When heart, kidney and metabolic problems pile up, thinking skills tend to slip faster

Extra body fat, high blood pressure, diabetes, weak kidneys and heart disease often come together, and each makes the others worse. Doctors have recently started treating this cluster as one condition, cardiovascular-kidney-metabolic (CKM) syndrome, and sorting it into five stages:

• Stage 0: normal weight and waist, no risk factors.
• Stage 1: too much body fat (a high body-mass index or waist) or prediabetes, blood sugar that is higher than normal but not yet diabetes.
• Stage 2: metabolic risk factors such as high blood pressure, high blood fats, diabetes, or chronic kidney disease, kidneys that filter blood less well than they should.
• Stage 3: hidden heart and blood-vessel disease: no heart attack or stroke yet, but in this study a predicted risk of at least 20% of one within ten years, or severe loss of kidney function.
• Stage 4: diagnosed heart and blood-vessel disease, or kidney failure.

Earlier work had linked the advanced stages to a higher risk of dementia. An international team now asked what happens to thinking skills over the years before any such diagnosis, and which parts of thinking are hit. The work is an observational study and a preprint, not yet peer-reviewed.

What they did

• Main group: 24,883 people without dementia from three large ageing surveys in Europe, England and China, followed for 6.5 years on average with simple memory, arithmetic and orientation tests.
• Second check: 3,359 people from four community studies in Australia, Italy, Greece and the US, followed for 5.4 years on average. Here fuller test batteries split thinking into five areas: memory, attention, executive function (planning, switching between tasks, controlling impulses), language and visual-spatial skills.
• Each person's CKM stage was worked out once, at the start. The team compared how fast test scores fell at each stage, taking age, sex, education, heavy drinking, low mood and inactivity into account.
• They also looked at depressive symptoms, six known dementia risk factors, and brain scans of 29,774 UK Biobank volunteers.

What they found

• Stage 2 made no clear difference. Compared with stages 0–1, people at stage 2 did not decline faster in either group.
• Stages 3 and 4 did. In the main group, global test scores at both stages fell about 0.03 standard deviations (a measure of how spread out scores are) per year faster than at stages 0–1. The second group showed a similar, slightly smaller pattern.
• Not every skill. Language, attention and executive function were linked to the CKM stage; memory and visual-spatial skills were not.
• Who. The link was stronger in people aged 70 or younger, in men, and (in the main group) in people with less schooling. Carrying APOE ε4, the best-known gene variant for Alzheimer's risk, did not change it.
• Mood. Among people whose thinking was still normal, advanced stages, especially stage 4, were linked to more depressive symptoms.
• Brain scans. People at stages 3–4 differed on 27 of the 34 brain measures. The biggest difference was in white matter hyperintensities, small bright spots on scans that mark damage from tiny blood vessels: their volume was about 14% larger. Total brain volume was not different.
• Other risk factors. Together, six factors (heavy drinking, inactivity, social isolation, depressive symptoms, hearing loss and vision loss) accounted for an estimated 24.8% of new cases of impaired thinking among people at stages 3–4, with social isolation the largest single share (7.0%).

What to keep in mind

• The authors' own caveats: fitting very different studies into one format meant losing detail and probably putting some people in the wrong group, partly because many diagnoses were self-reported and definitions differ between countries. CKM stage was measured only once, so changes over time were missed. Factors that weren't measured, such as diet or early brain disease, may explain part of the link. The brain scans are a single snapshot of a relatively healthy group.
• It is observational: advanced CKM was linked to faster decline, which does not show that it causes it, or that treating it would slow decline.
• The "24.8%" figure is a model estimate that assumes removing the six factors would remove their share of the risk; it is not the result of anyone changing those habits. The paper's summary and its results section also name different runners-up after social isolation.
• People who were left out of the analysis were older and had more depressive symptoms, and UK Biobank volunteers were aged 37–72 when they joined, younger than the other groups.

Why it matters

CKM syndrome is common in people over 65 in both the US and Asia. This study suggests that the thinking problems tied to it appear mainly once heart and blood-vessel disease, hidden or diagnosed, or serious kidney damage has set in, and that they show up first in attention, planning and language rather than memory. The brain scans point to damage in small blood vessels as one possible route. The team calls for testing whether spotting and managing CKM earlier, and paying attention to isolation, mood and inactivity, helps preserve thinking in later life; this study cannot answer that.