.23). Using these thresholds, 82 subjects were classified as A-T-, 29 as A+T-, and 15 as A+T+. Linear mixed effects models were used to assess differences in the longitudinal rate of change in plasma biomarkers between the groups. Amyloid-PET-positive individuals showed elevated levels of pTau181, and pTau231 and lower levels of Aβ 42/40 when compared with amyloid-PET-negative participants. Plasma pTau181 levels showed a greater increase over time in the A+T+ group when compared with the A-T- group (p = 0.01; Figure 1 ). Overall, the A+T- and A+T+ groups had lower levels of plasma Aβ 42/40 compared with the A-T- group (p = 0.05, p = 0.0189; Figure 2 ), and the A+T- group had higher pTau231 compared with A-T- participants (p = 0.0006; Figure 3 ). Longitudinal rate of change in Aβ 42/40 and pTau231 did not differ between the groups. We observed increased pTau181 levels and rate of change in those with both amyloid and tau pathology on PET. The slopes between PET groups did not differ across time when using pTau231 and Aβ biomarkers despite group differences in the overall level of pathology.

There is an urgent need for interventions that can prevent or delay cognitive decline and dementia. Decades of epidemiological research have identified potential pharmacological strategies for risk factor modification to prevent these serious conditions, but clinical trials have failed to confirm the potential efficacy for such interventions. Our multidisciplinary international group reviewed seven high-potential intervention strategies in an attempt to identify potential reasons for the mismatch between the observational and trial results. In considering our findings, we offer constructive recommendations for the next steps. Overall, we observed some differences in the observational evidence base for the seven strategies, but several common methodological themes that emerged. These themes included the appropriateness of trial populations and intervention strategies, including the timing of interventions and other aspects of trials methodology. To inform the design of future clinical trials, we provide recommendations for the next steps in finding strategies for effective dementia risk reduction.

Midlife hypercholesterolemia is a well-known risk factor for sporadic Alzheimer’s disease (AD), and like AD, it is highly influenced by genetics with heritability estimates of 32–63%. We thus hypothesized that genetics underlying peripheral blood total cholesterol (TC) levels could influence the risk of developing AD. We created a weighted polygenic score (TC-PGS) using summary data from a meta-analysis of TC genome-wide association studies for evaluation in three independent AD-related cohorts spanning pre-clinical, clinical, and pathophysiologically proved AD. APOE-ε4 variant was purposely included in the analysis as it represents an already well-established genetic risk factor for both AD and circulating TC. We could vastly improve the performance of the score when considering p-value thresholds for inclusion in the score, sex, and statin use. This optimized score (p-value threshold of 1 × 10−6 for inclusion in the score) explained 18.2% of the variance in TC levels in statin free females compared to 6.9% in the entire sample and improved prediction of hypercholesterolemia (receiver operator characteristics analysis revealed area under the curve increase from 70.8% to 80.5%). The TC-PGS was further evaluated for association with AD risk and pathology. We found no association between the TC-PGS and either of the AD hallmark pathologies, assessed by cerebrospinal fluid levels of Aβ-42, p-Tau, and t-Tau, and 18F-NAV4694 and 18F-AV-1451 positron emission tomography. Similarly, we found no association with the risk of developing amyloid pathology or becoming cognitively impaired in individuals with amyloid pathology.

Resting-state functional connectivity is suggested to be cross-sectionally associated with both vascular burden and Alzheimer's disease (AD) pathology. However, evidence is lacking regarding longitudinal changes in functional connectivity. This study includes 247 cognitively unimpaired individuals with a family history of sporadic AD (185 women/ 62 men; mean [SD] age of 63 [5.3] years). Plasma total-, HDL-, and LDL-cholesterol and systolic and diastolic blood pressure were measured at baseline. Global (whole-brain) brain functional connectivity and connectivity from canonical functional networks were computed from resting-state functional MRI obtained at baseline and ~3.5 years of annual follow-ups, using a predefined functional parcellation. A subsample underwent Aβ- and tau-PET (n=91). Linear mixed-effects models demonstrated that global functional connectivity increased over time across the entire sample. In contrast, higher total-cholesterol and LDL-cholesterol levels were associated with greater reduction of functional connectivity in the default-mode network over time. In addition, higher diastolic blood pressure was associated with global functional connectivity reduction. The associations were similar when the analyses were repeated using two other functional brain parcellations. Aβ and tau deposition in the brain were not associated with changes in functional connectivity over time in the subsample. These findings provide evidence that vascular burden is associated with a decrease in functional connectivity over time in older adults with elevated risk for AD. Future studies are needed to determine if the impact of vascular risk factors on functional brain changes precede the impact of AD pathology on functional brain changes.

Objective: To investigate the biological and clinical correlates of Aβ spatial extent deposition levels in cognitively unimpaired older adults. Methods: We included cognitively unimpaired older adults from three cohorts, totalling 529 participants (PREVENT-AD, n=129; ADNI, n=400 and HABS, n=288) who underwent Aβ positron emission tomography (PET). We used Gaussian-mixture models to identify region-specific thresholds of Aβ positivity in seven brain regions prone to early Aβ accumulation. Individuals were classified as having “widespread” Aβ deposition if they were positive in all seven regions, “regional” Aβ deposition if they were positive in one to six regions, or Aβ negative if negative in all regions. We compared demographics, genetics, tau-PET binding, and cognitive performance and decline between the three groups. Results: In all cohorts, most participants with regional Aβ-PET binding did not meet the cohort-specific criteria for Aβ-positivity (79% for PREVENT-AD, 57% for ADNI, and 100% for HABS). Regional Aβ groups had normal baseline cognition and relatively normal tau-PET binding, but a greater proportion of APOE ε4 carriers, decreased CSF Aβ 1-42 levels, and greater amount of longitudinal Aβ-PET binding accumulation (only available in ADNI and HABS) when compared with the Negative Aβ groups. Widespread Aβ groups had lower baseline cognitive performance (PREVENT-AD only), faster cognitive decline (all cohorts) and greater amount of longitudinal tau binding than the other groups (only available in ADNI and HABS). Conclusions: Individuals with regional Aβ deposition might be the best candidate for preventive trials since they do not yet have widespread tau and cognitive decline. Widespread levels of Aβ seem to be needed for tau spreading.

Identifying the leading health and lifestyle factors for the risk of incident dementia and Alzheimer's disease has yet to translate to risk reduction. To understand why, we examined the discrepancies between observational and clinical trial evidence for seven modifiable risk factors: type 2 diabetes, dyslipidemia, hypertension, estrogens, inflammation, omega-3 fatty acids, and hyperhomocysteinemia. Sample heterogeneity and paucity of intervention details (dose, timing, formulation) were common themes. Epidemiological evidence is more mature for some interventions (eg, non-steroidal anti-inflammatory drugs [NSAIDs]) than others. Trial data are promising for anti-hypertensives and B vitamin supplementation. Taken together, these risk factors highlight a future need for more targeted sample selection in clinical trials, a better understanding of interventions, and deeper analysis of existing data.

Objective To investigate relationships between flortaucipir (FTP) uptake, age, and established Alzheimer disease (AD) markers in asymptomatic adults at increased risk of AD. Methods One-hundred nineteen individuals with a family history of AD (Presymptomatic Evaluation of Experimental or Novel Treatments of Alzheimer’s Disease [PREVENT-AD] cohort, mean age 67 ± 5 years) underwent tau-PET ([18F]FTP), β-amyloid (Aβ)-PET ([18F]NAV4694 [NAV]), and cognitive assessment. Seventy-four participants also had CSF phosphorylated tau and total tau data available. We investigated the association between age and FTP in this relatively young cohort of older adults. We also investigated regional FTP standardized uptake value ratio (SUVR) differences between Aβ-positive and Aβ-negative individuals and regional correlations between FTP and NAV retention. In cortical regions showing consistent associations across analyses, we assessed whether FTP was in addition related to CSF tau and cognitive performance. Lastly, we identified the lowest FTP value at which associations with Aβ-PET, CSF, and cognition were detectable. Results Increased age was associated only with amygdala and transverse temporal lobe FTP retention. Aβ-positive individuals had higher FTP SUVR values in several brain regions, further showing correlation with NAV load through the cortex. Increased FTP SUVRs in medial temporal regions were associated with increased CSF tau values and worse cognition. The SUVRs at which associations between entorhinal FTP SUVR and other AD markers were first detected differed by modality, with a detection point of 1.12 for CSF values, 1.2 for Aβ-PET, and 1.4 for cognition. Conclusions Relatively low FTP-PET SUVRs are associated with pathologic markers of AD in the preclinical phase of the disease. Adjustment in the tau threshold should be considered, depending on the purpose of the tau classification.

Importance Fluid and imaging biomarkers of Alzheimer disease (AD) are often used interchangeably, but some biomarkers may reveal earlier stages of disease. Objective To characterize individuals with tau abnormality indicated by cerebrospinal fluid (CSF) assay or positron emission tomography (PET). Design, Setting, and Participants Between 2010 and 2019, 322 participants in the Alzheimer's Disease Neuroimaging Initiative (ADNI) underwent CSF and PET assessments of tau pathology. Data-driven, clinically relevant thresholds for CSF phosphorylated tau (P-tau) (≥26.64 pg/mL) and flortaucipir-PET meta-regions of interest (ROI) (standard uptake value ratio ≥1.37) indicated participants' tau status as CSF-/PET-, CSF+/PET-, CSF-/PET+, and CSF+/PET+. Of 1659 ADNI participants with a CSF or flortaucipir assessment, 588 had both measures (1071 were excluded). Among these, 266 were further excluded because they did not have flortaucipir and CSF testing within less than 25 months, leaving 322 for analysis. Of these, 213 were cognitively unimpaired (CU); 98 had mild cognitive impairment (MCI); and 11 had AD dementia. Main Outcomes and Measures We compared tau-positive vs tau-negative groups as indicated by either modality, demographic and clinical variables, amyloid β-PET burden, and flortaucipir-PET binding across Braak stage-related ROIs. We also compared 5-year rates of CSF P-tau accumulation and cognitive decline prior to flortaucipir-PET scanning. Results Among the 322 study participants, 180 were women (56%), and the mean (SD) age was 73.08 (7.37) years. Two hundred ten participants were CSF-/PET- (65%); 63 were CSF+/PET- (19.5%); 15 were CSF-/PET+ (4.6%); and 34 were CSF+/PET+ (10.5%). Most CSF-/PET+ participants had measures near CSF or PET tau thresholds. The CSF+/PET- participants showed faster 5-year accrual of P-tau and increased flortaucipir-PET binding in early Braak ROIs but similar memory decline compared with CSF-/PET- participants. Tau-positive individuals by either measure showed increased amyloid β-PET burden. All CSF+/PET+ individuals were amyloid-positive, and 26 had MCI or AD dementia (76%). Compared with the CSF-/PET- group, CSF+/PET+ individuals had experienced faster 5-year accrual of CSF P-tau and decline in memory and executive function, resulting in reduced cognitive abilities at the time of flortaucipir-PET assessment. Conclusions and Relevance Suprathreshold CSF P-tau without flortaucipir-PET abnormality may indicate a stage of AD development characterized by early tau abnormality without measurable loss in cognitive performance. Persons with both tau CSF and PET abnormality appear to have reduced cognitive capacities resulting from faster antecedent cognitive decline. Elevation of CSF P-tau appears to precede flortaucipir-PET positivity in the progression of AD pathogenesis and related cognitive decline.

Importance:Vascular risk factors are associated with increased risk of Alzheimer disease (AD), but it is unclear whether there is a direct association of these risk factors with AD pathogenesis. Objectives:To assess the associations of vascular risk factors with AD pathogenesis in asymptomatic individuals, and to test whether this association is moderated among individuals who use vascular medications. Design, Setting, and Participants:This cross-sectional study used data from the Presymptomatic Evaluation of Experimental or Novel Treatments for Alzheimer Disease (PREVENT-AD) cohort of cognitively unimpaired individuals aged 55 to 82 years with a parental or multiple-sibling history of sporadic AD, who were recruited via advertisement from the greater Montreal, Quebec, Canada, metropolitan area. Participants were enrolled between September 9, 2011, to May, 3, 2017, and stratified by use vs no use of vascular medications. Data were analyzed July 1, 2018, to April 5, 2019. Main Outcomes and Measures:Principal analyses investigated associations of total, high-density lipoprotein, and low-density lipoprotein cholesterol levels, systolic and diastolic blood pressure, pulse pressure, and a combined vascular risk score (measured using the Framingham Coronary Risk Profile) with global β-amyloid peptide (Aβ) and entorhinal tau burden as measured by positron emission tomography (PET). Potential moderating associations of use of vascular medications with these associations were examined. Secondary similar analyses considered cerebrospinal fluid (CSF) Aβ1-42 and phosphorylated tau levels. Results:Among 215 participants (mean [SD] age, 62.3 [5.0] years; 161 [74.8%] women), 120 participants underwent PET, including 75 participants (62.5%) who were not using vascular medications, and 162 participants underwent CSF assessment, including 113 participants (69.8%) who were not using vascular medications. There was an overlap of 67 participants who underwent PET and CSF assessment. Interaction analyses showed that among participants not using vascular medications, higher Aβ deposition as measured by PET was associated with higher total cholesterol level (β = -0.002 [SE, 0.001]; P = .02), low-density lipoprotein cholesterol level (β = -0.002 [SE, 0.001]; P = .006), systolic blood pressure (β = -0.006 [SE, 0.002]; P = .02), pulse pressure (β = -0.007 [SE, 0.002]; P = .004), and Framingham Coronary Risk Profile score (β = -0.038 [SE, 0.011]; P = .001), but such associations were absent in participants who used vascular medications. Interactions were also found between vascular medication use and high-density lipoprotein cholesterol (β = -3.302 [SE, 1.540]; P = .03), low-density lipoprotein cholesterol (β = 1.546 [SE, 0.754]; P = .04), and Framingham Coronary Risk Profile score (β = 23.102 [SE, 10.993]; P = .04) on Aβ1-42 burden as measured in CSF. Higher Framingham Coronary Risk Profile scores were associated with reduced tau burden among participants using vascular medications but not among participants not using vascular medications (interaction, β = -0.010 [SE, 0.005]; P = .046). Conclusions and Relevance:These findings corroborate previously reported associations of vascular risk factors with Aβ burden but not tau burden. However, these associations were found only among individuals who were not using vascular medications. These results suggest that medication use or other control of vascular risk factors should be considered in Alzheimer disease prevention trials.

IMPORTANCE Vascular risk factors are associated with increased risk of Alzheimer disease (AD), but it is unclear whether there is a direct association of these risk factors with AD pathogenesis. OBJECTIVES To assess the associations of vascular risk factors with AD pathogenesis in asymptomatic individuals, and to test whether this association is moderated among individuals who use vascular medications. DESIGN, SETTING, AND PARTICIPANTS This cross-sectional study used data from the Presymptomatic Evaluation of Experimental or Novel Treatments for Alzheimer Disease (PREVENT-AD) cohort of cognitively unimpaired individuals aged 55 to 82 years with a parental or multiple-sibling history of sporadic AD, who were recruited via advertisement from the greater Montreal, Quebec, Canada, metropolitan area. Participants were enrolled between September 9, 2011, to May, 3, 2017, and stratified by use vs no use of vascular medications. Data were analyzed July 1, 2018, to April 5, 2019. MAIN OUTCOMES AND MEASURES Principal analyses investigated associations of total, highdensity lipoprotein, and low-density lipoprotein cholesterol levels, systolic and diastolic blood pressure, pulse pressure, and a combined vascular risk score (measured using the Framingham Coronary Risk Profile) with global β-amyloid peptide (Aβ) and entorhinal tau burden as measured by positron emission tomography (PET). Potential moderating associations of use of vascular medications with these associations were examined. Secondary similar analyses considered cerebrospinal fluid (CSF) Aβ1-42 and phosphorylated tau levels. RESULTS Among 215 participants (mean [SD] age, 62.3 [5.0] years; 161 [74.8%] women), 120 participants underwent PET, including 75 participants (62.5%) who were not using vascular medications, and 162 participants underwent CSF assessment, including 113 participants (69.8%) who were not using vascular medications. There was an overlap of 67 participants who underwent PET and CSF assessment. Interaction analyses showed that among participants not using vascular medications, higher Aβ deposition as measured by PET was associated with higher total cholesterol level (β = −0.002 [SE, 0.001]; P = .02), low-density lipoprotein cholesterol level (β = −0.002 [SE, 0.001]; P = .006), systolic blood pressure (β = −0.006 [SE, 0.002]; P = .02), pulse pressure (β = −0.007 [SE, 0.002]; P = .004), and Framingham Coronary Risk Profile score (β = −0.038 [SE, 0.011]; P = .001), but such associations were absent in participants who used vascular medications. Interactions were also found between vascular medication use and high-density lipoprotein cholesterol (β = −3.302 [SE, 1.540]; P = .03), low-density lipoprotein cholesterol (β = 1.546 [SE, 0.754]; P = .04), and Framingham Coronary Risk Profile score (β = 23.102 [SE, 10.993]; P = .04) on (continued) Key Points Question Does cardiovascular medication use moderate the association of vascular risk factors with Alzheimer disease pathogenesis as measured by β-amyloid peptide and tau burdens among individuals who are cognitively unimpaired? Findings In this cross-sectional study of 215 middleand late-aged adults who were cognitively unimpaired, use of vascular medications moderated an association of higher lipid levels, blood pressure, and combined vascular risk scores with increased brain β-amyloid peptide burden. Regarding tau burden, use of vascular medications moderated none but the association of combined vascular risk with higher entorhinal tau deposition. Meaning This finding suggests that in individuals at risk for Alzheimer disease, treatment for common vascular risk factors may moderate or mask the associations of these factors with β-amyloid peptide burden. + Supplemental content Author affiliations and article information are listed at the end of this article. Open Access. This is an open access article distributed under the terms of the CC-BY License. JAMA Network Open. 2020;3(2):e1920780. doi:10.1001/jamanetworkopen.2019.20780 (Reprinted) February 7, 2020 1/16 Downloaded From: https://jamanetwork.com/ by a Washington University St Louis User on 03/08/2020 Abstract (continued)continued) Aβ1-42 burden as measured in CSF. Higher Framingham Coronary Risk Profile scores were associated with reduced tau burden among participants using vascular medications but not among participants not using vascular medications (interaction, β = −0.010 [SE, 0.005]; P = .046). CONCLUSIONS AND RELEVANCE These findings corroborate previously reported associations of vascular risk factors with Aβ burden but not tau burden. However, these associations were found only among individuals who were not using vascular medications. These results suggest that medication use or other control of vascular risk factors should be considered in Alzheimer disease prevention trials. JAMA Network Open. 2020;3(2):e1920780. doi:10.1001/jamanetworkopen.2019.20780

Introduction Cross-sectional studies suggest that cardiovascular risk factors and Alzheimer’s disease (AD) biomarkers are associated with abnormal brain resting-state functional connectivity in aging and AD; however, evidence is missing regarding longitudinal changes in functional connectivity. In this study, we investigate whether cholesterol levels and blood pressure are associated with changes in functional connectivity over time in asymptomatic individuals at risk for AD. The analyses were repeated with cerebral β-amyloid (Aβ) and tau deposition in a subset of the participants. Methods The study sample included 247 cognitively unimpaired individuals (185 women/ 62 men; mean [SD] age of 63 [5.3] years) of the PREVENT-AD cohort with a parental or multiple-sibling history of sporadic AD. Plasma total-, HDL-, and LDL-cholesterol and systolic and diastolic blood pressure were measured at baseline. Global brain functional connectivity, and connectivity from canonical functional networks, were computed from resting-state functional MRI obtained at baseline and up to four years of annual follow-ups, using a predefined functional parcellation. A subset of participants underwent tau -PET ([ 18 F]Flortaucipir) and Aβ-PET ([ 18 F]NAV4694). Vascular and AD measures were examined as predictors of brain functional connectivity changes in linear mixed-effects models. Results Higher total-cholesterol and LDL-cholesterol levels were associated with greater reduction of functional connectivity in the default-mode network over time. In addition, while overall whole-brain functional connectivity showed an increase over time across the entire sample higher diastolic blood pressure was associated with reduction in whole-brain functional connectivity. The associations were similar when the analyses were repeated using two other functional brain parcellations. The findings with total-cholesterol and diastolic blood pressure were also similar but attenuated when performed in a subsample of participants with PET (n=91), whereas AD biomarkers were not associated with changes in functional connectivity over time in this subsample. Conclusion These findings provide evidence that vascular burden is associated with a decrease in brain functional connectivity over time in older adults with elevated risk for AD. The impact of vascular risk factors on functional brain changes might precede AD pathology-related changes.

We studied 78 participants having a parental or multiple-sibling history of Alzheimer's disease (AD) in a two-year randomized placebo-controlled trial of naproxen 220 mg b.i.d. for mitigation of early AD pathogenesis. Naproxen was detected in cerebrospinal fluid at concentrations ~100 times lower than in plasma, but produced negligible change in immune markers. The repeated lack of benefit in AD prevention trials using naproxen and related drugs may reflect limited CNS permeability, lack of expected drug effects, or both. These findings suggest reconsideration of implications from results of AD prevention trials using anti-inflammatory drugs.

The influence of vascular risk factors (VRF) on Alzheimer's disease (AD) pathophysiology remains inconclusive. This study aims to examine the associations of lipids, blood pressure and combined VRF scores with Aß and tau pathology in the preclinical disease stage, considering the moderating impact of vascular drug treatment. Cognitively healthy individuals with family history of AD from the PREVENT-AD cohort were included (mean age: 62 years). Aß-PET [18F-NAV-4694] and tau-PET [Flortaucipir] scans were obtained from 120 individuals to examine the association between lipids [total cholesterol, high-density lipoprotein (HDL), low-density lipoprotein (LDL) cholesterol], blood pressure [systolic and diastolic blood pressure, pulse pressure], combined VRF scores [CAIDE, FCRP, FHS-CVD (see Figure1 legend)] and global Aß and entorhinal tau SUVR. Individuals were binarized for vascular medication (dyslipidemia and/or hypertensive drugs) to examine interaction effects, using linear regression models. Subsequently, we tested for within-group effects. All models were corrected for age, sex and time difference between VRF and PET measurements, while secondary models also included correction for apolipoproteinE ε4 (APOEε4) status. The analyses were repeated using CSF Aβ1-42 and p-tau biomarkers in 162 PREVENT-AD individuals (67 also included in the PET analyses). In most analyses, we found interactions between VRF and vascular medical treatment on Aß brain deposition (Figure1). In non-treated participants, higher levels of total cholesterol, LDL, systolic blood pressure, pulse pressure and all combined VRF scores were associated with higher Aß-PET deposition (all pnon-treated≤0.04). Similarly, total cholesterol, LDL and the CAIDE risk score were related to lower Aß1-42 in the CSF in non-treated participants only (all pnon-treated≤0.02). While PET results remained almost identical, CSF results were diminished after correction for APOEε4. No associations were found between VRF and tau.

Alzheimer's disease-(AD) related pathological changes are thought to occur decades prior to cognitive impairment. It was recently suggested that discrepancy between CSF and PET measures of amyloid-beta (Aβ) reflects timing of disease processes. We sought to assess whether similar observations were true for measures tau pathology. One-hundred seventeen non-demented participants (62 Healthy and 55 with Mild cognitive impairment) from the Alzheimer's Disease Neuroimaging Initiative (ADNI) had available CSF and PET (flortaucipir) measures of tau pathology within a 24-month interval. Using a data-driven, clinically relevant threshold for CSF P-tau (≥26.64 pg/mL) and a literature-based cut-off for entorhinal flortaucipir (SUVR≥1.3), we categorized individuals into four groups (CSF-/PET-; CSF+/PET-; CSF-/PET+ and CSF+/PET+). We then compared these groups on demographic/clinical variables, global Aβ-PET (AV-45) burden and tau-PET binding across all Braak stage ROIs. Finally, we assessed group differences in P-tau rates of accumulation in the years prior to flortaucipir scanning. Among all participants, 72 were CSF-/PET-, 18 were CSF+/PET-, 22 were CSF+/PET+, and only 6 were CSF-/PET+ (Table 1, Figure 1). Given the reduced inference from the CSF-/PET+ group, we did not consider it in our main analysis. All groups had comparable age, education years and sex ratios. There was an increase in Aβ-PET burden when comparing CSF-/PET-, CSF+/PET- and CSF+/PET+ individuals (Figure 2). CSF-/PET- and CSF+/PET- participants had comparable executive functioning, memory performance and a similar frequency of APOE ε4 carriers. When compared to both PET- groups, CSF+/PET+ individuals had worse cognitive and executive functioning performance (all P < 0.001). CSF+/PET- participants did not show any hints of elevated flortaucipir binding in Braak stage I-VI ROIs or at a single Desikan-Killiany atlas ROI level when compared to CSF-/PET- individuals. However, both CSF+ participant groups had faster retrospective rates of CSF P-tau accrual than CSF- participants (Figure 3).

The advent of amyloid-beta (Aβ) positron emission tomography (PET) imaging has transformed the field of Alzheimer's disease (AD) by enabling the quantification of cortical Aβ accumulation and propagation in vivo. This revolutionary tool has made it possible to measure direct associations between Aβ and other AD biomarkers, to identify factors that influence Aβ accumulation and to redefine entry criteria into clinical trials as well as measure drug target engagement. This chapter summarizes the main findings on the associations of Aβ with other biomarkers of disease progression across the AD spectrum. It discusses investigations of the timing at which Aβ pathology starts to accumulate, demonstrates the clinical utility of Aβ PET imaging and discusses some ethical implications. Finally, it presents genetic and potentially modifiable lifestyle factors that might influence Aβ accumulation and therefore be targets for AD prevention.

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