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IntroductionRecently, interest has emerged in subjective cognitive decline (SCD) as a potential precursor to Alzheimer’s disease (AD) dementia. Whether individuals with SCD harbor brain alterations in midlife, when AD-related pathology begins, is yet to be elucidated. Furthermore, the role of apolipoprotein ε4 (APOE ε4) allele, a robust AD risk factor, in the relationship between SCD and brain alterations is unknown. We examined whether APOE genotype modulates the association of SCD with brain measures in individuals at high AD risk.MethodsMiddle-aged adults with parental history of AD dementia underwent magnetic resonance imaging (MRI) and the Memory Functioning Questionnaire. Regression analysis tested the extent to which SCD was associated with activation during an functional MRI (fMRI) working-memory task, and white-matter microstructure. APOE ε4 genotype was tested as a moderator.ResultsAmong APOE ε4 carriers, but not among non-carriers, SCD was associated with higher activation in the anterior cingulate (p = 0.003), inferior, middle, and superior frontal cortices (p = 0.041, p = 0.048, p = 0.037, respectively); and with lower fractional anisotropy in the uncinate fasciculus (p = 0.002), adjusting for age, sex, and education.ConclusionIn middle aged, cognitively normal individuals at high AD risk, higher SCD was associated with greater brain alterations possibly reflecting incipient AD pathology. When accompanied by a family history of AD and an APOE ε4 allele, SCD may have important clinical value, allowing a window for early intervention and for participants’ stratification in AD prevention clinical trials.

ObjectivesMultiple risk loci for late-onset Alzheimer’s disease (LOAD) have been identified. Type 2 diabetes (T2D) is a risk factor for cognitive decline, dementia and Alzheimer’s disease (AD). We investigated the association of polygenic risk score (PRS) for LOAD with overall cognitive functioning and longitudinal decline, among older adults with T2D.MethodsThe study included 1046 Jewish participants from the Israel Diabetes and Cognitive Decline (IDCD) study, aged ≥ 65 years, diagnosed with T2D, and cognitively normal at baseline. The PRS included variants from 26 LOAD associated loci (at genome-wide significance level), and was calculated with and without APOE. Outcome measures, assessed in 18 months intervals, were global cognition and the specific domains of episodic memory, attention/working memory, executive functions, and language/semantic categorization. Random coefficient models were used for analysis, adjusting for demographic variables, T2D-related characteristics, and cardiovascular factors. Additionally, in a subsample of 202 individuals, we analyzed the association of PRS with the volumes of total gray matter, frontal lobe, hippocampus, amygdala, and white matter hyperintensities. Last, the association of PRS with amyloid beta (Aβ) burden was examined in 44 participants who underwent an 18F-flutemetamol PET scan.ResultsThe PRS was not significantly associated with overall functioning or decline in global cognition or any of the specific cognitive domains. Similarly, following correction for multiple testing, there was no association with Aβ burden and other brain imaging phenotypes.ConclusionOur results suggest that the cumulative effect of LOAD susceptibility loci is not associated with a greater rate of cognitive decline in older adults with T2D, and other pathways may underlie this link.

Associative processes, such as the encoding of associations between words in a list, can enhance episodic memory performance and are thought to deteriorate with age. Here, we examine the nature of age-related deficits in the encoding of associations, by using a free recall paradigm with visual arrays of objects. Fifty-five participants (26 young students; 20 cognitive healthy older adults; nine patients with Mild Cognitive Impairment, MCI) were shown multiple slides (experimental trials), each containing an array of nine common objects for recall. Most of the arrays contained three objects from three semantic categories, each. In the remaining arrays, the nine objects were unrelated. Eye fixations were also monitored during the viewing of the arrays, in a subset of the participants. While for young participants the immediate recall was higher for the semantically related arrays, this effect was diminished in healthy elderly and totally absent in MCI patients. Furthermore, only in the young group did the sequence of eye fixations show a semantic scanning pattern during encoding, even when the related objects were non- adjacent in the array. Healthy elderly and MCI patients were not influenced by the semantic relatedness of items during the array encoding, to the same extent as young subjects, as observed by a lack of (or reduced) semantic scanning. The results support a version of the encoding of the association aging-deficit hypothesis.