Can loneliness increase the risk for dementia?

Depression and loneliness are common among people with dementia, including Alzheimer’s disease, and a recent paper in Neurology suggests that loneliness may actually increase the chance of getting dementia. This was a retrospective analysis of data collected from the Framingham Study (September 9, 1948–December 31, 2018). At baseline, the 2038 participants were dementia-free and had loneliness assessed using one question from a depression rating scale.  They were asked how often they had felt lonely in the previous week. Participants were classified as lonely (3–7 days) or not lonely (0–2 days). Ten years later, those in the lonely group were 1½ times more likely to have dementia than those who were self-rated as not lonely at baseline. Also, among those who still did not have dementia at the 10-year mark, the participants who had self-rated as lonely were more likely to have poorer executive function (associated with prefrontal damage), smaller cerebral cortex volume, and more white matter brain damage despite scoring in the normal range on cognitive tests for dementia.

The results were interpreted as supporting the hypothesis that loneliness can be a driver of dementia pathology, increasing the risk of getting dementia. However, the authors admitted that there could be another explanation: loneliness could be an early symptom of dementia, perhaps occurring years before the onset of cognitive problems. They felt this was relatively unlikely given the 10-year hiatus between the onset of loneliness and the diagnosis of dementia.I disagree.  I think that both hypotheses are plausible, and perhaps both are correct, at least for Alzheimer’s disease.  The key here is understanding that Alzheimer’s pathology in the brain, the amyloid plaques and neurofibrillary tangles, can start to form up to 20 years before there is any cognitive impairment. Loss of the ability to smell is almost universal in Alzheimer’s, and it often begins years before the cognitive impairment. In fact, Alzheimer’s pathology is first seen in olfactory centers in the brain, later followed by the hippocampus and other memory-processing areas. The prefrontal cortex is also an early site of beta-amyloid deposition. This area of the brain is involved in executive function: making plans and decisions, expressing personality and moderating social behavior. Damage to the prefrontal cortex often results in apathy, an early symptom of Alzheimer’s disease. As an example, the amyloid PET scan of my brain done as part of a research study in 2015 shows moderate amounts of amyloid in my prefrontal cortex as well as in two olfactory centers, the piriform cortex and mesial orbitofrontal cortex.  At this time my cognitive testing was still in the normal range, but I had started to lose my sense of smell almost ten years before, and my abilities to make plans and socialize were already affected.

My point is this. Loss of the sense of smell is an early, nonspecific symptom of Alzheimer’s disease. It can start many years before there is any cognitive impairment. Amyloid deposition in the prefrontal cortex can also cause early personality changes including apathy before there is any cognitive change. I think it is entirely possible that loneliness may be another early, nonspecific symptom of Alzheimer’s. Perhaps loneliness might also predispose to getting dementia as proposed in this paper. We don’t know the answer yet.

Why is this important? It is becoming increasingly apparent that our first success with treating Alzheimer’s disease will come in the earliest stages, before cognitive impairment and death of nerve cells in the brain have progressed. Identifying these people who are on the Alzheimer’s trajectory but who do not yet have cognitive problems will be difficult. It may be possible to combine some of these nonspecific, pre-cognitive impairment symptoms, loss of smell, personality and apathy issues, with family history risks and known genetic markers to identify those who might benefit from more precise testing with blood biomarkers or PET scans. Early identification of Alzheimer’s disease before cognitive impairment has started is controversial, but it may be necessary for successful treatment.