Preclinical Alzheimer's Disease Pathology Research Articles

Clinical Manifestations.

Accelerated Long-term Forgetting (ALF) is the phenomenon whereby material is retained normally over short intervals (minutes or hours) but forgotten abnormally rapidly over longer periods (days or weeks). ALF may be an early marker of cognitive decline, but little is known about its relationships with preclinical Alzheimer's disease pathology in older adults, and how memory selectivity may influence which material is forgotten. Participants in 'Insight 46', a sub-study of the MRC National Survey of Health and Development (British 1946 birth cohort), completed cognitive and neuroimaging assessments at two time-points (baseline at age ∼70; follow-up ∼2.4 years later). At follow-up, we assessed Complex Figure Drawing (copy; immediate recall; 30-minute recall; 7-day recall). Complex Figure items were categorized as 'outline' or 'detail' (Fig1), to test the hypothesis that forgetting the outline of the structure would be more sensitive to the effect of brain pathologies. ALF scores were calculated as the proportion of material retained after 7 days, relative to 30 minutes. Rates of cerebral atrophy between baseline and follow-up were quantified from T1-weighted MRI using the Brain Boundary Shift Integral (BBSI). β-amyloid status (positive/negative) was determined from 18F-Florbetapir-PET. Baseline serum neurofilament light (NfL) was quantified (Quanterix Simoa assay). Multivariable regression models were used to investigate the effects (mutually adjusted) of β-amyloid status, BBSI and NfL on ALF in n = 316 clinically-normal individuals (50% female; 22% β-amyloid positive; 30% APOE-ε4 carriers), and to explore interactions between these predictors, adjusting for potential confounders including prospectively-collected childhood cognitive ability and education. 'Outline' items were better retained than 'detail' (Fig1). β-amyloid-positive participants had poorer ALF scores for 'outline' (but not 'detail') items (Fig1C; Table 1). Unexpectedly, higher NfL was associated with scores for 'outline' items (Table 1). Greater rate of cerebral atrophy predicted poorer retention among participants with elevated β-amyloid and higher NfL (Table 1; Fig2). These results provide evidence of associations between biomarkers of brain pathologies and ALF in 73-year-olds. Interactions between different biomarkers merit further exploration. ALF may be a sensitive outcome measure for therapeutic trials in preclinical AD. Better retention of 'outline' (vs. 'detail') items illustrates the strategic role of memory selectivity.

Early β-amyloid accumulation in the brain is associated with peripheral T cell alterations.

Fast and minimally invasive approaches for early diagnosis of Alzheimer's disease (AD) are highly anticipated. Evidence of adaptive immune cells responding to cerebral β-amyloidosis has raised the question of whether immune markers could be used as proxies for β-amyloid accumulation in the brain. Here, we apply multidimensional mass-cytometry combined with unbiased machine-learning techniques to immunophenotype peripheral blood mononuclear cells from a total of 251 participants in cross-sectional and longitudinal studies. We show that increases in antigen-experienced adaptive immune cells in the blood, particularly CD45RA-reactivated T effector memory (TEMRA) cells, are associated with early accumulation of brain β-amyloid and with changes in plasma AD biomarkers in still cognitively healthy subjects. Our results suggest that preclinical AD pathology is linked to systemic alterations of the adaptive immune system. These immunophenotype changes may help identify and develop novel diagnostic tools for early AD assessment and better understand clinical outcomes.

Modeling functional and structural brain‐predicted age in relation to Alzheimer disease and cognition

AbstractBackgroundEstimates of “brain‐predicted age” quantify apparent brain age compared to normative trajectories of neuroimaging features. Brain‐predicted age is elevated in symptomatic Alzheimer disease (AD), but is underexplored in preclinical AD. Prior studies have typically modeled brain‐predicted age with volumetric magnetic resonance imaging (MRI), but other modalities, including resting‐state functional connectivity (FC) and multimodal MRI, have more recently been explored. In the present study, we tested the sensitivity of brain‐age predictions derived from volumetric, FC, and multimodal MRI to group differences in AD status and individual differences in cognition.MethodWe trained three Gaussian process regression models to predict age from (1) FC, (2) regional brain volumes, and (3) multimodal MRI (FC+volumetric) in 493 control participants (cognitively normal, amyloid‐negative [A‐], 18‐89 years old). We applied the trained models to independent samples staged by the presence or absence of amyloid (A+/A‐) and tau (T+/T‐) using PET (Centiloid) and CSF (amyloid β‐42/40 ratio, phosphorylated tau 181): 122 A‐T‐, 62 A+T‐, 62 A+T+, as well as 154 symptomatic AD participants. Global cognition was assessed using an established composite of cognitive tests across multiple domains.ResultAll models successfully predicted age in the control training set, with the multimodal model (mean absolute error [MAE]=5.3 years) outperforming the unimodal volumetric (MAE=6.0 years) and FC models (MAE=8.3 years) (Figure 1). In all three models, the brain age gap (BAG) was significantly elevated in symptomatic AD compared to cognitively normal controls. In the FC and multimodal models, the BAG was significantly reduced in A+T+ participants compared to T‐ controls (Figure 2). In symptomatic AD, lower global cognitive composite scores were associated with elevated volumetric and multimodal BAGs (Figure 3).ConclusionBoth FC and volumetric estimates of brain age are sensitive to symptomatic AD, consistent with previous reports. Additionally, FC‐based brain age may exhibit a biphasic response to preclinical AD pathology while volumetric brain age may be sensitive to cognitive decline in the symptomatic stage. Multimodal estimates of brain age capture each of these modality‐specific relationships, and further, improve sensitivity to healthy age differences. Hence, multimodal neuroimaging models may be useful in staging early symptomatic and preclinical AD.

Predicting brain age from functional connectivity in symptomatic and preclinical Alzheimer disease

“Brain-predicted age” quantifies apparent brain age compared to normative neuroimaging trajectories. Advanced brain-predicted age has been well established in symptomatic Alzheimer disease (AD), but is underexplored in preclinical AD. Prior brain-predicted age studies have typically used structural MRI, but resting-state functional connectivity (FC) remains underexplored. Our model predicted age from FC in 391 cognitively normal, amyloid-negative controls (ages 18–89). We applied the trained model to 145 amyloid-negative, 151 preclinical AD, and 156 symptomatic AD participants to test group differences. The model accurately predicted age in the training set. FC-predicted brain age gaps (FC-BAG) were significantly older in symptomatic AD and significantly younger in preclinical AD compared to controls. There was minimal correspondence between networks predictive of age and AD. Elevated FC-BAG may reflect network disruption during symptomatic AD. Reduced FC-BAG in preclinical AD was opposite to the expected direction, and may reflect a biphasic response to preclinical AD pathology or may be driven by inconsistency between age-related vs. AD-related networks. Overall, FC-predicted brain age may be a sensitive AD biomarker.

Beta-amyloid moderates the relationship between cortical thickness and attentional control in middle- and older-aged adults

Although often unmeasured in studies of cognition, many older adults possess Alzheimer disease (AD) pathologies such as beta-amyloid (Aβ) deposition, despite being asymptomatic. We were interested in examining whether the behavior-structure relationship observed in later life was altered by the presence of preclinical AD pathology. A total of 511 cognitively unimpaired adults completed magnetic resonance imaging and three attentional control tasks; a subset (n = 396) also underwent Aβ-positron emissions tomography. A vertex-wise model was conducted to spatially represent the relationship between cortical thickness and average attentional control accuracy, while moderation analysis examined whether Aβ deposition impacted this relationship. First, we found that reduced cortical thickness in temporal, medial- and lateral-parietal, and dorsolateral prefrontal cortex, predicted worse performance on the attention task composite. Subsequent moderation analyses observed that levels of Aβ significantly influence the relationship between cortical thickness and attentional control. Our results support the hypothesis that preclinical AD, as measured by Aβ deposition, is partially driving what would otherwise be considered general aging in a cognitively normal adult population.

Association of CSF Biomarkers With Hippocampal-Dependent Memory in Preclinical Alzheimer Disease.

To determine whether memory tasks with demonstrated sensitivity to hippocampal function can detect variance related to preclinical Alzheimer disease (AD) biomarkers, we examined associations between performance in 3 memory tasks and CSF β-amyloid (Aβ)42/Aβ40 and phosopho-tau181 (p-tau181) in cognitively unimpaired older adults (CU). CU enrolled in the Stanford Aging and Memory Study (n = 153; age 68.78 ± 5.81 years; 94 female) completed a lumbar puncture and memory assessments. CSF Aβ42, Aβ40, and p-tau181 were measured with the automated Lumipulse G system in a single-batch analysis. Episodic memory was assayed using a standardized delayed recall composite, paired associate (word-picture) cued recall, and a mnemonic discrimination task that involves discrimination between studied "target" objects, novel "foil" objects, and perceptually similar "lure" objects. Analyses examined cross-sectional relationships among memory performance, age, and CSF measures, controlling for sex and education. Age and lower Aβ42/Aβ40 were independently associated with elevated p-tau181. Age, Aβ42/Aβ40, and p-tau181 were each associated with (1) poorer associative memory and (2) diminished improvement in mnemonic discrimination performance across levels of decreased task difficulty (i.e., target-lure similarity). P-tau mediated the effect of Aβ42/Aβ40 on memory. Relationships between CSF proteins and delayed recall were similar but nonsignificant. CSF Aβ42 was not significantly associated with p-tau181 or memory. Tests designed to tax hippocampal function are sensitive to subtle individual differences in memory among CU and correlate with early AD-associated biomarker changes in CSF. These tests may offer utility for identifying CU with preclinical AD pathology.

Fractal motor activity regulation and sex differences in preclinical Alzheimer's disease pathology.

IntroductionDegradation in fractal motor activity regulation (FMAR), a measure of multiscale self‐similarity of motor control, occurs in aging and accelerates with clinical progression to Alzheimer's disease (AD). Whether FMAR changes occur during the pre‐symptomatic phase of the disease in women and men remains unknown.MethodsFMAR was assessed in cognitively normal participants (n = 178) who underwent 7 to 14 days of home actigraphy. Preclinical AD pathology was determined by amyloid imaging‐Pittsburgh compound B (PiB) and cerebrospinal fluid (CSF) phosphorylated‐tau181 (p‐tau) to amyloid beta 42 (Aβ42) ratio.ResultsDegradation in daytime FMAR was overall significantly associated with preclinical amyloid plaque pathology via PiB+ imaging (beta coefficient β = 0.217, standard error [SE] = 0.101, P = .034) and increasing CSF tau181‐Aβ42 ratio (β = 0.220, SE = 0.084, P = .009). In subset analysis by sex, the effect sizes were significant in women for PiB+ (β = 0.279, SE = 0.112, P = .015) and CSF (β = 0.245, SE = 0.094, P = .011) but not in men (both Ps > .05). These associations remained after inclusion of daily activity level, apolipoprotein E ε4 carrier status, and rest/activity patterns.DiscussionChanges in daytime FMAR from actigraphy appear to be present in women early in preclinical AD. This may be a combination of earlier pathology changes in females reflected in daytime FMAR, and a relatively underpowered male group. Further studies are warranted to test FMAR as an early noncognitive physiological biomarker that precedes the onset of cognitive symptoms.

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

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

RACE MODIFIES THE RELATIONSHIP BETWEEN ALZHEIMER’S DISEASE (AD) BIOMARKERS AND COGNITION IN A COHORT OF MIDDLE-AGED INDIVIDUALS AT HIGH-RISK FOR AD

The rate of AD for African American's (AAs) is 64% higher than for non-Hispanic White Americans (Whites). It is hypothesized that poor peripheral vascular function, in combination with genetics, stress and inflammation may directly contribute to the accumulation of AD pathologic biomarkers. These risk factors may disproportionately affect AAs. We hypothesized that AD biomarkers in CSF differ by race, that peripheral vascular dysfunction and cognition are related to higher burden of CSF AD biomarkers, and that these relationships differ by race. The Association between Cardiovascular Risk and Preclinical Alzheimer's Disease Pathology (ASCEND) Study is a longitudinal, two-year observational study which enrolled 82 cognitively normal, middle-aged (45 and older) adults including AAs and Whites at high risk for AD due to parental history. Here, we present results of baseline data. Study procedures included lumbar puncture for CSF collection, peripheral vascular ultrasound and cognitive testing. 30 AAs and 50 Whites were enrolled. Participants were middle aged (60.1 ± 7.8yrs and 58.5 ± 6.1yrs in Whites and AAs, respectively). 83.3% of AAs were female compared to 56.0% of Whites. AAs performed more poorly on all cognitive tests, though participants were all cognitively normal. While participants were in overall good health (systolic blood pressure (SBP) 127.6 ± 13.3bpm in AAs and 125.1 ± 12.3bpm in Whites), AAs exhibited poorer indices of preclinical vascular health, including higher central SBP, central mean arterial pressure (MAP), and EndoPAT AI, a marker of arterial stiffness. Finally, AAs had significantly less CSF tau burden than Whites. After polynomial regression analysis, adjusted for age, gender, education, and ApoE4 status, we found that race significantly modified the relationship between total tau, phospho-tau and Trails b, a marker of executive function. Small differences in tau correlated with poorer cognition in AAs when compared to Whites (Figure 1, 2, and 3).

Cerebral metabolism in a mouse model of Alzheimer's disease characterized by two-photon fluorescence lifetime microscopy of intrinsic NADH.

.Disruptions and alterations to cerebral energy metabolism play a vital role in the onset and progression of many neurodegenerative disorders and cerebral pathologies. In order to precisely understand the complex alterations underlying Alzheimer’s disease (AD) progression, in vivo imaging at the microscopic level is required in preclinical animal models. Utilizing two-photon fluorescence lifetime imaging microscopy and the phasor analysis method, we have observed AD-related variations of endogenous fluorescence of reduced nicotinamide adenine dinucleotide (NADH) in vivo. We collected NADH FLIM images from the cerebral cortices of both APPswe:PS1dE9 mice to model amyloid plaque accumulation and corresponding age-matched wildtype controls. Distinct variations in NADH fluorescence lifetime between wildtype and AD mice, as well as variations related to proximity from amyloid plaques, are obvervable via the phasor method. The combination of NADH FLIM and phasor analysis allows for a minimally invasive, high-resolution technique to characterize the adverse effects of amyloid accumulation on mitochondrial energy metabolism and could guide our understanding of preclinical AD pathology.

The spectrum of preclinical Alzheimer's disease pathology and its modulation by ApoE genotype.

Sporadic Alzheimer's disease (AD) usually presents clinically after 65years of age, but its pathological changes begin decades earlier. We examined for AD pathology in the postmortem brains of 431 of subjects aged 30-65years not clinically characterized. Among 40-49year olds, 15% showed diffuse amyloid β (Aβ) plaques, with a prevalence of 80% in ApoE4/E4, 42% in E4/E3, and <1% in E3/E3 subjects. Aβ deposits appeared after age 49years in subjects with E3/E3 genotypes. Neuritic plaques first appeared after age 50years and increased steadily with age in all genotypes. Insoluble Aβ42 levels were highest in parietal, temporal, and frontal lobes, but barely detectable in precuneus. Tau lesions were present in the hippocampus and entorhinal cortex in 7% of subjects aged <40years and increased steadily with age reaching near 70% in the 60- to 65-year age group. In the locus coeruleus, tau lesions were present in 72% of subjects aged 31-40years and 94% in the 41- to 50-year age group. Both Aβ and tau lesions are present in the brains of young individuals decades before the age of clinical onset of AD. Aβ lesions closely correlate with the ApoE4 allele and appear as the earliest event in the development of senile plaques.

Preclinical Alzheimer's Disease: Implications for Refinement of the Concept.

Increasing interest in clinical trials and clinical research settings to identify Alzheimer's disease (AD) in the earliest stages of the disease has led to the concept of preclinical AD. Individuals with preclinical AD have AD pathology without clinical symptoms yet. Accumulating evidence has shown that biomarkers can identify preclinical AD and that preclinical AD is associated with a poor clinical outcome. Little is known yet about the role of vascular and lifestyle risk factors in the development of preclinical AD. In order to better understand preclinical AD pathology and clinical progression rates, there is a need to refine the concept of preclinical AD. This will be of great value for advancements in future research, clinical trials, and eventually clinical practice.

Circadian Rest-Activity Pattern Changes in Aging and Preclinical Alzheimer Disease

Circadian rhythm disturbances occur in symptomatic Alzheimer disease (AD) and have been hypothesized to contribute to disease pathogenesis. However, it is unknown whether circadian changes occur during the presymptomatic phase of the disease. To examine the associations between circadian function, aging, and preclinical AD pathology in cognitively normal adults. This cross-sectional study was conducted using community volunteers from the Knight Alzheimer's Disease Research Center at Washington University in St Louis. Cognitively normal participants (n = 205) underwent 7 to 14 days of actigraphy in their home environment between 2010 and 2012, in addition to clinical assessment, amyloid imaging with Pittsburgh Compound B (PiB), and cerebrospinal fluid biomarker collection. Data collected from 3 years before to 6 months after actigraphy were included. Sixteen participants were excluded owing to incomplete data collection. Circadian rhythm analysis was performed on actigraphy data using 3 methods: cosinor, nonparametric, and empirical mode decomposition. Preclinical AD was assessed by longitudinal clinical assessment, amyloid imaging with PiB, and cerebrospinal fluid biomarker collection. Data from 189 participants were included in the analyses. The mean (SD) age was 66.6 (8.3) years, and 121 participants (64%) were women. Older age (β = .247; P = .003) and male sex (β = .170; P = .04), in the absence of amyloid pathology, were associated with a significant increase in intradaily variability, a nonparametric measure of rest-activity rhythm fragmentation, as well as decreased amplitude by several measures. After correction for age and sex, the presence of preclinical amyloid plaque pathology, assessed by positive PiB imaging (mean [SD], 0.804 [0.187] for PiB negative vs 0.875 [0.178] for PiB positive; P = .05) or increasing cerebrospinal fluid phosphorylated-tau to amyloid β 42 ratio (β = .231; P = .008), was associated with increased intradaily variability, indicating rest-activity rhythm fragmentation. Preclinical AD is associated with rest-activity rhythm fragmentation, independent of age or sex. Aging was also associated with circadian dysfunction independently of preclinical AD pathology, particularly in men. The presence of circadian rhythm abnormalities in the preclinical phase of AD suggests that circadian dysfunction could contribute to early disease pathogenesis or serve as a biomarker of preclinical disease.

Process dissociation analyses of memory changes in healthy aging, preclinical, and very mild Alzheimer disease: Evidence for isolated recollection deficits.

Recollection and familiarity are independent processes that contribute to memory performance. Recollection is dependent on attentional control, which has been shown to be disrupted in early stage Alzheimer's disease (AD), whereas familiarity is independent of attention. The present longitudinal study examines the sensitivity of recollection estimates based on Jacoby's (1991) process dissociation procedure to AD-related biomarkers in a large sample of well-characterized cognitively normal middle-aged and older adults (N = 519) and the extent to which recollection discriminates these individuals from individuals with very mild symptomatic AD (N = 64). Participants studied word pairs (e.g., knee bone), then completed a primed, explicit, cued fragment-completion memory task (e.g., knee b_n_). Primes were either congruent with the correct response (e.g., bone), incongruent (e.g., bend), or neutral (e.g., &&&). This design allowed for the estimation of independent contributions of recollection and familiarity processes, using the process dissociation procedure. Recollection, but not familiarity, was impaired in healthy aging and in very mild AD. Recollection discriminated cognitively normal individuals from the earliest detectable stage of symptomatic AD above and beyond standard psychometric tests. In cognitively normal individuals, baseline CSF measures indicative of AD pathology were related to lower initial recollection and less practice-related improvement in recollection over time. Finally, presence of amyloid plaques, as imaged by PIB-PET, was also related to less improvement in recollection over time. These findings suggest that attention-demanding memory processes, such as recollection, may be particularly sensitive to both symptomatic and preclinical AD pathology. (PsycINFO Database Record

Odor identification as a biomarker of preclinical AD in older adults at risk.

Objective:To assess odor identification (OI) as an indicator of presymptomatic Alzheimer disease (AD) pathogenesis in cognitively normal aging individuals at increased risk of AD dementia.Methods:In 274 members of the PREVENT-AD cohort of healthy aging persons with a parental or multiple-sibling history of AD dementia, we assessed the cross-sectional association of OI with potential indicators of presymptomatic AD. Some 101 participants donated CSF, thus enabling assessment of AD pathology with the biomarkers total tau (t-tau), phospho-tau (P181-tau), and their ratios with β-amyloid (Aβ1-42). Adjusted analyses considered age, cognition, APOE ε4 status, education, and sex as covariates. We measured OI using the University of Pennsylvania Smell Identification Test and cognitive performance using the Repeatable Battery for Assessment of Neuropsychological Status. Standard kits provided assays of the AD biomarkers. Analyses used robust-fit linear regression models.Results:Reduced OI was associated with lower cognitive score and older age, as well as increased ratios of CSF t-tau and P181-tau to Aβ1-42 (all p < 0.02). However, the observed associations of OI with age and cognition were unapparent in adjusted models that restricted observations to CSF donors and included AD biomarkers. OI showed little association with CSF Aβ1-42 alone except in APOE ε4 carriers having lowest-quartile Aβ1-42 levels.Conclusions:These findings from healthy high-risk older individuals suggest that OI reflects degree of preclinical AD pathology, while its relationships with age and cognition result from the association of these latter variables with such pathology. Diminished OI may be a practical and affordable biomarker of AD pathology.

Tau PET: the next frontier in molecular imaging of dementia.

We have arrived at an exciting juncture in dementia research: the second major pathological hallmark of Alzheimer's disease (AD)-tau-can now be seen for the first time in the living human brain. The major proteinopathies in AD include amyloid-β plaques and neurofibrillary tangles (NFTs) made of hyperphosphorylated paired helical filament (PHF) tau. Since its advent more than a decade ago, amyloid PET imaging has revolutionized the field of dementia research, enabling more confident diagnosis of the likely pathology in patients with a variety of clinical dementia syndromes, paving the way for the identification of people with preclinical or prodromal AD pathology, and serving as a minimally invasive molecular readout in clinical trials of putative disease-modifying interventions. Now that we are on the brink of a second revolution in molecular imaging in dementia, it is worth considering the likely potential impact of this development on the field.

Can physical exercise in old age improve memory and hippocampal function?

Physical exercise can convey a protective effect against cognitive decline in ageing and Alzheimer's disease. While the long-term health-promoting and protective effects of exercise are encouraging, it's potential to induce neuronal and vascular plasticity in the ageing brain is still poorly understood. It remains unclear whether exercise slows the trajectory of normal ageing by modifying vascular and metabolic risk factors and/or consistently boosts brain function by inducing structural and neurochemical changes in the hippocampus and related medial temporal lobe circuitry-brain areas that are important for learning and memory. Hence, it remains to be established to what extent exercise interventions in old age can improve brain plasticity above and beyond preservation of function. Existing data suggest that exercise trials aiming for improvement and preservation may require different outcome measures and that the balance between the two may depend on exercise intensity and duration, the presence of preclinical Alzheimer's disease pathology, vascular and metabolic risk factors and genetic variability.

Alzheimer Disease Cerebrospinal Fluid Biomarkers Moderate Baseline Differences and Predict Longitudinal Change in Attentional Control and Episodic Memory Composites in the Adult Children Study.

Cognitive measures that are sensitive to biological markers of Alzheimer disease (AD) pathology are needed to (a) facilitate preclinical staging, (b) identify individuals who are at the highest risk for developing clinical symptoms, and (c) serve as endpoints for evaluating the efficacy of interventions. The present study assesses the utility of two cognitive composite scores of attentional control and episodic memory as markers for preclinical AD pathology in a group of cognitively normal older adults (N = 238), as part of the Adult Children Study. All participants were given a baseline cognitive assessment and follow-up assessments every 3 years over an 8-year period, as well as a lumbar puncture within 2 years of the initial assessment to collect cerebrospinal fluid (CSF) and amyloid tracer Pittsburgh compound-B scan for amyloid imaging. Results indicated that attentional control was correlated with levels of Aβ42 at the initial assessment whereas episodic memory was not. Longitudinally, individuals with high CSF tau exhibited a decline in both attention and episodic memory over the course of the study. These results indicate that measures of attentional control and episodic memory can be used to evaluate cognitive decline in preclinical AD and provide support that CSF tau may be a key mechanism driving longitudinal cognitive change.

Pathology of clinical and preclinical Alzheimer’s disease

Alzheimer's disease (AD) is characterized neuropathologically by the presence of amyloid plaques, neuritic plaques, and neurofibrillary tangles (NFTs). These lesions occur not only in demented individuals with AD but also in non-demented persons. In non-demented individuals, amyloid and neuritic plaques are usually accompanied with NFTs and are considered to represent asymptomatic or preclinical AD (pre-AD) pathology. Here, we defined and characterized neuropathological differences between clinical AD, non-demented pre-AD, and non-AD control cases. Our results show that clinical AD may be defined as cases exhibiting late stages of NFT, amyloid, and neuritic plaque pathology. This is in contrast to the neuropathological changes characteristic of pre-AD, which display early stages of these lesions. Both AD and pre-AD cases often exhibit cerebral amyloid angiopathy (CAA) and granulovacuolar degeneration (GVD), and when they do, these AD-related pathologies were at early stages in pre-AD cases and at late stages in symptomatic AD. Importantly, NFTs, GVD, and CAA were also observed in non-AD cases, i.e., in cases without amyloid plaque pathology. Moreover, soluble and dispersible, high-molecular-weight amyloid β-protein (Aβ) aggregates detected by blue-native polyacrylamide gel electrophoresis were elevated in clinical AD compared to that in pre-AD and non-AD cases. Detection of NFTs, GVD, and CAA in cases without amyloid plaques, presently classified as non-AD, is consistent with the idea that NFTs, GVD, and CAA may precede amyloid plaque pathology and may represent a pre-amyloid plaque stage of pre-AD not yet considered in the current recommendations for the neuropathological diagnosis of AD. Our finding of early stages of AD-related NFT, amyloid, and GVD pathology provides a more clear definition of pre-AD cases that is in contrast to the changes in clinical AD, which is characterized by late stages of these AD-related pathologies. The observed elevation of soluble/dispersible Aβ aggregates from pre-AD compared to that in AD cases suggests that, in addition to more widespread AD-related pathologies, soluble/dispersible Aβ aggregates in the neuropil play a role in the conversion of pre-AD to clinical AD.

Effects of Atorvastatin on Cerebral Blood Flow in Middle-Aged Adults at Risk for Alzheimer’s Disease: A Pilot Study

Hypercholesterolemia in midlife increases risk for Alzheimer's disease (AD) and contributes to cerebrovascular dysregulation - an early finding in preclinical AD pathology. Statins improve vascular reactivity, but it is unknown if they increase regional cerebral blood flow (CBF) in individuals at risk for AD. In a randomized, controlled, double-blind pilot study, 16 asymptomatic middle-aged adults with parental history of AD were randomized to atorvastatin or placebo daily for 4 months. At baseline and month 4, regional CBF was measured using arterial spin-labeling magnetic resonance imaging and endothelial function was measured using brachial artery ultrasound. At baseline, participants with low HDL-cholesterol, higher global vascular risk, and greater endothelial dysfunction had reduced regional CBF in areas of the brain related to memory and learning (all p < 0.03). Using voxel-based analysis, 4 months of atorvastatin increased CBF in bilateral hippocampi, fusiform gyrus, putamen and insular cortices compared to placebo. In this pilot study, atorvastatin increased regional CBF in persons at risk for AD. Further research is warranted to confirm whether statins increase CBF in areas of the brain related to memory and learning and whether such perfusion changes are associated with a delay in the onset of AD. http://clinicaltrials.gov Identifier: NCT00751907.