Understanding genetic contributions to neuropsychiatric symptoms in dementia

As well as progressive cognitive decline, most patients with Alzheimer’s disease and other dementias experience non-cognitive symptoms during disease progression.
Twelve non-cognitive symptoms are measured on the ‘Neuropsychiatric Inventory’ (NPI), including apathy, agitation, irritability, depression, anxiety, aberrant motor behaviours, disinhibition, euphoria, sleep disturbances, appetite changes, as well as delusions and hallucinations.

Project aims:

1. Derive a statistical model of which NPI items most commonly occur together to identify NPI symptom profiles.

2. Perform a genome wide association analysis (GWAS) on patients with the identified NPI symptoms profiles in AD compared to all other AD patients.

3. Upstream analysis using the GWAS output for the NPI symptom profiles will include: Identification of genes involved in specific biological pathways, heritability of the profiles, and the polygenetic crossover of these profiles with other neurological disorders and dementias.

Study Design:

GWAS meta-analysis. We already have genetic and phenotypic data from GERAD, BDR and the HUNT study.

Analysis
Principal component analysis, hierarchical clustering, and confirmatory factor analysis will be performed on the 12 item NPI to identify symptom profiles.

Genome wide association analysis (GWAS) between AD cases with the identified NPI symptom profiles vs all other AD cases will be performed. The exact case-control separation is undecided (i.e. dichotomous or continuous for the severity of the symptoms). However, the GWAS will control for confounders including sex, population stratification, and either age or time since disease diagnosis depending on data availability. Meta-analysis will be performed using METAL. Since all the participants in the GWAS are AD cases, we will assess and adjust for collider bias, as appropriate. Upstream GWAS analysis will include: Assessing the enrichment of SNPs in genes or biological pathways using MAGMA. Polygenic risk scores to assess genetic overlap with the identified NPI profiles and other characteristics. Genome Complex Trait Analysis (GCTA) will estimate the heritability of the NPI symptom profiles.

Dementia is characterized by progressive cognitive decline, but non memory symptoms are also present in most people living with dementia. These can include psychological symptoms such as apathy and psychosis, as well as behavioural changes such as disinhibition. For those living with dementia, these symptoms can cause significant distress and reduced quality of life, as well as a greater need to access healthcare services and an increased chance of requiring residential care. The medications used to treat these symptoms have significant side effects including increased stroke risk. These symptoms have largely been studied singularly, which does not reflect the experience of individuals with disease. The aim of this study is to investigate the genetics of Alzheimer’s Disease patients which present with the different subsets of non-cognitive symptoms which most commonly occur together. This approach has the potential to develop more tailored treatments for patients with dementia.