Association of Alzheimer’s related genotypes with cognitive decline in multiple domains: results from the Three-City Dijon study

Abstract

Several genetic polymorphisms have been associated with Late Onset Alzheimer's Disease (LOAD), but there has been limited evidence on whether these polymorphisms predict intermediary stage outcomes such as cognitive changes in prospective community-based studies. Our aim was to evaluate whether polymorphisms previously established as predictors of LOAD also predict worse cognitive function and accelerated decline across multiple cognitive domains. We analyzed data from the 3C-Dijon study, in which 4931 respondents aged 65+ were examined up to 5 times over 10 years with a neuropsychological assessment. We evaluated the associations of polymorphisms in APOE, CR1, BIN1, CLU, PICALM, ABCA7, MS4A6A, CD33, MS4A4E and CD2AP with level and change in 5 neuropsychological tests, assuming a dominant effect model. To optimize measurement, we used a mixed regression model with a latent process for each cognitive domain: global cognition (Mini Mental State Examination); verbal fluency (Isaac's Set Test); visual memory (Benton Visual Retention Test); information processing (Trail Making Test B) and literacy (National Adult Reading Test). APOE was associated with accelerated decline in global cognition and verbal fluency. Only two non-APOE genetic polymorphisms were associated with cognitive decline: CR1 was associated with rate of change in verbal fluency and BIN1 was associated with rate of change in global cognition. In a large prospective population-based study of dementia-free individuals, only a few cognitive domains were associated with established LOAD risk alleles. The most consistent associations were for global cognition and verbal fluency.

Pathway-Specific Polygenic Risk Scores as Predictors of Amyloid-β Deposition and Cognitive Function in a Sample at Increased Risk for Alzheimer’s Disease

“…Two other studies did find associations between cognitive function and an overall PRS using a subset of IGAP genes in general populations; however, removing APOE from the PRS eliminated the statistical significance[36, 37]. In our analyses, the Overall PRS including APOE was not statistically associated with any cognitive outcomes.…”

A Network of Genetic Effects on Non-Demented Cognitive Aging: Alzheimer’s Genetic Risk (CLU + CR1 + PICALM) Intensifies Cognitive Aging Genetic Risk (COMT + BDNF) Selectively for APOE ɛ4 Carriers

“…APOE is involved in regulating cholesterol levels which plays an important role in Aβ metabolism, aggregation, and deposition, leading to increased senile plaques and cerebral amyloid angiopathy in brains of APOE ε4 carriers diagnosed with AD. In healthy older adults, APOE ε4 homozygotes are associated with higher amyloid pathology, greater medial temporal lobe atrophy, elevated resting-state activity in the default mode network, neuroinflammation [17] and accelerated decline on cognitive tests [24,25]. …”

Potential contribution of the Alzheimer׳s disease risk locus BIN1 to episodic memory performance in cognitively normal Type 2 diabetes elderly

“…For example, among healthy young Chinese participants, BIN 1 rs744373 (which is in incomplete linkage disequilibrium (LD) with rs6733839, and the relationship between them is not clear) was associated with working memory, hippocampal volume and functional connectivity (Zhang et al, 2015). The same SNP was associated with rate of change in global cognition in a large prospective study of French elderly dementia-free individuals (Vivot et al, 2015). …”