We followed 988 people who started with mild cognitive impairment and no dementia, and counted how many were later diagnosed with dementia. About 8 in 100 had been diagnosed by one year, 21 in 100 by two years, 30 in 100 by three years and 38 in 100 by four years. Half had been diagnosed by roughly six and a half years. These are averages across a large group and say little about any one person.
Caveat. This is a research cohort of volunteers seen at memory clinics, so rates are higher than in the general population, and allowing for the timing of clinic visits moves the one-year figure up to about 13%.
Age/sex/education/APOE4 only (concordance) (n=297)
We built a risk model for who with mild impairment would develop dementia and tested it on 297 people it had never seen. Using age, sex, education and APOE4 alone, the model ranked people correctly about 64 times in 100 (0.635, where 0.5 is a coin toss). Adding memory and thinking tests raised this to about 85 in 100 (0.847). Adding spinal-fluid markers, brain MRI and amyloid/glucose PET on top moved it by less than one point each (0.855, 0.860, 0.863), and every one of those gains is within chance.
Caveat. Several of the cognitive tests are used by clinicians to decide the dementia diagnosis itself, which flatters their predictive power.
Rank correlation, total tau vs p-tau181 (log scale) (n=693)
In 693 people with spinal-fluid results, total tau and phosphorylated tau (p-tau181) were almost perfectly correlated (rank correlation 0.98). A model or report that includes both is adding very little new information over using one.
Caveat. Phosphorylated tau is a fraction of total tau, so a high correlation is partly built in; it does not mean the two carry identical clinical meaning.
Rank correlation, blood p-tau217/amyloid-42 ratio vs amyloid PET (n=113)
In 113 people who had both a blood test and an amyloid PET scan, the blood ratio of p-tau217 to amyloid-42 rose and fell with the amount of amyloid on the scan (rank correlation 0.75, 95% confidence range 0.66 to 0.81). That is a strong agreement but far from a one-to-one match.
Caveat. Only 113 people, one blood-test platform, and people with mild impairment, so it should not be read as how well the test performs for diagnosis in general.
We scored 751 older adults of European ancestry on a polygenic score for ADHD, leaving out the APOE region, and tested it against ten measures of cognition at the start and their change over time, including whether the link differed by amyloid status. Nothing was convincing: the smallest corrected p-value was 0.79. In 391 further people genotyped on a different platform it was again null (smallest corrected p 0.96), and pooling all 1,142 people gave 0.93.
Caveat. ADHD is not recorded in this cohort, the score captures only a few percent of ADHD liability, European ancestry only, and the second sample is mainly early-enrolled people with limited amyloid data, so the test of an amyloid interaction is weak.
Odds ratio, APOE-region variant, normal vs dementia (n=321)
We compared the genomes of roughly 320 cognitively normal people and people with Alzheimer's dementia. One variant in the APOE region, the best-known Alzheimer's risk gene, reached genome-wide significance (odds ratio 5.4, p = 6.4e-9); no other region did. Comparing normal with mild impairment in about 760 people found nothing significant, as expected for a sample this small. That the known gene shows up and the statistics are well behaved (inflation factor 0.97) is a useful check on the data.
Caveat. Only a few hundred people, so the odds ratio is inflated by comparing two extreme groups and this scan could not find new genes.
Reason. Not for stand-alone use: the tests help define the diagnosis being predicted, and most biomarker values were estimated by imputation for people who lacked them, which handicaps the biomarker side.
Reason. Not for stand-alone use: the result flips between significant and not depending on the marker and the correction, the composites share test components with the memory score, and it says nothing about ADHD itself.
Reason. Not for stand-alone use: only 36 Alzheimer's participants, and a cohort-wide same-direction methylation shift (inflation up to 2.35) means small effects could not be detected, so this is a weak null rather than a clean one.
Reason. Not for stand-alone use yet: the earlier 27-variant instrument set could not be reproduced (34 used), the MR-RAPS package was unavailable so a home-built robust estimator was used, and one nominal signal is unresolved.