Chronological Mapping of Comorbidities in Alzheimer's Disease and Vascular Dementia

BackgroundPre-existing long-term health conditions are highly prevalent in people living with dementia. There is an established relationship between these conditions, trajectories of decline and outcomes in dementia post-diagnosis. An understanding of when these conditions first occur and how they manifest over time within dementia populations remains unclear. The pathophysiology across major bodily systems changes before and after the clinical onset of dementia. However, the timing of various complex, chronic conditions, how they interact and their association with dementia are not yet fully understood. Understanding the complex relationship between multiple long-term conditions and dementia can enhance our understanding of the mechanisms of disease. This understanding can help identify "windows of opportunity" for early interventions in at-risk populations. Long-term conditions also continue to affect individual decline as the disease progresses. We set out to map these key comorbidities chronologically, specific to diagnoses of Alzheimers Disease and Vascular Dementia. MethodWe map comorbidities based on International Classification of Diseases (10th revision) system, in a population of people with Alzheimers Disease and Vascular Dementia from 20 years before through to 10 years after diagnosis. We used inpatient hospital electronic healthcare record data from 10,696 UK Biobank participants, with records spanning a median of 16.90 years (IQR = 10.10 years) for participants with dementia and 13.36 years (IQR = 13.52) for controls (no diagnosis of dementia). Controls were validated with lower polygenic risk scores than either dementia group. ResultsCharacteristic comorbidity signatures were observed in individuals with Alzheimers Disease and Vascular Dementia. Up to 20 years before diagnosis, depressive episodes, osteoporosis, arthritis and irritable bowel syndrome are characteristic of Alzheimers Disease, but not Vascular Dementia or control cohorts. From 15 years before diagnosis, type 1 diabetes, functional intestinal disorder and chronic obstructive pulmonary disease begin to emerge. Up to 10 years before, symptoms involving fluid and food intake are uniquely associated with the cohort of people diagnosed with Alzheimers Disease. In Vascular Dementia, 20 years before diagnosis cerebral infarctions, type 1 diabetes, cerebrovascular disease, peripheral vascular disease, intestinal disorders and rheumatoid arthritis are early conditions in the Vascular Dementia cohort, not seen in control or Alzheimers Disease cohorts. 15 years before Vascular Dementia, an increase in mental health conditions emerge such as depressive episodes as well as rheumatoid arthritis. 10 years before Vascular Dementia, an additional burden of cerebrovascular diseases, hypotension and dorsalgia. From 5 years up to diagnosis of Vascular Dementia, intra-cerebral haemorrhage, mental and behavioural disorders due to tobacco begin to emerge within this population. In the years following Alzheimers Disease diagnosis, acute lower respiratory infections and skin conditions such as decubitus ulcer emerge up to 2 years after diagnosis. After a diagnosis of Vascular Dementia, pneumonitis and decubitus ulcer and pressure area, are unique to this cohort. ConclusionIn this study, comorbid conditions were mapped in relation to Alzheimers Disease and Vascular Dementia pre- and post-diagnosis. Understanding prodromal and progressive changes in health over the course of these dementia sub-types could uncover opportunities for targeted screening, preventative measures and early interventions. SummaryDementia develops alongside multiple long-term health conditions1-3, yet the timing and subtype-specific patterns of these comorbidities remain unclear. Using hospital records from 10,696 UK Biobank participants, we mapped comorbidities from 20 years before to 10 years after diagnosis of Alzheimers Disease or Vascular Dementia. We show that distinct comorbidity signatures precede each dementia subtype: depression, osteoporosis and intestinal disorders are early features of Alzheimers Disease, while Vascular Dementia is characterised by cerebrovascular and peripheral vascular diseases, type 1 diabetes and arthritis up to two decades before diagnosis. Post-diagnosis, conditions such as respiratory infections and pressure ulcers show divergent trajectories. These findings reveal temporally distinct, disease-specific comorbidity profiles, suggesting differing pathological pathways and windows for targeted intervention. Understanding the longitudinal burden of comorbidities in dementia can inform screening, risk stratification, and preventative strategies long before clinical onset.