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Abstract Background Insulin-degrading enzyme (IDE) is the ubiquitously expressed enzyme responsible for insulin and amyloid beta (Aβ) degradation. IDE gene is located on chromosome region 10q23-q25 and exhibits a well-replicated peak of linkage with Type 2 diabetes mellitus (T2DM). Several genetic association studies examined IDE gene as a susceptibility gene for Alzheimer's disease (AD), however with controversial results. Methods We examined associations of three IDE polymorphisms (IDE2, rs4646953; IDE7, rs2251101 and IDE9, rs1887922) with AD, Aβ42 plasma level and T2DM risk in the longitudinal Vienna Transdanube Aging (VITA) study cohort. Results The upstream polymorphism IDE2 was found to influence AD risk and to trigger the Aβ42 plasma level, whereas the downstream polymorphism IDE7 modified the T2DM risk; no associations were found for the intronic variant IDE9. Conclusions Based on our SNP and haplotype results, we delineate the model that IDE promoter and 3' untranslated region/downstream variation may have different effects on IDE expression, presumably a relevant endophenotype with disorder-specific effects on AD and T2DM susceptibility.

The combination of multiple neurodegenerative proteinopathies is increasingly recognized. Together they can potentiate neuronal dysfunction and contribute to complex neurological symptoms. We report an octogenarian female case of multiple extraneural metastases of a rectal carcinoma. She attempted suicide, which ultimately led to cardiorespiratory failure nine days after hospital admission. Apart from the suicide attempt and late‐onset depression, other psychiatric or neurological symptoms were not reported. Unexpectedly, histopathologic examination revealed prominent aging‐related tau astrogliopathy (ARTAG) of all five types (subpial, subependymal, grey and white matter, and perivascular) affecting cortical and subcortical brain regions. This pathology was associated with intermediate Alzheimer's disease neuropathologic change (A2B2C2 score), cerebral amyloid angiopathy, Lewy body‐type α‐synuclein proteinopathy (Braak stage 4), and a multiple system transactivation response DNA‐binding protein of 43 kDa (TDP‐43) proteinopathy also involving the astroglia. In summary, we report a complex and extensive combination of multiple proteinopathies with widespread ARTAG of all five types in a patient who had attempted suicide. Although longitudinal psychometric tests and neuropsychological evaluations were not performed, this report poses the question of thresholds of cognition and pathology load, describes ARTAG affecting unusually widespread brain regions, and supports the notion that complex proteinopathies should be regarded as a frequent condition in the elderly. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented in response to the article "Incidence of dementia over three decades in the Framingham Heart Study," by C. L. Satizabal and colleagues in the Febraury 11, 2016 issue.