Preclinical Alzheimer's Disease Population Research Articles

Using Inflammatory Plasma Biomarkers to Predict Preclinical Alzheimer’s Disease

AbstractBackgroundPlasma biomarkers have recently emerged to detect symptomatic Alzheimer Disease (AD), but have yet to be validated in preclinical AD populations, where Aβ accumulates in the brain but older adults are cognitively unimpaired (CU). In addition to AD pathologic plasma biomarkers (amyloid and tau), inflammatory markers can accurately detect symptomatic AD. We used pathologic and inflammatory plasma biomarkers to predict amyloid PET status in CU older adults.MethodParticipants were 125 CU older adults (mean age = 68) from the Butler Hospital Alzheimer’s Prevention Registry who completed amyloid PET through a separate research study. Blood samples were collected and analyzed for the following: an inflammatory panel consisting of 21 proteins, Aβ40, Aβ42, tau (total), p‐tau181, p‐tau 231, p‐tau217, GFAP and NfL. Multiple regression was used to evaluate the best predictors of amyloid PET status (positive vs. negative) in CU older adults. Model 1 included predictors age, education, and gender. Model 2 and 3 added predictors APOE status, Aβ42/40 ratio and p‐tau181 respectively. Random forest (RF) modeling was used to establish the five proteomic markers that best predicted amyloid PET status, and these markers were added in Model 4.ResultWe tested RF models that included all 21 inflammatory proteins, as well as the top 10, 8 and 5 inflammatory proteins. Models were compared based on sensitivity, specificity, PPV, NPV, and AUC. The model including the top 5 inflammatory proteins (CRP, SAA, sVCAM1, TNFα, and TARC) was the best fit with sensitivity of .88, specificity of .31, PPV of .71, NPV of .57 and AUC of .63. Multiple regression analysis showed that the best model for predicting amyloid PET positivity included age, years of education, gender, APOE E4 status, Aβ42/40 ratio and p‐tau181(p<.01). Adding the top 5 proteomic markers did not significantly improve the model.ConclusionResults revealed that the proteomic inflammatory markers in plasma did not add predictive value to standard AD pathologic plasma biomarkers in predicting amyloid PET positivity in CU older adults. This may reflect that the changes associated with inflammatory biomarkers occur later downstream in the pathogenesis and disease progression of AD.

Developing Topics.

Phosphorylated tau (pTau) in cerebrospinal fluid (CSF) is a biomarker of Alzheimer's disease (AD) pathology. Recent studies confirm that pTau levels in plasma may provide a more cost-effective and less invasive method of assessing AD pathology, which have shown to also be relevant in preclinical populations. Neurofilament light (NfL) is a measure of neuroaxonal damage associated with poorer cognitive outcomes. Generalization is a validated cognitive marker of hippocampal dysfunction, with individuals showing deficits years before overt cognitive impairment. Using a computer generalization task sensitive to medial temporal lobe (MTL) pathology, the current study examined the relationship between generalization performance and plasma pTau and NfL levels in a population with elevated AD risk, older African Americans. 130 older, cognitively normal African Americans (M age = 71.60 years, SD = 6.58; M edu = 13.88 years, SD = 2.37; n = 98 women) provided blood samples and completed a hippocampal-dependent cognitive task. Participants' normal cognitive status was confirmed using the Mini-Mental State Examination (M MMSE = 26.98, SD = 2.14) and generalization performance was assessed using the Acquired Equivalence Task. Plasma was extracted from blood samples to assess pTau181, pTau231, and NfL levels. Based on the sample median thresholds, participants were characterized as plasma tau positive (≥16.189 for pTau181 and ≥17.537 for pTau231). Participants positive for plasma pTau231 (n = 76) demonstrated worse generalization performance with increased pTau231 levels, B = -0.296, p = 0.024, as did participants positive for plasma pTau181, B = -0.247. p = 0.042, demonstrating that tau positivity status is related to MTL dysfunction. Moreover, pTau231 was more strongly associated with generalization performance, indicating that it is a more sensitive biomarker than pTau181 among preclinical AD populations. Higher levels of plasma NfL were also significantly associated with lower generalization performance B = -0.243. p = 0.008. Plasma isoforms pTau181 and pTau231 may reflect different phases of tau progression, with plasma pTau231 shown to be better at capturing subtle MTL dysfunction. Plasma tau positivity status and measures of axonal damage along with lower generalization performance scores may be useful indicators of cognitive dysfunction in preclinical AD populations.

Early effects of amyloid-β on structural and vascular brain changes in mid-life cognitively unimpaired individuals.

The apolipoprotein E (APOE) is the strongest genetic risk factor for late-onset Alzheimer's disease (AD). It has been shown that APOE ε4 allele (ε4) relates to early pathological accumulation of cerebral amyloid-β (Aβ), leading to decade earlier age-of-onset of AD. However vascular and anatomical brain changes in the presence of Aβ and ε4 gene have not yet been fully examined in middle age. We aim to investigate how ε4 and Aβ level influence MR neuroimaging biomarkers such as white-matter hyperintensities and hippocampus volume in mid-life (45-65 year old) cognitively unimpaired (CU) individuals. 149 middle age (44 to 66 years of age) CU adults (age 58.2±5.4, 115 Females, years of education 13.5±2.8) underwent 3T MRI and amyloid PET scans using 18 F-Florbetaben as part of the PISA study. Of this ε4 enriched cohort (N=78 ε4 carriers), 12 were classified as Aβ+ (Centiloid≥20). 5 participants with ε2ε4 genotypes were excluded due to the protective effect of the ε2 allele. Multivariable general linear models were implemented to study the association of ε4 and Aβ with structural neuroimaging markers including white-matter hyperintensity volume (WMHV) and Hippocampus volume (HV). Both volumes were normalised using total intracranial volume, and age, gender and years-of-education were used as independent covariates. There was no age difference between ε4+ and ε4- groups (Kruskal-Wallis test, p-value=0.8), but Aβ+ participants were older compared to Aβ- (p-value=0.005). There was no HV differences between ε4+ and ε4- groups when controlling for Centiloid (p-value=0.55). When comparing HV differences between groups based on joint ε4 and Aβ, Aβ+ε4+ had significantly lower HV compared to Aβ-ε4+ (p-value=0.01) and Aβ-ε4- (p-value=0.021) as shown in Figure 1. For WMHV differences, a trend towards significance exists for Aβ+ε4+ when compared to and Aβ+ε4- and Aβ-ε4- (p-value=0.069) as shown in Figure 2. In this study, we found that early signs of hippocampus degeneration may occur in the middle age in the presence of both high Aβ level and APOE ε4 allele. Future studies will investigate the effective age spread for middle-aged preclinical AD population which will be beneficial for participant recruitment for new clinical trials.

Neuritic and Diffuse Plaque Associations with Memory in Non-Cognitively Impaired Elderly.

The presence of Alzheimer's disease (AD)-related neuropathology among cognitively normal individuals has been well documented. It has been proposed that these individuals may represent a pre-clinical AD population. Previous studies have demonstrated a negative association between the presence of both amyloid-β (Aβ) plaques and neurofibrillary tangles with ante-mortem cognitive performance, a relationship which is likely influenced by a number of factors including age and APOE ɛ4 carrier status. The present study determined whether the presence of neuritic plaques (NPs) and diffuse plaques (DPs) are associated with performance in a number of cognitive domains after accounting for APOE ɛ4 carrier status and neurofibrillary tangle presence in a cohort of 123 older participants from the Rush Religious Order Study who died with a premortem clinical diagnosis of no cognitive impairment (NCI). After adjusting for age at death, education, gender, Braak stage, and APOE ɛ4 carrier status, the presence of NPs was associated with lower performance in the cognitive domains of Global Cognition (p = 0.002), Episodic Memory (p = 0.03), Semantic Memory (p = 0.009), and Visuospatial performance (p = 0.006), while DPs showed no association with any cognitive domain examined. These results suggest that decreases in cognition in elderly NCI individuals are associated with an increase in NPs and not DPs when age at death, education, gender, APOE ɛ4 status, and Braak stage are taken into consideration.

Progressive impairment in olfactory working memory in a mouse model of Mild Cognitive Impairment

Patients with Mild Cognitive Impairment (MCI), exhibiting both working memory and olfactory deficits are likely to progress to Alzheimer's disease (AD). Targeting this pre-clinical AD population with disease modifying agents or cognitive enhancers represents the best strategy for halting or delaying the impact of this pernicious disease. However, there is a paucity of animal models of MCI with which to assess putative therapeutic strategies. We describe an odour span task which assesses the ability of mice to remember lists of odours, and report subtle cognitive deficits in human amyloid over-expressing (Tg2576) mice, at an age prior to plaque deposition. Four-month-old Tg2576 mice exhibited normal acquisition and performance in the standard 12-span task, but were significantly impaired when memory load was increased to 22 odours. By 8-months, a performance deficit was apparent in the 12-span task and by 1-year mice also exhibited significant acquisition deficits. Thus, by assessing olfactory working memory in Tg2576 mice we can model aspects of MCI in rodents and aid development of future therapeutic strategies for AD.

Do neuropsychological tests detect preclinical Alzheimer's disease: Individual-test versus cognitive-discrepancy score analyses.

Attempts to identify cognitive markers of a preclinical phase of Alzheimer's disease (AD) have yielded inconsistent findings. The problem may stem in part from methodologies that are insensitive to potential subgroups within the at-risk, preclinical AD population (PCAD). The present study investigated the utility of asymmetric cognitive profiles in identifying individuals at risk for AD. Twenty elderly adults who were later diagnosed with AD (PCAD) and 20 matched control participants were compared on measures of cognitive asymmetry derived from difference scores on tests of verbal and visuospatial ability. Although both groups performed similarly on the individual tests, comparisons using difference scores revealed significantly larger discrepancies between naming and visuoconstruction skills in the PCAD group. The PCAD group also had a higher frequency of asymmetric cognitive profiles relative to a normative group.