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Replies to post #179040 on Anavex Life Sciences Corp (AVXL)
Differential Effect of APOE ?4 Status and Elevated Pulse Pressure on Functional Decline in Cognitively Normal Older Adults.
Werhane ML1,2,3, Thomas KR1,3, Edmonds EC1,3, Bangen KJ1,3, Tran M4, Clark AL1,2,3, Nation DA5, Gilbert PE2, Bondi MW1,3, Delano-Wood L1,3; Alzheimer’s Disease Neuroimaging Initiative.
Author information
Abstract
BACKGROUND/OBJECTIVE:
The APOE ?4 allele and increased vascular risk have both been independently linked to cognitive impairment and dementia. Since few studies have characterized how these risk factors affect everyday functioning, we investigated the relationship between APOE ?4 genotype and elevated pulse pressure (PP) on functional change in cognitively normal participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI).
METHODS:
738 normally aging participants underwent APOE genotyping, and baseline PP was calculated from blood pressure indices. The Functional Activities Questionnaire (FAQ) was completed by participants' informant at baseline and 6, 12, 24, 36, and 48-month follow-up visits. Multiple linear regression and multilevel modeling were used to examine the effects of PP and APOE ?4 genotype on cross-sectional and longitudinal FAQ scores, respectively.
RESULTS:
Adjusting for demographic and clinical covariates, results showed that both APOE ?4 status and elevated PP predicted greater functional difficulty trajectories across four years of follow-up. Interestingly, however, elevated PP was associated with greater functional decline over time in ?4 non-carriers versus carriers.
CONCLUSION:
Results show that, although APOE ?4 status is the prominent predictor of functional difficulty for ?4 carriers, an effect of arterial stiffening on functional difficulty was observed in non-carriers. Future studies are needed in order to clarify the etiology of the association between PP and different brain aging processes, and further explore its utility as a marker of dementia risk. The present study underscores the importance of targeting modifiable risk factors such as elevated PP to prevent or slow functional decline and pathological brain aging.
KEYWORDS:
Activities of daily living; aging; apolipoprotein E4; arterial stiffness; genetic susceptibilit
The current study focuses on a subpopulation of elderly people with the lowest cognitive or functional impairments (Clinical Dementia Rate 0.5) that can be objectified and those without noticeable impairments (CDR zero). A closer look at the subjects’ characteristics reveals that 50 percent of the participants (independent of CDR) suffer from hypertension. Though cardiovascular risk factors were well controlled for, and severe vascular injuries such as vascular cognitive impairment and vascular dementia were excluded, it is not unthinkable that these subjects have cerebral small-vessel-disease (cSVD), which is common in the elderly, especially those with hypertension. For such a population, inherent radiological features, including white-matter hyperintensities and microbleedings, are expected. White-matter intensities of cSVD often express in the deeper (periventricular) white matter, but not the hippocampus, and are known correlates of cognitive decline in aging and (preclinical) Alzheimer’s disease. Recent insights linked the white-matter hyperintensities to a malfunctioning neurovascular unit, where, among other matters, blood perfusion and permeability are tightly regulated. For the current study it remains to be shown to what extent the presence of white-matter hyperintensities affect or may explain the differences in the observed BBB disintegrity and cognitive impairment between the two groups.
A major achievement of the authors is investigating the correlation with CSF-derived protein markers of AD. Because in this cross-sectional study the variation in BBB leakage could not be explained by differences in Aß or tau level, the influence of vascular pathology on cognitive impairment was considered independent from the key AD biomarkers Aß and tau. Also, no correlation between hippocampal volume and cognitive impairment was found, emphasizing the early disease stage of cognitively impaired subjects. Taken together, this means that BBB breakdown and abnormal expressions of AD biomarkers, i.e., molecular fluid markers and neurodegeneration, are non-contemporary findings. Ideally, longitudinal studies are needed to conclude more firmly the timeline of the pathological cascade. Such studies may disentangle whether BBB breakdown truly initiates this cascade and its initial cognitive decrements, continues its extension, leads to vascular injuries, and/or adds to the full cognitive and functional disabilities of AD. This will be a long-lasting endeavour, also because only a limited number of subjects with MCI will converge into Alzheimer’s disease. Multiple cross-sectional studies on subjects in various disease stages ranging from mild cognitive impairment to full AD seem more feasible. Such studies, either longitudinal or cross-sectional, are, however, hampered by the quantification issues for DCE-MRI, as addressed above, which need further improvement and harmonization
