Background
A small proportion of patients with Alzheimer’s disease (AD) carry autosomal-dominant mutations in the APP, PSEN1, or PSEN2 genes (adAD) [
1]. For these individuals, the onset of disease typically occurs early in life, before 65 years of age [
2,
3]. However, the genetic background of most patients diagnosed with sporadic AD (sAD) is unknown. The onset of disease varies from early to late in life. The mechanisms involved in disease development in these individuals could involve gene–gene or gene-environment interactions, comorbidity, lifestyle choices, resilience, or compensation [
1,
4].
Although adAD and sAD patients generally vary in age of onset and details of clinical expression, they share similarities in the development of neuropathological features such as neuronal loss, amyloid plaques, and neurofibrillary and tau loads [
5‐
8]. Individuals with adAD or sAD can also share clinical characteristics such as mode of onset, type of symptoms, progression, duration details [
9,
10], patterns of brain atrophy [
11,
12] and connectivity [
13], as well as levels of biomarkers for the disease such as CSF biomarker levels of beta-amyloid (Aβ
42), total-tau, and phosphorylated tau (p-tau) [
14]. Subsequently, adAD and sAD are thought to be variants of the same biological disease. In fact, the clinical diagnoses of sAD and adAD follow the same criteria, as expressed in the National Institute of Neurological and Communicative Disorders and Stroke, and Alzheimer’s Disease and Related Disorders Association (NINCDS-ADRDA) manual [
15], the Diagnostic and Statistical Manual of Mental Disorders (DSM-V) [
16] and the International Classification of Diseases (ICD-10) [
17]. In recent years, the NINCDS-ADRDA criteria have been challenged by biomarker-based criteria such as the NII-AA [
18] and the IWG-2 [
19] criteria.
In patients carrying the mutations for adAD, it is possible to calculate the years to the estimated clinical onset (YECO) of disease [
20,
21] using the subject’s present age minus the family-specific age of onset of adAD obtained from medical files for individuals of the specific family. This method has made it possible to devise a general disease-onset time scale for adAD. This type of time scale has proven reliable, has been validated in relation to biomarkers of disease development, and has been successfully used in adAD research [
20,
22‐
26].
In previous sAD research, time scales of disease progression have been designed from cross-sectional data or short-term changes in sAD patients. In a recent example, short-term changes in CSF biomarkers, PET
18F-fluorodeoxyglucose (FDG) metabolism, and cognition (global and episodic memory) were used to predict longitudinal trajectories in patients with sAD [
27]. The results showed that early changes in episodic memory, hippocampal volume, and CSF biomarkers (Aβ
42 and p-tau) were best fitted to a model of the time course of disease. A similar study showed that short-term changes from mild cognitive impairment (MCI) to AD were reliably predicted by changes in visuoconstructive performance, hippocampal volume, and FDG PET results [
28]. In another approach, a cross-sectional study used machine learning with combined multimodal brain MR, CSF, and PET measures in patients with adAD to predict disease progression in a second sample of sAD patients [
29]. Based on the large number of predictors and covariates (age, APOE status, current diagnostic state, and the time interval between clinical visits), the probability of reaching a more advanced state was modeled in cognitively normal, MCI, and AD individuals. Results established a complex pattern of preclinical changes and the clinical outcome [
30]. To date, both quantitative measures (various biomarkers) and qualitative data (clinical stages, ATN nomenclature [
31] including amyloid/tau/neurodegeneration) have been used to predict future status in AD. In addition, the traditional evaluation of symptom onset and duration of symptoms has recently been reviewed [
32]; it was found that estimates of disease duration (before as well as after diagnosis) vary considerably, which hampers the drawing of reliable conclusions. In all the reported studies, the common denominator dealt with describing or predicting the expression of sAD during disease progression have used various system constructs (molecular, cell, tissue, brain, and human function), in a similar vein to the methods used to describe the temporal continuum of biological aging [
33].
In this study, the main objective was to design an objective cognition-based time scale in years of disease progression for sAD using data on the decline in cognitive function but also taking cognitive reserve into account (in this case, years of education) [
4]. The second aim was to validate the time scale in patients with sAD in relation to quantitative measures such as CSF beta-amyloid, p-tau, and t-tau [
34]; PET
11C-Pittsburgh compound B (PiB) beta-amyloid and FDG metabolism [
35]; and ATN framework [
31].
Methods
Participants
The participants in this study were recruited from patients at the Memory Clinic, Karolinska University Hospital, Stockholm, Sweden, who had participated in PET research regarding beta-amyloid and glucose metabolism [
36]. One group was diagnosed with MCI (
n = 46) and another with AD (
n = 48). Initially, all participants were examined according to a standardized comprehensive clinical procedure (see below) that did not include PET examination. The exclusion criteria were alcohol and drug abuse and psychiatric disease. Patients with marked cerebrovascular burden verified in the clinical examination were excluded as well.
The participants were subdivided into amyloid pathology using PET PiB cut-off (positive if neocortical PiB ≥ 1.41 and negative if neocortical PiB ≤ 1.40) resulting into four subgroups: PiB + AD (
n = 40), PiB + MCI (
n = 25), PiB − AD (
n = 8), and PiB − MCI (
n = 21). The PiB + subgroups can be understood as Alzheimer’s disease [
31] and PiB − subgroups as non-AD pathologic change [
31].
Clinical examination
The clinical examination included medical history; a somatic, neurological, and psychiatric examination; cognitive screening with MMSE; an interview with a close informant; cognitive assessment (see below); routine analyses of blood, urine, and CSF (Aβ42, total-tau, and p-tau); MR imaging of the brain to evaluate the degree of atrophy (general, medial temporal, frontal and posterior) and other brain abnormalities.
Diagnosis
The clinical diagnosis was decided at a consensus meeting of medical professionals (geriatricians, neurologists, psychologists, and nurses) and was based on all available examination reports except PET imaging. The dementia diagnosis followed the classical criteria of the DSM-V [
37], and the NINCDS-ADRDA [
15] as well as modified criteria that included CSF biomarkers [
18,
19]. The MCI diagnosis was made according to the revised Petersen criteria [
38].
CSF biomarker levels
CSF levels of beta-amyloid, p-tau, and total-tau were included in the standard clinical protocol and measured as part of the clinical evaluation of the patients as described in detail in previous research [
34]. The epitope of p-tau was 181. Abnormality was defined by the following cut-off values: beta-amyloid < 450 pg/mL, p-tau > 60 pg/mL, and total-tau > 400 pg/mL.
Regional PET examination of PiB and FDG
The PET examinations were carried out at the Uppsala PET center within a few months of the clinical examinations; they covered 13 regions and measured PiB amyloid and FDG metabolism as described in previous publications [
36]. The PET neocortical PiB value was used to classify the participants into amyloid-positive (≥ 1.41) and amyloid-negative (≤ 1.40) groups, as previously recorded [
36]. The measurement of glucose metabolism used an index of aggregated values in the temporal, parietal, and posterior gyrus cinguli regions; abnormality was defined according to cut-off values for the index: positive (≤ 1.50) and negative (≥ 1.51) [
39].
Assessment of cognitive function
The standard clinical assessment of cognition included current global cognitive function, based on five subtests (the Information, Digit Span, Similarities, Block Design, and Digit Symbol tests) from the Wechsler Adult Intelligence Scale Revised [
40,
41]. Short-term memory/attention was assessed using the Digit Span Forward test and the Corsi Span test [
42]. The total score on the Rey Auditory Verbal Learning (RAVL)[
42] test was used to assess verbal learning and 30 min retention in episodic memory. The Rey-Osterrieth 30 min retention test (RO retention) [
42] was used to assess visuospatial episodic memory. Executive function was assessed using the Digit Symbol and Trail Making tests (TMTA and TMTB) [
42]. Raw scores were converted to z-scores using a reference group of healthy adults at Karolinska University Hospital [
43].
Years to estimated clinical onset (YECO)
For each participant, the YECO were calculated using the equations obtained in a previous study of patients with adAD [
20]. These equations were obtained for each cognitive test in carriers of five mutations associated with adAD [
20]; they described the relationship between the test performance and three predictors: linear and quadratic YECO and years of education. The same three predictors and the associated beta weights were used in the present study, together with the cognitive test results, to find the unknown YECO in patients with AD or MCI. The median YECO was estimated from the five AD-sensitive tests (Similarities, Block Design, RAVL learning, RO retention, and Digit symbol) [
20]. The concept of YECO has been shown to be valid and reliable in previous research in adAD [
21,
44]
Statistical analysis
Descriptive statistics and t-tests were used to analyze the baseline information. The formulas from the previous study of patients with adAD on the relationships between cognitive test results and linear and curvilinear YECO were used, along with years of education to represent cognitive reserve [
20]: cognitive test result (raw score) = beta weight × YECO + beta weight × YECO
2 + beta weight × years of education. The beta weights were taken from the previous study and the test results were from the present study, while YECO was unknown. YECO was obtained as the two roots of the equation, negative if the current stage of disease progression was prior to the estimated clinical onset (preclinical stage) and positive if the current stage of disease progression was later than the estimated clinical onset (clinical stage).
The validity of YECO as a marker of disease progression was evaluated by means of the association between YECO and the investigated biomarkers in PET and CSF, as assessed using Pearson correlation coefficients. These values were compared with the corresponding values for chronological age vs biomarkers in PET and CSF. A second validation was based on the ATN framework, using clinical cut-off values for binarization of all five biomarkers (PET PiB and FDG index, CSF Aβ42, total-tau, and p-tau) as normal or abnormal and binarization of YECO as negative or positive. The strength of association was expressed as the phi (ϕ) correlation coefficient together with p-values in χ2-statistics.
The estimated age of disease onset for each participant was calculated as their current age minus the median YECO obtained from five cognitive tests, in agreement with corresponding calculations in patients with adAD. A χ2-test was used to check whether the distribution of age at disease onset was normal. A χ2-test was used also used to analyze the association between early- vs late-onset and amyloid abnormality.
A k-means cluster analysis was applied to the median age at disease onset assuming two clusters, because the frequency distribution of age at disease onset was evaluated as bimodal showing two subgroups, one with early-onset and a second with late-onset disease.
The difference in biomarker levels between the early- and late-onset subgroups was analyzed using a t-test with and without control for the stage of disease progression (YECO) using covariance analyses.
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