Summary of study methodology and key findings
| Author(s) & year | Title of study | Study objective | Sample size | Study methods | Key findings | Strength | Limitation | Statements |
| Amieva et al, 200825 | Prodromal Alzheimer’s disease: the successful emergence of clinical symptoms. | To examine the emergence of the first clinical symptoms over a 14-year period of follow-up before dementia. | 350 | A longitudinal nested case-control study. | Activities of daily living scores were the least to appear at 13–14 years of the study, MMSE scores remained the same until the 12th year, memory decline was reported 2 years into the study, closely followed the same year by cognitive decline and depressive symptoms, verbal decline in the 4th year and visual disturbance in the last 5–6 years into the study. | Nested case control of a 14-year period, contributing to evidence on the long duration of the predementia phase. | The absence of an accurate measure of episodic memory. The composition of the study sample was heterogeneous. | The first symptom to appear was memory loss, followed by a cognitive decline, depression, visual disturbance and verbal memory loss; (0.05% point/year) from the 11 years. |
| Devier et al, 201020 | Predictive utility of type and duration of symptoms at initial presentation in patients with MCI. | To assess (1) the duration and symptoms and (2) the impact of the symptoms on predicting conversion to AD. | 148 | Longitudinal assessment, interviewing reliable informants to collect data. | Heterogeneity in the first symptom to appear with sequence and timing (average time in months) as follows: memory loss, 38.5; depressed mood, 37.4; performance, 36.8; personality, 32.5; behaviour, 31.1; language, 29.2; disorientation, 29.1; and psychosis, 14.0. For the converters, the average time from the onset of the first symptom to AD diagnosis was 62 months (a range from 19 to 176 months). Average time in the presentation was 62 months. | The provision of new information about the relationship of early symptoms in person presenting with cognitive decline. | A small number of converters within a group of EOAD. No detailed reports on the timing from first symptoms report to AD diagnosis. | Memory loss was reported as the first symptom in 80% of cases, depression in 9%, language deficit in 4%, cognitive changes in 2%, behavioural and personality changes in 1%. |
| Fox et al, 199826 | Presymptomatic cognitive deficits in individuals at risk of familial AD. | To assess the earliest clinical and neuropsychological features of familial AD. | 63 | Case selection of asymptomatic at-risk members of early-onset familial AD. | The study suggests that memory decline is one of the earliest measurable cognitive deficits in AD, with the verbal memory more discriminating than the non-verbal. Cognitive decline was present 2–3 years before symptoms manifestation and 4–5 years before fulfilling the criteria for probable AD. | The study demonstrates that cognitive deficits predict symptoms in familiar AD by several years. | No comparison group. It was not possible to determine the exact point at which AD became clinically diagnosable within the 3-year follow-up. | 7 subjects were left handed, 55 right handed and 1 ambidextrous. Of the 63 subjects, 10 converted to AD with no difference in gender, age or left-handedness. |
| Schmidt et al, 201027 | Clinical features of rapidly progressive AD. | To examine the clinical features in terms of symptoms frequency, time span until onset and time point of onset relative to disease. | 32 | Retrospective case analysis. | 35 neurological, psychiatric and autonomic symptoms were identified in a rapid progressive AD, with a median time to survival being 26.4 months. | The study reported the symptom frequency, time span until onset and time point of onset relative to disease end point. | Fast-declining AD cases without control and few numbers of subjects, which could limit generalisation. | The most common symptoms reported were myoclonus (75%), disturbed gait (66%) and rigidity (50%). The sequence in the appearance of symptoms was disorientation, depression, impaired concentration, anxiety, disturbed gait, seizures, myoclonus and hallucination, consecutively; rigidity, sleep disturbance, apathy, weight loss and disinhibition. |
AD, Alzheimer’s disease; EOAD; early-onset AD; MMSE, mini-mental state examination.