AbstractBackgroundPlasma measures of amyloid‐β (Aβ) peptides recently emerged as a potential equivalent to brain positron‐emission tomography (PET) imaging and cerebrospinal fluid (CSF) measurements in determining Aβ status. Low plasma Aβ42/40 has been associated with Alzheimer’s disease. However, further studies are needed to validate its use for predicting cognitive impairment. This study aimed to investigate the associations between plasma Aβ42/40 and cognitive decline over time among community‐dwelling older adults.MethodObservational study using data of 483 subjects ≥70 years (mean age 76.9 years, SD = 4.5; 59.2% women), volunteers from the Multidomain Alzheimer Preventive Trial (MAPT), who were followed for 5 years. Plasma Aβ42 and Aβ40 were measured at 12 months for 92.8% of participants and at 24 months for the rest. Participants were classified as low Aβ42/40 (≤0.107) or normal Aβ42/40. Cognitive function was assessed at 12, 24, 36, 48 and 60 months of follow‐up, by a composite cognitive score (based on four tests); Mini Mental State Examination (MMSE); Clinical Dementia Rating (CDR) sum of boxes; Alzheimer's Disease Cooperative Study ‐ Activities of Daily Living (ADCS‐ADL). Linear mixed models were performed. Potential confounders included age, sex, education, body mass index, ApoE ε4 genotype and MAPT groups.ResultFrom the total, 33.3% (n = 161) were classified as low plasma Aβ42/40. After adjusting for potential confounders, low plasma Aβ42/40 was associated with higher decline in composite cognitive score, decline in MMSE score and with higher increase in CDR sum of boxes after 4 years, compared to the normal Aβ42/40 group. Those with low Aβ42/40 had approximately 2‐fold acceleration in outcomes evolution. Sensitivity analysis considering the 25th percentile of Aβ42/40 (≤0.103) as an alternative cutoff provided similar findings.ConclusionLow plasma Aβ42/40 was associated with higher impairment in cognitive function (measured by multiple outcomes) over time among community‐dwelling older adults. Findings points towards the use of this inexpensive measure to quickly identify people at risk of Alzheimer’s disease and other neurodegenerative diseases, over more complex and expensive measures such as PET or CSF. Further studies with long follow‐ups are needed to confirm its utility in clinical practice and public health.