Background Here, we address a pivotal factor in Alzheimer’s prevention—identifying those at risk early, when dementia can still be avoided. Recent research highlights an accelerated forgetting phenotype as a risk factor for Alzheimer’s disease. We hypothesized that delayed recall over 4 weeks would predict cognitive decline over 1 year better than 30-min delayed recall, the current gold standard for detecting episodic memory problems which could be an early clinical manifestation of incipient Alzheimer’s disease. We also expected hippocampal subfield volumes to improve predictive accuracy. Methods Forty-six cognitively healthy older people (mean age 70.7 ± 7.97, 21/46 female), recruited from databases such as Join Dementia Research, or a local database of volunteers, performed 3 memory tasks on which delayed recall was tested after 30 min and 4 weeks, as well as Addenbrooke’s Cognitive Examination III (ACE-III) and CANTAB Paired Associates Learning. Medial temporal lobe subregion volumes were automatically measured using high-resolution 3T MRI. The ACE-III was repeated after 12 months to assess the change in cognitive ability. We used univariate linear regressions and ROC curves to assess the ability of tests of delayed recall to predict cognitive decline on ACE-III over the 12 months. Results Fifteen of the 46 participants declined over the year (≥ 3 points lost on ACE-III). Four-week verbal memory predicted cognitive decline in healthy older people better than clinical gold standard memory tests and hippocampal MRI. The best single-test predictor of cognitive decline was the 4-week delayed recall on the world list (R2 = .123, p = .018, β = .418). Combined with hippocampal subfield volumetry, 4-week verbal recall identifies those at risk of cognitive decline with 93% sensitivity and 86% specificity (AUC = .918, p < .0001). Conclusions We show that a test of accelerated long-term forgetting over 4 weeks can predict cognitive decline in healthy older people where traditional tests of delayed recall cannot. Accelerated long-term forgetting is a sensitive, easy-to-test predictor of cognitive decline in healthy older people. Used alone or with hippocampal MRI, accelerated forgetting probes functionally relevant Alzheimer’s-related change. Accelerated forgetting will identify early-stage impairment, helping to target more invasive and expensive molecular biomarker testing.

Background Early Alzheimer’s disease (AD) diagnosis is vital for development of disease-modifying therapies. Prior to significant brain tissue atrophy, several microstructural changes take place as a result of Alzheimer’s pathology. These include deposition of amyloid, tau and iron, as well as altered water homeostasis in tissue and some cell death. T2 relaxation time, a quantitative MRI measure, is sensitive to these changes and may be a useful non-invasive, early marker of tissue integrity which could predict conversion to dementia. We propose that different microstructural changes affect T2 in opposing ways, such that average ‘midpoint’ measures of T2 are less sensitive than measuring distribution width (heterogeneity). T2 heterogeneity in the brain may present a sensitive early marker of AD pathology. Methods In this cohort study, we tested 97 healthy older controls, 49 people with mild cognitive impairment (MCI) and 10 with a clinical diagnosis of AD. All participants underwent structural MRI including a multi-echo sequence for quantitative T2 assessment. Cognitive change over 1 year was assessed in 20 participants with MCI. T2 distributions were modelled in the hippocampus and thalamus using log-logistic distribution giving measures of log-median value (midpoint; T2μ) and distribution width (heterogeneity; T2σ). Results We show an increase in T2 heterogeneity (T2σ; p < .0001) in MCI compared to healthy controls, which was not seen with midpoint (T2μ; p = .149) in the hippocampus and thalamus. Hippocampal T2 heterogeneity predicted cognitive decline over 1 year in MCI participants (p = .018), but midpoint (p = .132) and volume (p = .315) did not. Age affects T2, but the effects described here are significant even after correcting for age. Conclusions We show that T2 heterogeneity can identify subtle changes in microstructural integrity of brain tissue in MCI and predict cognitive decline over a year. We describe a new model that considers the competing effects of factors that both increase and decrease T2. These two opposing forces suggest that previous conclusions based on T2 midpoint may have obscured the true potential of T2 as a marker of subtle neuropathology. We propose that T2 heterogeneity reflects microstructural integrity with potential to be a widely used early biomarker of conditions such as AD.

A better understanding of early brain changes that precede loss of independence in diseases like Alzheimer's disease (AD) is critical for development of disease-modifying therapies. Quantitative MRI, such as T2 relaxometry, can identify microstructural changes relevant to early stages of pathology. Recent evidence suggests heterogeneity of T2 may be a more informative MRI measure of early pathology than absolute T2. Here we test whether T2 markers of brain integrity precede the volume changes we know are present in established AD and whether such changes are most marked in medial temporal lobe (MTL) subfields known to be most affected early in AD. We show that T2 heterogeneity was greater in people with mild cognitive impairment (MCI; n = 49) compared to healthy older controls ( n = 99) in all MTL subfields, but this increase was greatest in MTL cortices, and smallest in dentate gyrus. This reflects the spatio-temporal progression of neurodegeneration in AD. T2 heterogeneity in CA1-3 and entorhinal cortex and volume of entorhinal cortex showed some ability to predict cognitive decline, where absolute T2 could not, however further studies are required to verify this result. Increases in T2 heterogeneity in MTL cortices may reflect localised pathological change and may present as one of the earliest detectible brain changes prior to atrophy. Finally, we describe a mechanism by which memory, as measured by accuracy and reaction time on a paired associate learning task, deteriorates with age. Age-related memory deficits were explained in part by lower subfield volumes, which in turn were directly associated with greater T2 heterogeneity. We propose that tissue with high T2 heterogeneity represents extant tissue at risk of permanent damage but with the potential for therapeutic rescue. This has implications for early detection of neurodegenerative diseases and the study of brain-behaviour relationships.

A better understanding of early brain changes that precede loss of independence in diseases like Alzheimer's disease (AD) is critical for development of disease-modifying therapies. Quantitative MRI, such as T2 relaxometry, can identify microstructural changes relevant to early stages of pathology. Recent evidence suggests heterogeneity of T2 may be a more informative measure of early pathology than absolute T2. Here we test whether T2 markers of brain integrity precede the volume changes we know are present in established AD and whether such changes are most marked in medial temporal lobe (MTL) subfields known to be most affected early in AD. We show that T2 heterogeneity was greater in people with mild cognitive impairment (MCI; n=49) compared to healthy older controls (n=99) in all MTL subfields, but this increase was greatest in MTL cortices, and smallest in dentate gyrus. This reflects the spatio-temporal progression of neurodegeneration in AD. T2 heterogeneity in the entorhinal cortex also predicted cognitive decline over a year in people with MCI, where measures of volume or T2 in any other subfield or whole hippocampus could not. Increases in T2 heterogeneity in MTL cortices may reflect localised pathological change and may present as one of the earliest detectible brain changes prior to atrophy. Finally, we describe a mechanism by which memory, as measured by accuracy and reaction time on a paired associate learning task, deteriorates with age. Age-related memory deficits were explained in part by lower subfield volumes, which in turn were directly associated with greater T2 heterogeneity. We propose that tissue with high T2 heterogeneity represents extant tissue at risk of permanent damage but with the potential for therapeutic rescue. This has implications for early detection of neurodegenerative disease.