Efficacy and Safety of Gantenerumab in Patients With Alzheimer Disease: A Systematic Review and Meta-analysis.

To the Editor .— We are writing to you about a recent article that appeared in Pediatrics .1 The authors of this very interesting article claimed that posttraumatic stress disorder (PTSD) “symptoms and cortisol levels at baseline are associated with changes in hippocampal volume over an ensuing 12- to 18-month interval” after a stressful life event. However, we believe that this strong claim is not supported by the data the authors presented. The first problem is that the methods the authors used to measure hippocampal volume are of low precision. In all studies that use MRI to measure brain volume, experimental variance can be introduced during data acquisition (eg, patient motion, changes in scanner hardware or software, scanner field variation) and during data analysis (eg, partial-volume problems, voxel misclassification, manual delineation error).2 Among the 15 children who they evaluated, the authors acknowledged (in line 3 of “Results”) that there was 1 child who showed an increase in right hippocampal volume that amounted to a full SD, or ∼15%. This child was excluded from additional evaluation. However, the existence of 1 outlier this extreme suggests that the method of measuring hippocampal volume was relatively imprecise. This inference is consistent with the fact that the authors measured interrater reliability but did not report the results. If we hypothesize that the volume-measurement methods used were imprecise and that hippocampal volume of these subjects did not actually change over the time interval studied, what results would have been obtained? We would expect that hippocampal volume change scores would have fluctuated randomly and would not have been significantly different from 0. This is precisely the outcome shown in Table 1, in …

Alzheimer’s Disease (AD) is the most common single cause of dementia in our ageing society. Traditionally thought of as an untreatable degenerative condition, recent advances in drug therapy have challenged this view. The disease is characterised by an insidious decline in cognitive and non-cognitive function. Classically, short and long-term memory is impaired while language skills, concentration and attention are often affected. This results in impaired ability to learn and retain new skills as well as the loss of existing ones. Non-cognitive function is the global term used to describe problems such as depression, agitation, personality changes, delusions and hallucinations. These factors have a significant impact on patient behaviour and a very real impact on the quality of life for both patients and caregivers. Diagnosis of AD is clinically based, and using the NINCDS-ADRDA criteria (Table 1) [1], a diagnosis of probable or possible AD can be made. Definitive diagnosis relies on pathological confirmation, which in the majority of cases is rarely completed. With the development of AD specific treatments, definition of AD from other types of dementia is very important. Table 1 NINCDS-ADRDA Criteria for clinical diagnosis of Alzheimer’s disease. Pathogenesis The pathogenesis of AD has not yet been elucidated. It is widely accepted that a combination of genetic susceptibility factors and environmental triggers are responsible for late onset sporadic AD, the most common form of the disease. An understanding of the disease mechanism remains elusive, and is the key to developing a disease modifying agent. Currently, it is proposed that beta amyloid protein, abnormal tau protein or possibly both play key factors in the development of disease. It has been widely postulated that oxidative damage and a slow inflammatory process are two possible mechanisms involved. As yet, no product with proven disease modifying properties is available, and current treatments offer symptomatic benefit only. The development of acetylcholinesterase (AChe) inhibitor drugs has followed the finding that cholinergic pathways in the cerebral cortex and basal forebrain are compromised in AD [2] and the resultant cholinergic deficit contributes to the cognitive impairment of these patients [3]. Although many believe this ‘cholinergic hypothesis’ to be important, others feel it represents a less significant component of the disease process [4]. Many other neurotransmitters are affected in AD, and the relative importance of each in relation to clinical findings has not been fully elucidated. Initial work focused on the use of acetylcholine precursors, using a similar rationale to dopamine therapy in Parkinson’s disease. A series of small trials using precursors such as choline and phosphatidylcholine showed no reliable improvement in cognitive function, with only 10 out of 43 trials reporting any positive effect [5]. There has been renewed interest in muscarinic agonists drugs, which when first introduced, had major problems with adverse cholinergic effects. Better understanding of the molecular pathology of muscarinic receptors and their subtypes has led to the development of more specific agonists. Drugs such as xanomeline, milameline, and civimeline have reached clinical trials, and the improvements seen in cognitive function are reviewed by Avery et al. [6]. There are also claims that these drugs have disease modifying properties, with effects on APP processing and tau phosphorylation. Muscarinic agonists remain in trial, but have yet to fulfil their potential in AD treatment. The only group of drugs currently licensed for AD treatment is the AChe inhibitors, which act through inhibition of the enzyme acetylcholinesterase (AChe), responsible for the breakdown of ACh in the neural synapse. A meta-analysis of the early AChe inhibitor treatments was encouraging [7] and these proceeded to larger placebo controlled double-blind trials.

Numerous studies suggest that the development of Alzheimer's Disease (AD) leads to a reduction in overall hippocampal volume. However, there is limited research exploring whether pre-morbid differences in hippocampal volume impact the risk of AD. This study aims to delve into the causal relationship between hippocampal subregional volume and AD using bidirectional Mendelian Randomization (MR) methods. We extracted 44 instrumental variables for hippocampal subregional volume from the GWAS Catalog, involving 21,282 European individuals. Data on Alzheimer's Disease were sourced from the Psychiatric Genomics Consortium, comprising 1,126,563 European individuals. Rigorous methods were employed to select instrumental variables, with the primary analysis conducted using the Inverse Variance Weighted method. Several sensitivity analyses included tests for heterogeneity, pleiotropy, and outliers. The obtained SNPs were mapped to genes for pathway enrichment analysis to explore the potential mechanisms underlying the regulation of hippocampal volume in Alzheimer's disease. The study found significant causal associations between increased volume of the 5 hippocampal subfields with increased risk of AD. Conversely, increased Left hippocampus amygdala-transition-area volume was associated with reduced risk of AD. In reverse MR, AD was found to decrease the volume of 8 hippocampal subfields, while increasing the volume of the left hippocampal-fissure region. Amyloid-beta formation, leukocyte activation, and positive regulation of immune response mediated the changes in hippocampal subregional volume due to AD. This MR study provides evidence that AD is causally related to hippocampal subfield volume, highlighting the roles of amyloid-beta formation and immune alterations in this context.

BackgroundMRI‐derived brain‐age prediction is a promising biomarker of biological brain aging. Accelerated brain aging has been found in Alzheimer’s disease (AD) and other neurodegenerative diseases. However, no previous studies have investigated the relationship between specific pathophysiological pathways in AD and biological brain aging. Here, we studied whether glial activation and synaptic dysfunction are associated with biological brain aging in the earliest stages of the Alzheimer’s continuum.MethodWe included 418 cognitively unimpaired individuals (CU) from the ALFA+ study with available structural MRI, and CSF biomarkers of amyloid‐ß (Aß42/40) and tau pathology (p‐tau181), synaptic dysfunction (neurogranin, GAP43, SYT1, SNAP25), glial activation (sTREM2, YKL40, GFAP, interleukin‐6 and S100b) and a‐synuclein (Table 1). Aß42/40, neurogranin and the glial activation biomarkers were measured using the Roche NeuroToolKit. We computed brain‐age delta as the difference between chronological and predicted brain‐age. The latter was estimated using a previously pretrained machine learning algorithm on cerebral morphological measurements on individuals from the UKBioBank cohort (N = 22.000). General linear modeling was used to test the associations between CSF biomarkers and brain‐age delta, adjusting by p‐tau, age, APOE status and sex. For the biomarkers whose associations were significant, we evaluated the interaction term “biomarker” × AT status while adjusting by age, APOE status and sex. AT staging was performed using pre‐established cut‐off values. We then used hippocampal volume as a marker of AD‐related neurodegeneration and repeated the same association studies with CSF biomarkers, adjusting by p‐tau, age, APOE status, sex and TIV.ResultBrain‐age delta was negatively associated with CSF sTREM2 (Padjusted<0.001), meaning that younger‐appearing brains showed higher levels of this biomarker (Table 1). None of the other biomarkers survived multiple comparisons. Hippocampal volume was not significantly associated with any of the CSF biomarkers (Table 2). There was no significant interaction between AT status and CSF sTREM2 for brain‐age delta, nor for hippocampal volume.ConclusionThese results showed that higher levels of CSF sTREM2 were associated with younger‐appearing brains in CU individuals independently of AT status, which might indicate a protective effect of this microglial phenotype in brain aging. This effect might not be AD‐related.

Objective To investigate the correlation and influencing factors between mild cognitive impairment （MCI） and the changes of hippocampal and entorhinal cortex volume and to evaluate the value of using MRI volumetric measurement of hippocampus and entorhinal cortex to identify MCI and normal cognition （NC）. Methods Twenty-one subjects selected from physical examinations were divided into an MCI group and 18 subjects were divided into an NC group. The general assessment, laboratory tests and neuropsychological scale evaluation were conducted. The MRI volumetric measurement of hippocampus and entorhinal cortex was used and its correlation with memory function was analyzed, The specificity and sensibility of diagnosing MCI of hippocampal and entorhinal cortex volume were analyzed by non-conditional Logistic regression. The influencing factors of hippocampal and entorhinal cortex volume were analyzed by multiple linear regressions. Results The hippocampal and entorhinal cortex volume in subjects with MCI was 6. 19 ± 0. 74 and 2.66 ± 0. 17 cm^3, respectively; they were significantly smaller than 6.80 ±0.79 and 3.03 ±0. 12 cm^3 in the NC group （P 〈0.05）. The hippocampal volume was significantly correlated with the entorhinal cortex volume （r = 0. 566, P 〈0. 001 ）; the hippocampal volume was significantly correlated with the total score of Clinical Memory Scale （r = 0. 430, P = 0. 04）, and the entorhinal cortex volume was significantly correlated with the total score of Clinical Memory Scale （r =0.722, P 〈0. 001）. The specificity and sensitivity of using hippocampal volume to differentiate MCI and NC were 66.7% and 76.2%, respectively. The specificity and sensitivity of using entorhinal cortex volume to differentiate MCI and NC were 88.9% and 90. 5%, respectively. In addition, There was a negative correlation between the hippocampal volume and 2 h postprandial blood glucose （P 〈 0.05）, systolic blood pressure （P 〈 0.05 ）, diastolic blood pressure （P 〈 0.05 ）, and plasma total cholesterol levels （P 〈0.01）, while the entorhinal cortex volume was not affected by the above factors. Conelusiom The atrophy of entorhinal cortex and hippocampal volume are closely associated with the memory disorders. The entorhinal cortex and hippocampal volume measured by MRI have some values for the identification of MCI and NC, and the specificity and sensitivity of entorhinal cortex volume are superior to hippocampal volume. The increased blood pressure, blood glucose, and serum lipid levels may accelerate the transformation of MCI to Alzheimer＇s disease by affecting the hippocampal volume. Key words: Cognition disorders; Hippocampus; Entorhinal cortex; Atrophy; Magnetic resonance imaging

Sustaining the human brain's hippocampus from atrophy throughout ageing is critical. Exercise is proven to be effective in promoting adaptive hippocampal plasticity, and the hippocampus has a bidirectional relationship with the physical environment. Therefore, this systematic review explores the effects of walking, a simple physical activity in the environment, on hippocampal formation volume changes for lifelong brain and cognitive health. PubMed, Scopus, and Web of Science were searched for studies on humans published up to November 2022 examining hippocampal volume changes and walking. Twelve studies met the inclusion criteria. Study quality was assessed using the PEDro scale and ROBINS-I tool. A narrative synthesis explored walking factors associated with total, subregional, and hemisphere-specific hippocampal volume changes. Overall, walking had positive effects on hippocampal volumes. Several studies found benefits of higher-intensity and greater amounts of walking for total hippocampal volume. The subiculum increased after low-intensity walking and nature exposure, while the parahippocampal gyrus benefited from vigorous intensity. The right hippocampus increased with spatial navigation during walking. No studies examined the effect of walking on the dentate gyrus. This systematic review highlights walking as a multifaceted variable that can lead to manifold adaptive hippocampal volume changes. These findings support the promotion of walking as a simple, effective strategy to enhance brain health and prevent cognitive decline, suggesting the design of physical environments with natural and biophilic characteristics and layouts with greater walkability and cognitive stimulation. Future research is encouraged to explore the hippocampal subregional changes instead of focusing on total hippocampal volume, since the hippocampal formation is multicompartmental and subfields respond differently to different walking-related variables.

Objective: According to the stress-toxicity hypothesis of depression, hippocampal volumes may diminish as the disease progresses. We sought to examine the changes in hippocampal and amygdala volumes at baseline and at 3 years after an acute depressive episode, and the impact of reduced hippocampal volumes on the outcome. Methods: In a prospective, longitudinal study, we examined the hippocampus and amygdala of 30 inpatients with major depression from the Department of Psychiatry and Psychotherapy and 30 healthy participants from the community (control group) using high-resolution magnetic resonance images at baseline and after 3 years. Psychopathology was assessed at baseline, weekly during the inpatient phase and then after 1, 2 and 3 years. Results: During the 3-year follow-up period, neither hippocampal nor amygdala volumes changed significantly among patients or participants in the control group. However, in the subgroup of patients who took antidepressants over the full 3 years, the left hippocampal volumes increased significantly. Patients with small hippocampal volumes and previous depressive episodes had a worse clinical outcome compared with patients with large hippocampal volumes and previous depressive episodes. Conclusion: Overall, our results suggest that a relatively small hippocampal volume may be a vulnerability factor for a bad treatment response in major depression. Subtle changes in hippocampal volumes may be detectable during continuous antidepressant therapy. Such changes may be the result of neuroplastic processes.

To compare volumetric MRI of whole brain and medial temporal lobe structures to clinical measures for predicting progression from amnestic mild cognitive impairment (MCI) to Alzheimer disease (AD). Baseline MRI scans from 129 subjects with amnestic MCI were obtained from participants in the Alzheimer's Disease Cooperative Study group's randomized, placebo-controlled clinical drug trial of donepezil, vitamin E, or placebo. Measures of whole brain, ventricular, hippocampal, and entorhinal cortex volumes were acquired. Participants were followed with clinical and cognitive evaluations until formal criteria for AD were met, or completion of 36 months of follow-up. Logistic regression modeling was done to assess the predictive value of all MRI measures, risk factors such as APOE genotype, age, family history of AD, education, sex, and cognitive test scores for progression to AD. Least angle regression modeling was used to determine which variables would produce an optimal predictive model, and whether adding MRI measures to a model with only clinical measures would improve predictive accuracy. Of the four MRI measures evaluated, only ventricular volumes and hippocampal volumes were predictive of progression to AD. Maximal predictive accuracy using only MRI measures was obtained by hippocampal volumes by themselves (60.4%). When clinical variables were added to the model, the predictive accuracy increased to 78.8%. Use of MRI measures did not improve predictive accuracy beyond that obtained by cognitive measures alone. APOE status, MRI, or demographic variables were not necessary for the optimal predictive model. This optimal model included the Delayed 10-word list recall, New York University Delayed Paragraph Recall, and the Alzheimer's Disease Assessment Scale-Cognitive Subscale total score. In moderate stages of amnestic mild cognitive impairment, common cognitive tests provide better predictive accuracy than measures of whole brain, ventricular, entorhinal cortex, or hippocampal volumes for assessing progression to Alzheimer disease.

To determine whether and how longitudinal rates of change in MRI volumetrics, CSF concentrations of Alzheimer-related proteins, molecular imaging of cerebral fibrillar amyloid with PET using the [(11)C] benzothiazole tracer, Pittsburgh compound B (PiB), and cognition were associated among asymptomatic middle-aged to older individuals. Multivariate mixed models for repeated measures were used to assess the correlations on the rates of changes across markers. Among 209 asymptomatic middle-aged to older individuals longitudinally followed for up to 11 years (mean 6.7 years), a faster intraindividual decrease in CSF Aβ42 was associated with a faster increase in PiB mean cortical standardized uptake value ratio (MCSUVR, p = 0.04), but not others. The rate of change in CSF tau (and Ptau181) was correlated with the rate of change in PiB MCSUVR (p = 0.002), hippocampal volume (p = 0.04), and global cognition (p = 0.008). The rate of change in hippocampal volume was correlated with the rate of change in global cognition (p = 0.04). Only 3 significant correlations were observed at baseline: CSF Aβ42 and PiB MCSUVR (p < 0.001), CSF tau and PiB MCSUVR (p < 0.001), and CSF Aβ42 and global cognition (p = 0.01). CSF tau (Ptau181), PiB MCSUVR, and hippocampal volume were all longitudinally correlated with each other, whereas CSF Aβ42 was correlated only with PiB binding. Unlike the baseline values, the longitudinal change in CSF tau (Ptau181) and hippocampal volume were correlated with the longitudinal change in global cognition, validating the role of these biomarkers in Alzheimer disease prevention trials.

BackgroundRecently, two monoclonal antibodies that lower amyloid plaques have shown promising results for the treatment of Mild Cognitive Impairment (MCI) and mild dementia due to Alzheimer’s disease (AD). These treatments require the identification of cognitively impaired older adults with biomarker evidence of AD pathology using CSF biomarkers or amyloid-PET. Previous studies showed plasma biomarkers (plasma Aβ42/Aβ40 and p-tau181) and hippocampal volume from structural MRI correlated with brain amyloid pathology. We hypothesized plasma biomarkers with hippocampal volume would identify patients who are suitable candidates for disease-modifying therapy.ObjectivesTo evaluate the performance of plasma AD biomarkers and hippocampal atrophy to detect MCI or AD with amyloid pathology confirmed by amyloid-PET or CSF biomarkers in ADNI.DesignA cross-sectional and longitudinal study.Setting and ParticipantsData were from the Alzheimer’s Disease Neuroimaging Initiative. Participants were aged 55–90 years old with plasma biomarker and structural MRI brain data.MeasurementsThe optimum cut-off point for plasma Aβ42/Aβ40, p-tau181, and NFL and the performance of combined biomarkers and hippocampal atrophy for detecting cognitive impairment with brain amyloid pathology were evaluated. The association between baseline plasma biomarkers and clinical progression, defined by CDR-Sum of Boxes (CDR-SB) and diagnostic conversion over two years, was evaluated using a Weibull time-to-event analysis.ResultsA total of 428 participants were included; 167 had normal cognition, 245 had MCI, and 16 had mild AD. Among MCI and AD, 140 participants had elevated amyloid levels by PET or CSF. Plasma Aβ42/Aβ40 provided the best accuracy (sensitivity 79%, specificity 66%, AUC 0.73, 95% CI 0.68–0.77) to detect drug candidate participants at baseline. Combined plasma Aβ42/40, p-tau181, and hippocampal atrophy increased the specificity for diagnosis (96%), but had lower sensitivity (34%), and AUC (0.65). Hippocampal atrophy combined with the abnormal plasma p-tau181 or hippocampal atrophy alone showed high sensitivity to detect clinical progression (by CDR-SB worsening) of the drug-candidate participants within the next 2 years (sensitivity 93% and 89%, respectively).ConclusionPlasma biomarkers and structural MRI can help identify patients who are currently eligible for anti-amyloid treatment and are likely to progress clinically, in cases where amyloid-PET or CSF biomarkers are not available.

Commentary on “Biomarkers in Alzheimer's disease drug development.” Can't live without ‘em

BackgroundPlasma neurofilament light chain (NfL) is a blood biomarker of neurodegeneration, including Alzheimer’s disease. However, its usefulness may be influenced by common conditions in older adults, including amyloid-β (Aβ) deposition and cardiometabolic risk factors like hypertension, diabetes mellitus (DM), impaired kidney function, and obesity. This longitudinal observational study using the Alzheimer’s Disease Neuroimaging Initiative cohort investigated how these conditions influence the prognostic capacity of plasma NfL.MethodsNon-demented participants (cognitively unimpaired or mild cognitive impairment) underwent repeated assessments including the Alzheimer’s Disease Assessment Scale-Cognitive subscale (ADAS-Cog) scores, hippocampal volumes, and white matter hyperintensity (WMH) volumes at 6- or 12-month intervals. Linear mixed-effect models were employed to examine the interaction between plasma NfL and various variables of interest, such as Aβ (evaluated using Florbetapir positron emission tomography), hypertension, DM, impaired kidney function, or obesity.ResultsOver a mean follow-up period of 62.5 months, participants with a mean age of 72.1 years (n = 720, 48.8% female) at baseline were observed. Higher plasma NfL levels at baseline were associated with steeper increases in ADAS-Cog scores and WMH volumes, and steeper decreases in hippocampal volumes over time (all p-values < 0.001). Notably, Aβ at baseline significantly enhanced the association between plasma NfL and longitudinal changes in ADAS-Cog scores (p-value 0.005) and hippocampal volumes (p-value 0.004). Regarding ADAS-Cog score and WMH volume, the impact of Aβ was more prominent in cognitively unimpaired than in mild cognitive impairment. Hypertension significantly heightened the association between plasma NfL and longitudinal changes in ADAS-Cog scores, hippocampal volumes, and WMH volumes (all p-values < 0.001). DM influenced the association between plasma NfL and changes in ADAS-Cog scores (p-value < 0.001) without affecting hippocampal and WMH volumes. Impaired kidney function did not significantly alter the association between plasma NfL and longitudinal changes in any outcome variables. Obesity heightened the association between plasma NfL and changes in hippocampal volumes only (p-value 0.026).ConclusionThis study suggests that the prognostic capacity of plasma NfL may be amplified in individuals with Aβ or hypertension. This finding emphasizes the importance of considering these factors in the NfL-based prognostic model for neurodegeneration in non-demented older adults.

N-acetylaspartate (NAA) in the medial temporal lobe (MTL) and parietal lobe gray matter (GM) is diminished in Alzheimer disease (AD). Because NAA is considered a marker of neuronal integrity, reduced medial temporal and parietal lobe NAA could be an early indication of dementia-related pathology in elderly individuals. 1) To determine whether cognitively impaired but nondemented (CIND) elderly individuals exhibit a similar pattern of reduced medial temporal and parietal lobe NAA as AD patients. 2) To compare regional NAA patterns, hippocampal and neocortical gray matter (GM) volumes in CIND patients who remained cognitively stable and those who became demented over 3.6 years of follow-up. 3) To examine the relationship between memory performance, medial temporal lobe NAA, and hippocampal volume. Seventeen CIND, 24 AD, and 24 cognitively normal subjects were studied using MRSI and MRI. Relative to controls, CIND patients had reduced MTL NAA (19 to 21%, p = 0.005), hippocampal (11 to 14%, p < or = 0.04), and neocortical GM (5%, p = 0.05) volumes. CIND patients who later became demented had less MTL NAA (26%, p = 0.01), hippocampal (17 to 23%, p < or = 0.05), and neocortical GM (13%, p = 0.02) volumes than controls, but there were no significant differences between stable CIND patients and controls. MTL NAA in combination with hippocampal volume improved discrimination of CIND and controls over hippocampal volume alone. In AD and CIND patients, decreased MTL NAA correlated significantly with impaired memory performance. Reduced medial temporal lobe N-acetylaspartate, together with reduced hippocampal and neocortical gray matter volumes, may be early indications of dementia-related pathology in subjects at high risk for developing dementia.

Neurobiological changes in the hippocampus are a common consequence of aging. However, there are differences in the rate of decline and overall volume loss in people with no cognitive impairment compared to those with mild cognitive impairment (MCI) and Alzheimer's disease (AD). This systematic literature review was conducted to determine the relationship between hippocampal atrophy and changes in hippocampal volume in the non-cognitively impaired brain and those with MCI or AD. This systematic review was guided by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) methodology. The PubMed database was searched up to September 15, 2022, for longitudinal magnetic resonance imaging studies reporting hippocampal atrophy or volume change in cognitively normal aging individuals and patients with MCI and/or AD. Study selection was divided into two steps: (1) identification and retrieval of relevant studies; (2) screening the studies by (a) title/abstract and (b) full text. Two teams, each consisting of two independent reviewers, determined whether the publications met the inclusion criteria for the systematic review. An evidence table was populated with data extracted from eligible publications and inclusion in the final systematic review was confirmed. The systematic search identified 357 publications that were initially screened by title/abstract, of which, 115 publications were retrieved and reviewed by full text for eligibility. Seventeen publications met the eligibility criteria; however, during data extraction, two studies were determined to not meet the inclusion criteria and were excluded. The remaining 15 studies were included in the systematic review. Overall, the results of these studies demonstrated that the hippocampus and hippocampal subfields change over time, with both decreased hippocampal volume and increased rate of hippocampal atrophy observed. Hippocampal changes in AD were observed to be greater than hippocampal changes in MCI, and changes in MCI were observed to be greater than those in normal aging populations. Published literature suggests that the rate of hippocampal decline and extent of loss is on a continuum that begins in people without cognitive impairment and continues to MCI and AD, and that differences between no cognitive impairment, MCI, and AD are quantitative rather than qualitative.

Non-invasive biomarkers will enable widespread screening and early diagnosis of Alzheimer's disease (AD). We hypothesized that the considerable loss of brain tissue in AD will result in detection of brain lipid components in urine, and that these will change in concert with CSF and brain biomarkers of AD. We examined urine dicarboxylic acids (DCA) of carbon length 3-10 to reflect products of oxidative damage and energy generation or balance that may account for changes in brain function in AD. Mean C4-C5 DCAs were lower and mean C7-C10 DCAs were higher in the urine from AD compared to cognitively healthy (CH) individuals. Moreover, mean C4-C5 DCAs were lower and mean C7-C9 were higher in urine from CH individuals with abnormal compared to normal CSF amyloid and Tau levels; i.e., the apparent urine changes in AD also appeared to be present in CH individuals that have CSF risk factors of early AD pathology. In examining the relationship between urine DCAs and AD biomarkers, we found short chain DCAs positively correlated with CSF Aβ42, while C7-C10 DCAs negatively correlated with CSF Aβ42 and positively correlated with CSF Tau levels. Furthermore, we found a negative correlation of C7-C10 DCAs with hippocampal volume (p < 0.01), which was not found in the occipital volume. Urine measures of DCAs have an 82% ability to predict cognitively healthy participants with normal CSF amyloid/Tau. These data suggest that urine measures of increased lipoxidation and dysfunctional energy balance reflect early AD pathology from brain and CSF biomarkers. Measures of urine DCAs may contribute to personalized healthcare by indicating AD pathology and may be utilized to explore population wellness or monitor the efficacy of therapies in clinical trials.