Seshadri, Sudha

AbstractBackgroundLate‐onset Alzheimer's disease (AD) is heritable with 20 genes showing genome‐wide association in the International Genomics of Alzheimer's Project (IGAP). To identify the biology underlying the disease, we extended these genetic data in a pathway analysis.MethodsThe ALIGATOR and GSEA algorithms were used in the IGAP data to identify associated functional pathways and correlated gene expression networks in human brain.ResultsALIGATOR identified an excess of curated biological pathways showing enrichment of association. Enriched areas of biology included the immune response (P = 3.27 × 10−12 after multiple testing correction for pathways), regulation of endocytosis (P = 1.31 × 10−11), cholesterol transport (P = 2.96 × 10−9), and proteasome‐ubiquitin activity (P = 1.34 × 10−6). Correlated gene expression analysis identified four significant network modules, all related to the immune response (corrected P = .002–.05).ConclusionsThe immune response, regulation of endocytosis, cholesterol transport, and protein ubiquitination represent prime targets for AD therapeutics.

AbstractBackgroundPlasma amyloid‐β (Aβ) peptide levels have been examined as a low‐cost accessible marker for risk of incident Alzheimer's disease (AD) and dementia, but results have varied between studies. We reassessed these associations in one of the largest, prospective, community‐based studies to date.MethodsA total of 2189 dementia‐free, Framingham Study participants aged >60 years (mean age, 72 ± 8 years; 56% women) had plasma Aβ1‐42 and Aβ1‐40 measured and were followed prospectively (mean, 7.6 ± 3.0 years) for dementia/AD.ResultsIncreased plasma Aβ1‐42 levels were associated with lower risk of dementia (Aβ1‐42: hazard ratio [HR] = 0.80 [0.71‒0.90], P < .001; Aβ1‐42‐to‐Aβ1‐40 ratio: HR = 0.86 [0.76‒0.98], P = .027) and AD (Aβ1‐42: HR = 0.79 [0.69‒0.90], P < .001; Aβ1‐42‐to‐Aβ1‐40 ratio: HR = 0.83 [0.72‒0.96], P = .012).ConclusionOur results suggest that lower plasma Aβ levels are associated with risk of incident AD and dementia. They encourage further evaluation of plasma Aβ levels as a biomarker for risk of developing clinical AD and dementia.

This article focuses on the effects of operational differences in case ascertainment on estimates of prevalence and incidence of cognitive impairment and/or dementia of the Alzheimer type. Experience and insights are discussed by investigators from the Framingham Heart Study, the East Boston Senior Health Project, the Chicago Health and Aging Project, the Mayo Clinic Study of Aging, the Baltimore Longitudinal Study of Aging, and the Aging, Demographics, and Memory Study. There is a general consensus that the single most important factor determining prevalence estimates of Alzheimer's disease (AD) is the severity of cognitive impairment used as a threshold to define cases. Studies that require a level of cognitive impairment in which persons are unable to provide self‐care will have much lower estimates than the studies aimed at identifying persons in the earliest stages of AD. There are limited autopsy data from the aforementioned epidemiological studies to address accuracy in the diagnosis of etiological subtype, namely the specification of AD alone or in combination with other types of pathology. However, other community‐based cohort studies show that many persons with mild cognitive impairment and also some persons without dementia or mild cognitive impairment meet pathological criteria for AD, thereby suggesting that the number of persons who would benefit from an effective secondary prevention intervention is probably higher than the published prevalence estimates. Improved accuracy in the clinical diagnosis of AD is anticipated with the addition of molecular and structural biomarkers in the next generation of epidemiological studies.