👤 Christopher J E Denning

Protein truncating variants (PTVs) in To identify high-priority missense variants (HPVs), we applied ‘domain mapping of disease mutations’ for the 637 unique coding In this sample, PTVs and HPVs associated with respectively a 35- and 10-fold increased risk of early onset AD and 17- and 6-fold increased risk of overall AD. The median age at onset (AAO) of PTV- and HPV-carriers was 62 and 64 years, and Our results justify a debate on whether HPV carriers should be considered for clinical counseling. The online version contains supplementary material available at 10.1186/s13024-025-00907-z. Show less

The early initiation of binge-drinking and biological sex are critical risk factors for the development of affective disturbances and cognitive decline, as well as neurodegenerative diseases including Alzheimer's disease. Further, a history of excessive alcohol consumption alters normal age-related changes in the pattern of protein expression in the brain, which may relate to an acceleration of cognitive decline. Here, we aimed to disentangle the interrelation between a history of binge-drinking during adolescence, biological sex and normal aging on the manifestation of negative affect, cognitive decline and associated biochemical pathology. To this end, adolescent male and female C57BL/6J mice (PND 28-29) underwent 30 days of alcohol binge-drinking using a modified drinking-in-the-dark (DID) paradigm. Then, mice were assayed for negative affect, sensorimotor gating and cognition at three developmental stages during adulthood-mature adulthood (6 months), pre-middle age (9 months) and middle age (12 months). Behavioural testing was then followed by immunoblotting to index the protein expression of glutamate receptors, neuropathological markers [Tau, p (Thr217)-Tau, p (Ser396)-Tau, BACE, APP, Aβ], as well as ERK activation within the entorhinal cortex, prefrontal cortex and amygdala. Across this age span, we detected only a few age-related changes in our measures of negative affect or spatial learning/memory in the Morris water maze and all of these changes were sex-specific. Prior adolescent binge-drinking impaired behaviour only during reversal learning in 9-month-old females and during radial arm maze testing in 12-month-old females. In contrast to behaviour, we detected a large number of protein changes related to prior binge-drinking history, several of which manifested as early as 6 months of age, with the prefrontal cortex particularly affected at this earlier age. While 6-month-old mice exhibited relatively few alcohol-related protein changes within the entorhinal cortex and amygdala, the number of alcohol-related protein changes within the entorhinal cortex increased with age, while the 12-month-old mice exhibited the largest number of protein changes within the amygdala. Approximately a third of the alcohol-related protein changes were sex-selective. Taken together, the results of our longitudinal study using a murine model of binge-drinking indicate that a prior history of heavy alcohol consumption, beginning in adolescence, is sufficient to induce what we presume to be latent changes in protein indices of cellular activity, glutamate transmission and neuropathology within key brain regions governing cognition, executive function and emotion that appear to precede the onset of robust behavioural signs of dysregulated affect and cognitive impairment. Show less

APOE ɛ4, the most significant genetic risk factor for Alzheimer disease (AD), may mask effects of other loci. We re-analyzed genome-wide association study (GWAS) data from the International Genomics of Alzheimer's Project (IGAP) Consortium in APOE ɛ4+ (10 352 cases and 9207 controls) and APOE ɛ4- (7184 cases and 26 968 controls) subgroups as well as in the total sample testing for interaction between a single-nucleotide polymorphism (SNP) and APOE ɛ4 status. Suggestive associations (P<1 × 10(-4)) in stage 1 were evaluated in an independent sample (stage 2) containing 4203 subjects (APOE ɛ4+: 1250 cases and 536 controls; APOE ɛ4-: 718 cases and 1699 controls). Among APOE ɛ4- subjects, novel genome-wide significant (GWS) association was observed with 17 SNPs (all between KANSL1 and LRRC37A on chromosome 17 near MAPT) in a meta-analysis of the stage 1 and stage 2 data sets (best SNP, rs2732703, P=5·8 × 10(-9)). Conditional analysis revealed that rs2732703 accounted for association signals in the entire 100-kilobase region that includes MAPT. Except for previously identified AD loci showing stronger association in APOE ɛ4+ subjects (CR1 and CLU) or APOE ɛ4- subjects (MS4A6A/MS4A4A/MS4A6E), no other SNPs were significantly associated with AD in a specific APOE genotype subgroup. In addition, the finding in the stage 1 sample that AD risk is significantly influenced by the interaction of APOE with rs1595014 in TMEM106B (P=1·6 × 10(-7)) is noteworthy, because TMEM106B variants have previously been associated with risk of frontotemporal dementia. Expression quantitative trait locus analysis revealed that rs113986870, one of the GWS SNPs near rs2732703, is significantly associated with four KANSL1 probes that target transcription of the first translated exon and an untranslated exon in hippocampus (P ⩽ 1.3 × 10(-8)), frontal cortex (P ⩽ 1.3 × 10(-9)) and temporal cortex (P⩽1.2 × 10(-11)). Rs113986870 is also strongly associated with a MAPT probe that targets transcription of alternatively spliced exon 3 in frontal cortex (P=9.2 × 10(-6)) and temporal cortex (P=2.6 × 10(-6)). Our APOE-stratified GWAS is the first to show GWS association for AD with SNPs in the chromosome 17q21.31 region. Replication of this finding in independent samples is needed to verify that SNPs in this region have significantly stronger effects on AD risk in persons lacking APOE ɛ4 compared with persons carrying this allele, and if this is found to hold, further examination of this region and studies aimed at deciphering the mechanism(s) are warranted. Show less