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SummaryHere we elucidate the effect of Alzheimer disease (AD)-predisposing genetic backgrounds, APOE4, PSEN1ΔE9, and APPswe, on functionality of human microglia-like cells (iMGLs). We present a physiologically relevant high-yield protocol for producing iMGLs from induced pluripotent stem cells. Differentiation is directed with small molecules through primitive erythromyeloid progenitors to re-create microglial ontogeny from yolk sac. The iMGLs express microglial signature genes and respond to ADP with intracellular Ca2+ release distinguishing them from macrophages. Using 16 iPSC lines from healthy donors, AD patients and isogenic controls, we reveal that the APOE4 genotype has a profound impact on several aspects of microglial functionality, whereas PSEN1ΔE9 and APPswe mutations trigger minor alterations. The APOE4 genotype impairs phagocytosis, migration, and metabolic activity of iMGLs but exacerbates their cytokine secretion. This indicates that APOE4 iMGLs are fundamentally unable to mount normal microglial functionality in AD.

The association between level of educational attainment and cognitive performance is well studied. People with higher education perform better across a broad range of cognitive tasks. However, there is uncertainty as to whether education moderates the trajectory of age‐related cognitive decline. This review paper addresses the potential link between education and age‐related cognitive decline by evaluating relevant research published since 2000. Studies reporting data on education and its association with the rate of cognitive decline across various cognitive domains were reviewed. A total of 10 studies were identified with a mean follow‐up period of 7.6 years; each contained a population‐based, non‐demented sample. In the majority of studies, results showed that education did not moderate age‐associated cognitive decline. The few studies that did find an association between education and decline in specific cognitive functions should be interpreted with caution because of methodological issues. The literature reveals little consistent evidence that normal age‐related cognitive decline is moderated by education attainment. This supports a passive theory of cognitive reserve: people with a higher level of education will continue to perform at a higher level of cognitive functioning than their lower educated peers, which may delay the onset of impairment in the future.

BackgroundTo ensure carers of people with dementia receive support, community services increasingly use measures of caregiver (carer) burden to assess for unmet need. This study used Bradshaw's taxonomy of need to explore the link between measures of carer burden (normative need), service use (expressed need), and carer's stated need (felt need).MethodsThis mixed method exploratory study compared measures of carer burden with community services received and unmet needs, for 20 community-dwelling carer/care-recipient pairs.ResultsA simple one-item measure of carers' felt need for more services was significantly related to carer stress as measured on the GHQ-30. Qualitative data showed that there are many potential stressors for carers, other than those related to the care-giving role. We found a statistically significant rank correlation (p = 0.01) between carer's use of in-home respite and the care-recipient's cognitive and functional status which is likely to have been related to increased requirement for carer vigilance, effort and the isolation of spouse carers. Otherwise, there were no statistically significant relationships between carer burden or stress and level of service provision.ConclusionWhen carers are stressed or depressed, they can recognise that they would like more help from services, even if measures of carer burden and care recipient status do not clearly indicate unmet service needs. A question designed to elicit carer' felt need may be a better indicator of service need, and a red flag for recognising growing stress in carers of people with dementia. Assessment of service needs should recognise the fallibility of carer burden measures, given that carer stress may not only come from caring for someone with dementia, but can be significantly compounded by other life situations.

We have investigated alterations in myelin associated with Abeta plaques, a major pathological hallmark of Alzheimer's disease (AD), in human tissue and relevant transgenic mice models. Using quantitative morphological techniques, we determined that fibrillar Abeta pathology in the grey matter of the neocortex was associated with focal demyelination in human presenilin-1 familial, sporadic and preclinical AD cases, as well as in two mouse transgenic models of AD, compared with age-matched control tissue. This demyelination was most pronounced at the core of Abeta plaques. Furthermore, we found a focal loss of oligodendrocytes in sporadic and preclinical AD cases associated with Abeta plaque cores. In human and transgenic mice alike, plaque-free neocortical regions showed no significant demyelination or oligodendrocyte loss compared with controls. Dystrophic neurites associated with the plaques were also demyelinated. We suggest that such plaque-associated focal demyelination of the cortical grey matter might impair cortical processing, and may also be associated with aberrant axonal sprouting that underlies dystrophic neurite formation.