Neuropsychological Profiles,Etiologies,and Medical Comorbidities in Early-Onset Dementia and Cognitive Impairment: A Memory Outpatient Clinic Cohort Study

Abstract

Background:

Although early-onset dementia (EOD) is associated with diagnostic challenges that differ from those of related to late-onset dementia, only limited studies have addressed the neuropsychological and health characteristics or specified the diagnoses underlying early-onset cognitive impairment in a real-world clinical setting.

Objective:

To investigate the neuropsychological profiles, etiologies, and comorbidities of an unselected cohort of memory clinic patients (≤65 years at symptom onset).

Methods:

The patients’ (n = 210) diagnoses were determined based on comprehensive diagnostic workup. Medical comorbidities and neuropsychological profiles were compared between clinically relevant patient groups, namely early-onset dementia (n = 55), mild cognitive impairment due to vascular or suspected neurodegenerative (MCI-n, n = 35) or non-neurodegenerative (MCI-o, n = 106) etiologies, and subjective cognitive decline (n = 14).

Results:

The most prevalent diagnoses were Alzheimer’s disease (AD, 14%) and depression (11%). Multiple prior medical conditions were common (67%); however, EOD patients had fewer other diagnoses (p = 0.008) than MCI-o patients. Compared to other groups, EOD patients had more severe deficits (p < 0.001) on immediate and delayed memory, processing speed, symptom awareness, and global cognition. AD patients had weaker memory retention ability but less behavioral symptoms than frontotemporal dementia (FTD) patients (p≤0.05). Depression was associated with better immediate memory, symptom awareness, and global cognition than AD and FTD (p < 0.05).

Conclusions:

EOD is associated with more severe and widespread neuropsychological deficits but fewer prior medical diagnoses than nondegenerative etiologies of cognitive impairment. AD and depression are common etiologies and the neuropsychological profiles are partly overlapping; however, memory, symptom awareness and global cognitive impairment measures may help in the differential diagnosis.

Keywords

Alzheimer’s disease cognition dementia depression frontotemporal dementia multimorbidity

INTRODUCTION

Early-onset dementia (EOD, symptom onset before the age of 65 years) differs from the more common late-onset dementia (LOD) in terms of the underlying etiologies. Although Alzheimer’s disease (AD), vascular dementia (VaD), and frontotemporal dementia (FTD) are the most prevalent disorders in all ages [1], AD is less common in EOD than in LOD and younger patients have more often atypical, rare, and secondary forms of dementia [2 –4]. In addition, EOD patients have fewer comorbidities and lower prevalence rates of diabetes, cerebrovascular diseases, and other medical conditions [5, 6]. Differential diagnostics of EOD is particularly demanding, as reflected by more frequent misdiagnoses [7] and diagnostic delays [8]. The challenges are partly due to the differences in the neuropsychological presentations between EOD and LOD [9] including a more severe impairment on executive functions and other nonmemory domains [10 –14], as well as a higher prevalence and severity of neuropsychiatric symptoms [15, 16]. Moreover, there is marked overlap in neuropsychological presentations between neurodegenerative disorders and other conditions affecting cognition and behavior (e.g., AD, FTD, and psychiatric conditions) [17, 18], but research specifically on the neuropsychological features between early-onset patient groups is scarce.

The underlying causes of early-onset cognitive impairment in patients referred to memory clinic evaluation are diverse and fall more often than in older patients into the categories between normal cognition and dementia [19, 20], i.e., mild cognitive impairment (MCI) or subjective cognitive decline (SCD). While cognitive functioning in MCI is below expected range for that individual, SCD is a self-experienced worsening of cognition without objective cognitive impairment [21]. However, SCD patients at memory clinics may show minor cognitive impairments, more genetic risk factors for AD and AD pathology based on cerebrospinal fluid (CSF) biomarkers [22]. Although MCI has been predominantly studied in the context of preclinical AD [23], it can also result from other neurodegenerative or neurovascular pathologies and nondegenerative etiologies such as psychiatric conditions, sleep disorders, or substance abuse [24]. Like EOD, early-onset MCI seems to entail specific clinical and neuropsychological characteristics [25, 26]. Considering that 50% of early-onset MCI patients have non-amnestic presentations [27] and that the symptoms of early-onset AD are heterogenous, investigating etiological subtypes may be particularly relevant within the early-onset MCI research.

Since previous research has mainly compared early and late-onset patients, much less is known about the neuropsychological features and comorbidities across various etiologies and levels of early-onset cognitive impairment. The Cognitive Impairment and Work Ability (CIWA) project was established to study memory outpatient clinic patients with symptom onset at 65 years or younger. The aim was to investigate the diagnoses underlying cognitive symptoms and to compare the neuropsychological characteristics and medical comorbidities associated with EOD, MCI etiological subtypes (degenerative/vascular and nondegenerative), and SCD. As differential diagnostics between early stages of AD, FTD, and clinical depression is a common challenge [28], neuropsychological data were also analyzed in these groups.

MATERIALS AND METHODS

Participants of the CIWA study

All patients referred to diagnostic evaluation due to neuropsychological symptoms at the memory outpatient clinics in Oulu and Kuopio University Hospitals in Finland between March 1, 2019–March 31, 2021 and who were ≤65 years old at symptom onset were offered to participate in the study. These memory clinics are responsible for diagnosing neurodegenerative diseases in the catchment areas of patients aged 65 years or younger.

All patients (n = 210) underwent a full diagnostic evaluation including medical history, a neurological clinical examination, a comprehensive neuropsychological assessment, brain imaging with structural magnetic resonance imaging, and laboratory tests. When clinically indicated, a CSF sample (Aβ₄₂, tau, and phospho-tau, n = 81) and fluorodeoxyglucose-positron emission topography (n = 12) were analyzed. The imaging and laboratory tests were performed for clinical purposes and used in the diagnostic evaluation. Experienced neurologists specialized in dementia and memory disorders set the diagnosis for each patient per current diagnostic criteria [29 –34]. When necessary, the patients were followed up for up to two years before they received the diagnosis. The diagnosis was evaluated to be the primary cause underlying the cognitive impairment. All patients received oral and written information on the study and provided written informed consent in accordance with the Declaration of Helsinki. The ethics committees of the Northern Ostrobothnia and Northern Savo Hospital districts approved the study.

Diagnostic groups

The clinical diagnoses were used to form the EOD, MCI-neurological (MCI-n), MCI-other (MCI-o), and SCD groups (Fig. 1). The EOD group included progressive neurodegenerative disorders, VaD, and other non-reversible dementias. The patients in the MCI-n group had MCI due to a suspected neurodegenerative disorder or brain imaging-confirmed vascular etiology, whereas the patients in the MCI-o group had other causes than degenerative or vascular etiologies. In accordance with research guidelines and recent findings [21, 22], the SCD group patients reported cognitive symptoms and a concern associated with the symptoms, but they did not meet the criteria of MCI and there was no suspicion of a neurodegenerative or vascular brain disease.

Fig. 1

The primary diagnoses in the memory clinic cohort. EOD, early-onset dementia; MCI-n, mild cognitive impairment-neurological; MCI-o, mild cognitive impairment-other; SCD, subjective cognitive decline; AD, Alzheimer’s disease; FTD, frontotemporal dementia; VaD, vascular dementia.

Medical history

The following data on prior medical diagnoses were collected from hospital records: hypertension, hypercholesterolemia, coronary artery disease, atrial fibrillation, diabetes, cancer, fibromyalgia, chronic pain, substance abuse, brain injury, stroke, transient ischemic attack, epilepsy, sleep apnea, depression, anxiety, burnout and psychotic disorder.

Neuropsychological assessment and determining the neuropsychological impairment level

A comprehensive clinical neuropsychological assessment was conducted for all participants by experienced psychologists specialized in assessing patients with memory disorders (Table 1). The assessment was conducted primarily for clinical purposes and therefore some tests were not available for all participants. The tests were used to evaluate twelve neuropsychological domains: verbal immediate and delayed memory, visual immediate and delayed memory, working memory, attention, executive functions, processing speed, reasoning, language and visuospatial skills and behavioral/affective symptoms. The impairment level was specified by clinical judgement, i.e., integrative interpretation of the test results, considering age-adjusted normative scores, education, estimated premorbid intelligence level and qualitative performance features [35, 36]. The scoring ranged from 0 to 4, where 0 = normal performance, 1 = subtle impairment, 2 = mild impairment, 3 = moderate impairment, 4 = severe impairment. The mean of all cognitive domains was calculated, and the score was used as an estimate of global cognitive impairment level.

Table 1

Neuropsychological assessment methods used to assess cognitive domains in the CIWA study

Cognitive domain	Neuropsychological tests used in the assessment
Verbal immediate memory	WMS III [56]: Logical Memory I and Word List I
Verbal delayed memory	WMS III [56]: Logical Memory II and Word List II+recognition task
Visual immediate memory	WMS III [56]: Visual Reproduction I, CFT immediate recall [58]
Visual delayed memory	WMS III [56]: Visual Reproduction II, CFT delayed recall [58]
Working memory	WAIS IV [57]: Digit Span and Letter-Number Sequencing
Attention/vigilance	Cancellation test [58]
Executive functions	Trail Making Test Part B [59], Stroop test [60], Serial alternating S [58], dual task (phonemic fluency and serial alternating S)
Processing speed	Trail Making Test Part A [59], WAIS IV [57]: Digit Symbol Coding and Symbol Search
Language skills	Semantic and phonemic fluency [58], 15-Item version of the Boston Naming Test [61]
Visuospatial skills	Visuo-constructional drawings, Clock hands, CFT [58]
Reasoning	WAIS IV [57]: Similarities, Comprehension, Block Design and Visual Puzzles
Behavioral/Affective	Modified Frontal Behavioral Inventory [62], Patient Health Questionnaire [63]

CIWA, Cognitive Impairment and Work Ability Study; WMS III, Wechsler Memory Scale III; CFT, Complex Figure Test; WAIS IV, Wechsler Adult Intelligence Scale IV.

The level of symptom awareness and the most prominent cognitive symptom were also determined. The evaluation of symptom awareness was based on how the patient recognized his/her cognitive deficits and the previously described 0 to 4 scale was applied. A more detailed memory performance analysis for AD and FTD patients was conducted: a memory retention score was calculated by subtracting the delayed memory score from the immediate memory score. The neuropsychological assessment and the report were completed before the patient had received the diagnosis and therefore, the diagnosis did not affect the neuropsychological evaluation.

Data analysis

All statistical analyses were performed using the IBM SPSS version 27.0 software. Group differences in gender, education and health characteristics were studied using the Pearson Chi-square or Fisher’s exact test, as appropriate. As Shapiro-Wilk test indicated that the memory retention score was normally distributed, the independent samples t-test was used to examine differences between the AD and FTD groups on this variable. Due to a violation of the normality assumption and/or variable properties, a nonparametric Kruskal-Wallis test was used to study group differences in age and in all other neuropsychological variables. The global cognitive impairment level in diagnostic groups was further analyzed with linear regression model adjusted for age, education, and sex.

A p-value≤0.05 was considered statistically significant. For pairwise group comparisons, adjusted (Bonferroni method) significance values are reported.

RESULTS

The study cohort characteristics

Demographics are summarized in Table 2. The EOD (n = 55), MCI-n (n = 35), MCI-o (n = 106), and SCD (n = 14) groups did not differ in relation to gender ratio or education level. However, the EOD and the MCI-n patients were older than the MCI-o and the SCD patients (p < 0.001).

Table 2

Demographic information for the total study population and diagnostic groups

Demographic information	All	EOD	MCI-n	MCI-o	SCD	p
n	210	55	35	106	14
Age at first visit (M, SD)¹	57.6 (6.0)	60.1 (4.5)	60.6 (5.2)	55.6 (5.2)	55.5 (5.1)	<0.001²
Gender: female, n (%)	120 (57.1)	30 (54.5)	19 (54.3)	62 (58.5)	9 (64.3)	0.888
Education, n (%) ³						0.467
<9 y	35 (16.8)	10 (18.2)	5 (14.7)	19 (18.1)	1 (7.1)
9–12 y	110 (52.9)	30 (54.5)	22 (64.7)	52 (49.5)	6 (42.9)
12 + y	63 (30.3)	15 (27.3)	7 (20.6)	34 (32.4)	7 (50.0)

¹Age at first visit = age at the time of the neuropsychological assessment. ²Significant (p < 0.05) pairwise comparisons, after the Bonferroni correction: EOD versus MCI-o; EOD versus SCD; MCI-n versus MCI-o; MCI-n versis SCD. ³Missing data from two participants. EOD, early-onset dementia; MCI-n, mild cognitive impairment-neurological; MCI-o, mild cognitive impairment-other; SCD, subjective cognitive decline.

Primary diagnoses underlying cognitive impairment

The primary diagnoses underlying cognitive impairment are displayed in Fig. 1. Altogether 20 different underlying causes were identified, of which the most prevalent diagnoses were AD (14%) and depression (11%). The MCI-o patients formed the largest group (50%), whereas 26% of the patients were diagnosed with EOD.

The most frequent diagnoses in the EOD group were AD (55%), FTD (18%), and VaD (13%). Four patients with AD and one patient with FTD were identified with a secondary diagnosis of vascular cognitive impairment. No other mixed dementias were observed. Of all MCI patients (n = 141) regardless of its etiology, 75% had a potentially treatable/reversible condition underlying the cognitive impairment (i.e., the MCI-o group). In the MCI-n group (n = 35), 43% had vascular and 57% had other suspected neurodegenerative etiology. The most common diagnoses in the MCI-o group (n = 106) were depression (23%), sleep disorders (15%) and burnout or stress symptom (15%).

Health characteristics and comorbidities

Hypertension (42%), hypercholesterolemia (33%), and depression (32%) were the most frequent diseases identified from the patient records (Table 3). At least two medical diagnoses were identified in 67% of all patients. Statistical analyses revealed that diabetes and sleep apnea were more prevalent in the MCI-o group than in the EOD group (p < 0.05). The MCI-o group had also more often four or more comorbid diseases, whereas EOD patients had more often one or no prior medical diagnoses (p = 0.008).

Table 3

Health characteristics in the total study population and in the diagnostic subgroups

Condition, n (%)	All	EOD	MCI-n	MCI-o	SCD	p
Hypertension	88 (41.9)	23 (41.8)	17 (48.6)	44 (41.5)	4 (28.6)	0.661
Hypercholesterolemia	69 (32.9)	18 (32.7)	15 (42.9)	33 (31.1)	3 (21.4)	0.466
Coronary artery disease	8 (3.8)	0 (0)	1 (2.9)	7 (6.6)	0 (0)	0.199
Atrial fibrillation	4 (1.9)	2 (3.6)	0 (0)	2 (1.9)	0 (0)	0.729
Diabetes	25 (11.9)	1 (1.8)	4 (11.4)	19 (17.9)	1 (7.1)	0.013¹
Cancer	17 (8.1)	2 (3.6)	4 (11.4)	10 (9.4)	1 (7.1)	0.462
Fibromyalgia	10 (4.8)	1 (1.8)	2 (5.7)	7 (6.6)	0 (0)	0.576
Chronic pain	53 (25.2)	8 (14.5)	9 (25.7)	35 (33.0)	1 (7.1)	0.027
Substance abuse	27 (12.9)	6 (10.9)	4 (11.4)	16 (15.1)	1 (7.1)	0.874
Brain injury	10 (4.8)	3 (5.5)	0 (0)	7 (6.6)	0 (0)	0.497
Stroke	11 (5.2)	3 (5.5)	6 (17.1)	2 (1.9)	0 (0)	0.010
TIA	3 (1.4)	2 (3.6)	0 (0)	1 (.9)	0 (0)	0.410
Epilepsy	7 (3.3)	1 (1.8)	2 (5.7)	4 (3.8)	0 (0)	0.752
Sleep apnea	43 (20.5)	4 (7.3)	7 (20.0)	28 (26.4)	4 (28.6)	0.032¹
Depression	68 (32.4)	14 (25.5)	7 (20.0)	43 (40.6)	4 (28.6)	0.072
Anxiety	16 (7.6)	2 (3.6)	2 (5.7)	12 (11.3)	0 (0)	0.200
Burnout	27 (12.9)	3 (5.5)	4 (11.4)	18 (17.0)	2 (14.3)	0.222
Psychotic disorders	8 (3.8)	1 (1.8)	2 (5.7)	5 (4.7)	0 (0)	0.782
Health condition count (%)						0.008 ¹
–0–1 diagnoses	33.3	47.3	34.3	23.6	50.0
–2–3 diagnoses	45.2	45.5	40.0	47.2	42.9
–4 diagnoses or more	21.4	7.3	25.7	29.2	7.1

¹Significant (p < 0.05) pairwise comparisons between EOD and MCI-o, after the Bonferroni correction. EOD, early-onset dementia; MCI-n, mild cognitive impairment -neurological; MCI-o, mild cognitive impairment -other; SCD, subjective cognitive decline; TIA, transient ischemic attack.

The comorbidity results for AD, FTD, and VaD are presented in Table 4. Brain injuries were more common (p = 0.048) in FTD and VaD patients than in AD patients. The prevalence of depression was higher (p = 0.017) for patients with VaD than for AD or FTD patients. Further, VaD patients had more often (p = 0.008) two or more comorbid medical conditions than AD or FTD patients.

Table 4

Health characteristics in the three largest neurodegenerative disorder groups of the study

Condition, n (%)	AD, n = 30	FTD, n = 10	VaD, n = 7	p
Hypertension	10 (33)	4 (40)	4 (57)	0.512
Hypercholesterolemia	7 (23)	4 (40)	4 (57)	0.179
Coronary artery disease	0	0	0	n/a
Atrial fibrillation	1 (3)	0	0	1.00
Diabetes	0	0	0	n/a
Cancer	1 (3)	1 (10)	0	0.598
Fibromyalgia	0	0	1 (14)	0.149
Musculoskeletal system pain	3 (10)	3 (30)	1 (14)	0.289
Substance abuse	1 (3)	1 (10)	1 (14)	0.294
Brain injury	0	2 (20)	1 (14)	0.042^1,2
Stroke	2 (7)	1 (10)	0	1.00
TIA	2 (7)	0	0	1.00
Epilepsy	1 (3)	0	0	1.00
Sleep apnea	3 (10)	0	0	0.732
Depression	5 (17)	2 (20)	5 (71)	0.017^2,3
Anxiety	0	0	1 (14)	0.149
Burnout	3 (10)	0	0	0.732
Psychotic disorders	1 (3)	0	0	1.00
Health condition count (%)
–0–1 diagnoses	19 (63)	4 (40)	0	0.008^2,3
–2–3 diagnoses	10 (33)	5 (50)	7 (100)
–4 diagnoses or more	1 (3)	1 (10)	0

Significant (p < 0.05) Bonferroni corrected pairwise comparisons between ¹AD and FTD; ²AD and VaD; ³FTD and VaD. AD, Alzheimer’s disease; FTD, frontotemporal dementia; TIA, transient ischemic attack; VaD, vascular dementia.

Neuropsychological impairment

The most common predominantly impaired cognitive function in the cohort was memory (38%), followed by executive functions (15%) and attention/vigilance (14%). The results from the neuropsychological evaluation for the diagnostic groups are reported in Table 5 and displayed in Fig. 2. Significant differences (p < 0.001) were observed in the global cognitive impairment level and all the individual cognitive domains and symptom awareness, but the differences in the severity of behavioral/affective symptoms did not quite reach statistical significance (p = 0.056). The association between the diagnostic groups and global cognitive impairment level remained significant (p < 0.001) after adjustment for age, education, and sex.

Table 5

Neuropsychological assessment results in the EOD, MCI-n, MCI-o, and SCD groups

Neuropsychological function, Md (IQR)	EOD	MCI-n	MCI-o	SCD	p
Verbal immediate	3 (2–3)	2 (1–3)	2 (1–2)	0 (0–0)	<0.001¹²³⁴⁵
Verbal delayed	3 (2–3)	2 (1–2)	1 (0–2)	0 (0–1)	<0.001¹²³⁴⁵
Visual immediate	3 (1–4)	1 (0–3)	0 (0–2)	0 (0–0.25)	<0.001¹²³
Visual delayed	3 (2–4)	2 (0.5–3)	2 (0–3)	0 (0–1)	<0.001¹²³⁴⁵
Working memory	2 (0–3)	1 (0–2)	0 (0–2)	0 (0–0)	<0.001²³⁴
Attention	2 (0–3)	2 (1–3)	2 (0–2)	0 (0–1)	<0.001³⁴⁵
Executive functions	3 (2–3)	2 (1–3)	2 (0–2)	0 (0–0)	<0.001²³⁴⁵
Processing speed	2 (0.75–3)	0 (0–2)	0 (0–2)	0 (0–0)	<0.001¹²³
Language skills	2 (0–2)	1 (0–2)	1 (0–2)	0 (0–0)	<0.001³⁴⁵
Visuospatial skills	2 (1–3)	1 (0–2)	1 (0–2)	0 (0–0)	<0.001²³⁴⁵
Reasoning	2 (1–3)	1 (1–2)	1 (0–2)	0 (0–0)	<0.001³⁴⁵
Behavioral affective	2 (0–3)	1 (0–2)	0 (0–2)	0.5 (0–2)	0.056
Global cognitive impairment	2 (1.2–2.7)	1.3 (0.9–1.7)	1.1 (0.7–1.4)	0.2 (0.2–0.3)	<0.001¹²³⁴⁵
Symptom awareness	0 (0–3)	0 (0–0)	0 (0–0)	0 (0–0)	<0.001¹²³

Scale 0–4, where 0 = normal cognition, 4 = severe cognitive impairment. Significant (p < 0.05) Bonferroni corrected pairwise comparisons between ¹EOD and MCI-n; ²EOD and MCI-o; ³EOD versus SCD; ⁴MCI-n versus SCD; ⁵MCI-o versus SCD. EOD, early-onset dementia; MCI-n, mild cognitive impairment-neurological; MCI-o, mild cognitive impairment-other; SCD, subjective cognitive decline.

Fig. 2

Neuropsychological profiles represented as means for a) EOD, MCI-n, MCI-o, and SCD; and b) AD, FTD, and depression. Nested circles represent cognitive impairment levels (center = severe impairment; outermost circle = normal functioning). EOD, early-onset dementia; MCI-n, mild cognitive impairment-neurological; MCI-o, mild cognitive impairment-other; SCD, subjective cognitive decline; AD, Alzheimer’s disease; FTD, frontotemporal dementia.

Pairwise analyses revealed (p < 0.05 in all) that the EOD group had the highest impairment level on global cognition, symptom awareness, immediate and delayed memory (verbal and visual) and processing speed as compared to all other groups. The EOD patients had also more impaired working memory, executive functions, and visuospatial skills as compared to the MCI-o and SCD groups. The SCD group outperformed EOD patients on all cognitive domains and both MCI groups on majority of cognitive domains.

Neuropsychological performance in early-onset AD, FTD, and depression

Results on the level of neuropsychological impairment in AD, FTD and depression groups are shown in Table 6. The diagnosis remained statistically significant (p < 0.001) determinant of the level of global cognitive impairment after adjustment for age, education and sex. Pairwise analyses revealed that patients with depression had significantly (p < 0.05 in all) milder neuropsychological deficits in global cognitive functioning, symptom awareness and verbal and visual immediate memory as compared to AD and FTD patients. Patients with depression also outperformed AD patients in verbal and visual delayed memory and FTD patients in executive functions and processing speed. AD and FTD patients differed in the level of behavioral and affective symptoms. Further, memory retention scores differed statistically significantly (p = 0.034) between AD (M=–0.4, SD = 2.0) and FTD (M = 1.2, SD = 2.1) groups.

Table 6

Neuropsychological assessment results for patients with AD, FTD, and depression

Neuropsychological function (Md, IQR)	AD	FTD	Depression	p
Verbal immediate	3 (2–4)	3 (2–4)	2 (1–2)	0.005²³
Verbal delayed	2.5 (2–3.25)	2.5 (0.75–3.25)	1 (0–2)	<0.001²
Visual immediate	2.5 (1.75–3.25)	3.5 (2–4)	0 (0–2)	<0.001²³
Visual delayed	3 (2–4)	3 (1–4)	2 (0–3)	0.030²
Working memory	2 (0–3)	2.5 (0–3)	0 (0–2.75)	0.333
Attention	2 (0.75–3)	0.5 (0–3)	2 (0.5–3)	0.550
Executive functions	2 (1–3)	3 (2–4)	2 (0.25–2)	0.006³
Processing speed	1 (0–3)	2 (1.5–2.5)	0 (0–2)	0.041³
Language skills	1 (0–2)	2 (0.75–3)	1 (0–2)	0.124
Visuospatial skills	1.5 (0–3)	1.5 (1–3)	1 (0–2)	0.114
Reasoning	1 (0–3)	2 (1.75–3)	1 (0–2)	0.053
Behavioral affective	1 (0–2)	3 (1.5–3.25)	2 (1–3)	0.050¹
Global cognitive impairment	1.6 (1.0–2.6)	2.3 (1.7–2.8)	1.1 (0.9–1.4)	<0.001²³
Symptom awareness	0.5 (0–3)	1.5 (0–3.25)	0 (0–0)	0.003²³

Scale 0–4, where 0 = normal cognition, 4 = severe cognitive impairment. Significant (p < 0.05) Bonferroni corrected pairwise comparisons between ¹AD and FTD; ²AD and Depression; ³FTD and Depression. AD, Alzheimer’s disease; FTD, frontotemporal dementia.

DISCUSSION

The objective of the study was to investigate the etiologies for early-onset cognitive dysfunction in a real-world clinical setting and to compare the neuropsychological profiles and comorbidities in clinically relevant diagnostic groups. To our knowledge, comorbidities of memory clinic referral population with symptom onset before the age of 65 years have not been previously studied and investigations on the neuropsychological features in patients with early-onset cognitive impairment are scarce. The main findings were that 1) 26% of memory clinic patients receive EOD diagnosis, 17% have MCI due to suspected or confirmed neurological causes, 50% have MCI due to nondegenerative etiologies, and 7% have normal cognitive functioning; 2) 67% have multiple medical diagnoses, but EOD patients have fewer comorbidities than MCI-o patients; 3) a comprehensive neuropsychological assessment is useful in the clinical evaluation of EOD and other memory clinic patient groups, as well as in the differential diagnostics of early-onset AD, FTD, and depression.

As in previous findings [1], AD was the most prevalent disorder underlying EOD followed by FTD and VaD. In the whole memory clinic cohort, AD (14%) was the most common primary diagnosis, followed by depression (11%). Cognitive impairment due to nondegenerative conditions, including mood and other psychiatric disorders, sleep disorders, substance abuse, pain problems and other somatic conditions, accounted for a significant proportion (50%) of etiologies of cognitive impairment. Only 7% of referred individuals were evaluated to have normal cognitive functioning (i.e., the SCD group) indicating that the referral criteria from primary or occupational health care to a specialized memory clinic evaluation were quite adequate. In contrast with the current results, a previous study found that 55% of memory clinic patients under 60 years old had normal cognition [20]. The incongruity may partly be explained by methodological issues. In the previous study, neuropsychological assessment was performed for only 65% of patients, whereas all our study participants underwent a comprehensive neuropsychological assessment, allowing a detailed evaluation of cognitive functioning. Thus, the current results imply that cognitive impairment in memory clinic patients aged 65 years or younger may be more common than previously reported.

In the whole cohort, the most prevalent priorly diagnosed medical conditions were hypertension (42%), hypercholesterolemia (33%), and depression (32%). The prevalence rates for most conditions were mainly similar across the memory clinic patient groups, but diabetes was roughly 10 times and sleep apnea 3–4 times less frequent in EOD patients than in MCI-o patients. Previous stroke was expectedly common in MCI-n (17%) due to many patients having vascular cognitive impairment, but the pairwise comparisons between MCI-n and other groups did not reach statistical significance. Multiple comorbidities were common (67%) in the whole cohort, but EOD patients had statistically significantly fewer comorbidities than the MCI-o patients, despite of being older. The EOD group resembled more the SCD group in this matter, as in both groups roughly 50% had only one or no prior diseases and less than 10% had four or more diagnoses. Similarly, EOD patients and healthy controls have been previously found to have comparable levels of vascular risk factors [37], whereas EOD patients have fewer comorbidities than LOD patients [6]. Conversely, early-onset MCI patients have been reported to have a rather high prevalence in several diseases including depression (58%), dyslipidemia (33%), and hypertension (30%) [27]. Taken together, comorbidities may play a smaller role in EOD, particularly in AD and FTD, but be more relevant in early-onset MCI when the impairment is evaluated to be due to nondegenerative causes. This raises further questions for future research, for instance, whether comorbidities in early-onset MCI moderate conversion rates to dementia at later ages.

The predominantly impaired cognitive domains in the whole cohort were memory, executive functions, and attention. Memory and executive functions deficits are salient features in many EOD subtypes [12 –14], but less is known about how neuropsychological characteristics differ between early-onset patients referred to a memory clinic. In our study, the EOD patients exhibited more deficits on the immediate and delayed memory on verbal and visual modalities, as well as in processing speed and global cognition than all other patient groups. Several other significant differences in neuropsychological impairment levels between clinical groups were identified, including a difference in the level of executive deficits between EOD and MCI-o as well as between EOD and SCD patients. Attentional deficits were similar in EOD and both MCI groups. Further, as the neuropsychological impairment profiles in MCI-n and MCI-o were very similar, the role of anamnestic clinical interview, brain imaging and other biomarkers is crucial in distinguishing degenerative and nondegenerative etiologies [38].

EOD has been previously associated with a higher level of symptom awareness than LOD [39]. In our study, lower symptom awareness differentiated EOD patients from other memory clinic patient groups, even though EOD patients were mainly at early stages of dementia disorder as reflected by the mean level of global cognitive impairment being in the mild range. The level of behavioral/affective symptoms did not differ between groups, probably due to behavioral and affective symptoms being common not only in EOD but also in early-onset MCI and SCD [40 –42] and they are among the factors contributing to the challenges of differential diagnostics [17]. Affective symptoms may even explain why some individuals with SCD seek medical help [43].

In line with a previous report [44], there were more similarities than differences in the cognitive profiles of early-onset AD and FTD patients, including congruent levels of executive dysfunction and immediate and delayed memory deficits. However, AD patients had more deficits in retaining previously learned material than FTD patients. Similar results have been reported by Economou et al. [45]. Our results also support earlier findings [46 –48] on behavioral and affective symptoms being more severe in FTD than in AD. Additionally, there was a tendency towards worse reasoning abilities in FTD, but the difference did not quite reach statistical significance.

Another key question in the clinical practice is to differentiate depression from early phases of neurodegenerative disorders, as both may be associated with mood disturbances and cognitive deficits [17, 49]. Hence, previous studies comparing the neuropsychological symptoms have shown conflicting results [50 –52]. We found that AD and FTD patients have more severe impairment than patients with depression in the global cognitive impairment level, symptom awareness and verbal and visual immediate memory. Additionally, AD patients had a more profound impairment in delayed memory domains than patients with depression and on the other hand, FTD patients exhibited more problems in executive function and processing speed. By contrast, the behavioral/affective domain seems to have less utility in differentiating AD or FTD from depression. As the clinical presentations of EODs, especially FTD, often resemble that of primary psychiatric disorders [17], the differential diagnostics might require considering the type of behavioral or affective symptoms in more detail than what we did in our analyses.

The main strength of the study is that the results represent a typical population of patients referred to diagnostic evaluation due to early-onset neuropsychological symptoms, since all patients in the area are evaluated at these clinics. As all neuropsychological data were gathered at the time of first referral, the results reflect the stages of the diseases when differential diagnostics is timely. Additionally, the results represent early clinical changes related to the diseases, as the EOD group patients had on average mild cognitive impairments.

There are limitations to consider. We estimated based on previous findings [20] that a sample of roughly 200 participants would produce sufficient group sizes, but the number of SCD patients was lower than expected. Additionally, one could argue that determining the cognitive impairment level by clinical evaluation is less precise than the test scores. This approach was chosen to resemble the professional practice of neuropsychology in memory clinics where cognitive testing is an integrative part of the assessment that also utilizes other information to render an evaluation [35]. For example, the assessment considers qualitative performance features that have been found to enhance the diagnostic accuracy of neurodegenerative diseases [53 –55]. Thus, the cognitive impairment determined by clinical evaluation may resemble the individual’s actual cognitive ability level closer than single or combined test scores.

In conclusion, majority of early-onset memory clinic patients have cognitive deficits. The possible underlying causes for cognitive impairment are numerous. Moreover, comorbidity is common in this population, but EOD patients seem to have fewer comorbidities than MCI-o patients. The results highlight the value of a comprehensive neuropsychological assessment in the differential diagnosis of early-onset cognitive impairment and dementia. In the future, more research with sizeable samples will be needed in this clinically relevant field of determining specific features associated with early-onset cognitive impairment.

Footnotes

ACKNOWLEDGMENTS

We thank the participating patients and study nurse Pirkko Holappa for all her practical help at the Oulu University Hospital. We are also grateful to PhD Tanja Nordström for her guidance in the statistical analyses and M.Sc. Teppo Valtonen for data management.

FUNDING

The Finnish Work Environment Fund (grant number 180038) supported the CIWA study. This study was supported also by a grant from Academy of Finland (grant number 315460). First author has received personal research grants from the Finnish Brain Foundation sr and the University of Oulu Scholarship Foundation. No funding source had any role in the designing, analysis, or interpretation of the results in this study.

CONFLICT OF INTEREST

The authors have no conflict of interest to report.

DATA AVAILABILITY

The data supporting the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.

References

Hendriks

, Peetoom

, Bakker

, Van Der Flier

, Papma

, Koopmans

, Verhey

FRJ

, De Vugt

, Köhler

, Withall

, Parlevliet

, Uysal-Bozkir

, Gibson

, Neita

, Nielsen

, Salem

, Nyberg

, Lopes

, Dominguez

, De Guzman

, Egeberg

, Radford

, Broe

, Subramaniam

, Abdin

, Bruni

, Di Lorenzo

, Smith

, Flicker

, Mol

, Basta

, Yu

, Masika

, Petersen

, Ruano

(2021) Global prevalence of young-onset dementia: A systematic review and meta-analysis. JAMA Neurol 78, 1080–1090.

Picard

, Pasquier

, Martinaud

, Hannequin

, Godefroy

(2011) Early onset dementia: Characteristics in a large cohort from academic memory clinics. Alzheimer Dis Assoc Disord 25, 203–205.

Masellis

, Sherborn

, Neto

, Sadovnick

, Hsiung

GYR

, Black

, Prasad

, Williams

, Gauthier

(2013) Early-onset dementias: Diagnostic and etiological considerations. Alzheimers Res Ther 5, S7.

Rossor

, Fox

, Mummery

, Schott

, Warren

(2010) The diagnosis of young-onset dementia. Lancet Neurol 9, 793–806.

Gerritsen

AAJ

, Bakker

, Verhey

FRJ

, de Vugt

, Melis

RJF

, Koopmans

RTCM

(2016) Prevalence of comorbidity in patients with young-onset Alzheimer disease compared with late-onset: A comparative cohort study. J Am Med Dir Assoc 17, 318–323.

Ryan

, Martinez Ruiz

, Rivera-Rodriguez

, Curtis

, Cheung

(2021) Sociodemographic and clinical characteristics of 1350 patients with young onset dementia: A comparison with older patients. Alzheimer Dis Assoc Disord 35, 200–207.

Woolley

, Khan

, Murthy

, Miller

, Rankin

(2011) The diagnostic challenge of psychiatric symptoms in neurodegenerative disease: Rates of and risk factors for prior psychiatric diagnosis in patients with early neurodegenerative disease. J Clin Psychiatry 72, 126–133.

van Vliet

, de Vugt

, Bakker

, Pijnenburg

YAL

, Vernooij-Dassen

, Koopmans

RTCM

, Verhey

FRJ

(2013) Time to diagnosis in young-onset dementia as compared with late-onset dementia. Psychol Med 43, 423–432.

Mendez

(2019) Early-onset Alzheimer disease and its variants. Continuum (Minneap Minn) 25, 34–51.

10.

Joubert

, Gour

, Guedj

, Didic

, Guériot

, Koric

, Ranjeva

J-P

, Felician

, Guye

, Ceccaldi

(2016) Early-onset and late-onset Alzheimer’s disease are associated with distinct patterns of memory impairment. Cortex 74, 217–232.

11.

Tort-Merino

, Falgàs

, Allen

, Balasa

, Olives

, Contador

, Castellví

, Juncà-Parella

, Guillén

, Borrego-Écija

, Bosch

, Fernández-Villullas

, Ramos-Campoy

, Antonell

, Rami

, Sánchez-Valle

, Lladó

(2022) Early-onset Alzheimer’s disease shows a distinct neuropsychological profile and more aggressive trajectories of cognitive decline than late-onset. Ann Clin Transl Neurol 12, 1962–1973.

12.

Palasí

, Gutiérrez-Iglesias

, Alegret

, Pujadas

, Olabarrieta

, Liébana

, Quintana

, Álvarez-Sabín

, Boada

(2015) Differentiated clinical presentation of early and late-onset Alzheimer’s disease: Is 65 years of age providing a reliable threshold? J Neurol 262, 1238–1246.

13.

Jang

, Kwon

, Kim

, Jung

, Lee

, Chin

, Im

, Jeon

, Lee

, Seong

J-K

, Kim

, Choe

, Lee

K-H

, Kim

, Lee

, Na

, Seo

, Kim

(2016) Early-vs late-onset subcortical vascular cognitive impairment. Neurology 86, 527–534.

14.

, Choi

, Han

S-H

, Kim

, Yang

D-W

, Park

, Han

, Youn

, Choi

B-O

, Kim

, Woo

S-Y

, Na

, Kim

E-J

(2015) Clinical and neuropsychological comparisons of early-onset versus late-onset frontotemporal dementia: A CREDOS-FTD Study. J Alzheimers Dis 45, 599–608.

15.

Baillon

, Gasper

, Wilson-Morkeh

, Pritchard

, Jesu

, Velayudhan

(2019) Prevalence and severity of neuropsychiatric symptoms in early- versus late-onset Alzheimer’s disease. Am J Alzheimers Dis Other Demen 34, 433–438.

16.

Falgàs

, Allen

, Spina

, Grant

, Piña Escudero

, Merrilees

, Gearhart

, Rosen

, Kramer

, Seeley

, Neylan

, Miller

, Rabinovici

, Grinberg

, Walsh

(2022) The severity of neuropsychiatric symptoms is higher in early-onset than late-onset Alzheimer’s disease. Eur J Neurol 29, 957–967.

17.

Ducharme

, Dols

, Laforce

, Devenney

, Kumfor

, van den Stock

, Dallaire-Theroux

, Seelaar

, Gossink

, Vijverberg

, Huey

, Vandenbulcke

, Masellis

, Trieu

, Onyike

, Caramelli

, de Souza

, Santillo

, Waldo

, Landin-Romero

, Piguet

, Kelso

, Eratne

, Velakoulis

, Ikeda

, Perry

, Pressman

, Boeve

, Vandenberghe

, Mendez

, Azuar

, Levy

, Le Ber

, Baez

, Lerner

, Ellayosyula

, Pasquier

, Galimberti

, Scarpini

, van Swieten

, Hornberger

, Rosen

, Hodges

, Diehl-Schmid

, Pijnenburg

(2020) Recommendations to distinguish behavioural variant frontotemporal dementia from psychiatric disorders. Brain 143, 1632–1650.

18.

Mendez

(2021) The relationship between anxiety and Alzheimer’s disease. J Alzheimers Dis Rep 5, 171–177.

19.

Hejl

, Høgh

, Waldemar

(2002) Potentially reversible conditions in 1000 consecutive memory clinic patients. J Neurol Neurosurg Psychiatry 73, 390–394.

20.

Vraamark Elberling

, Stokholm

, Høgh

, Waldemar

(2002) Diagnostic profile of young and middle-aged memory clinic patients. Neurology 59, 1259–1262.

21.

Jessen

, Amariglio

, Van Boxtel

, Breteler

, Ceccaldi

, Chételat

, Dubois

, Dufouil

, Ellis

, Van Der Flier

, Glodzik

, Van Harten

, De Leon

, McHugh

, Mielke

, Molinuevo

, Mosconi

, Osorio

, Perrotin

, Petersen

, Rabin

, Rami

, Reisberg

, Rentz

, Sachdev

, De La Sayette

, Saykin

, Scheltens

, Shulman

, Slavin

, Sperling

, Stewart

, Uspenskaya

, Vellas

, Visser

, Wagner

(2014) A conceptual framework for research on subjective cognitive decline in preclinical Alzheimer’s disease. Alzheimers Dement 10, 844–852.

22.

Wolfsgruber

, Kleineidam

, Guski

, Polcher

, Frommann

, Roeske

, Spruth

, Franke

, Priller

, Kilimann

, Teipel

, Buerger

, Janowitz

, Laske

, Buchmann

, Peters

, Menne

, Fuentes Casan

, Wiltfang

, Bartels

, Düzel

, Metzger

, Glanz

, Thelen

, Spottke

, Ramirez

, Kofler

, Fließbach

, Schneider

, Heneka

, Brosseron

, Meiberth

, Jessen

, Wagner

, Group

(2020) Minor neuropsychological deficits in patients with subjective cognitive decline. Neurology 95, e1134–e1143.

23.

Albert

, DeKosky

, Dickson

, Dubois

, Feldman

, Fox

, Gamst

, Holtzman

, Jagust

, Petersen

, Snyder

, Carrillo

, Thies

, Phelps

(2011) The diagnosis of mild cognitive impairment due to Alzheimer’s disease: Recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement 7, 270–279.

24.

Petersen

, Caracciolo

, Brayne

, Gauthier

, Jelic

, Fratiglioni

(2014) Mild cognitive impairment: A concept in evolution. J Intern Med 275, 214–228.

25.

Tábuas-Pereira

, Baldeiras

, Duro

, Santiago

, Ribeiro

, Leitão

, Oliveira

, Santana

(2016) Prognosis of early-onset vs. late-onset mild cognitive impairment: Comparison of conversion rates and its predictors. Geriatrics (Switzerland) 1, 11.

26.

, Seo

, Lee

, Kim

, Choi

, Lee

, Kim

, Han

, Na

, Kim

E-J

(2012) Neuropsychological performance and conversion to Alzheimer’s disease in early-compared to late-onset amnestic mild cognitive impairment: CREDOS Study clinical differences between EOMCI and LOMCI. Dement Geriatr Cogn Disord 34, 156–166.

27.

Esteban De Antonio

, Pérez-Cordón

, Gil

, Orellana

, Cano

, Alegret

, Espinosa

, Alarcón-Martín

, Valero

, Martínez

, De Rojas

, Sotolongo-Grau

, Martín

, Vivas

, Gomez-Chiari

, Tejero

, Bernuz

, Tárraga

, Ruiz

, Marquié

, Boada

(2021) BIOFACE: A prospective study of risk factors, cognition, and biomarkers in a cohort of individuals with early-onset mild cognitive impairment. Study rationale and research protocols. J Alzheimers Dis 83, 1233–1249.

28.

Tsoukra

, Velakoulis

, Wibawa

, Malpas

, Walterfang

, Evans

, Farrand

, Kelso

, Eratne

, Loi

(2022) The diagnostic challenge of young-onset dementia syndromes and primary psychiatric diseases: Results from a retrospective 20-year cross-sectional study. J Neuropsychiatry Clin Neurosci 34, 44–52.

29.

McKhann

(2011) Changing concepts of Alzheimer disease. JAMA 305, 2458–2459.

30.

O’Brien

, Erkinjuntti

, Reisberg

, Roman

, Sawada

, Pantoni

, Bowler

, Ballard

, DeCarli

, Gorelick

, Gauthier

, DeKosky

(2003) Vascular cognitive impairment. Lancet Neurol 2, 89–98.

31.

Rascovsky

, Hodges

, Knopman

, Mendez

, Kramer

, Neuhaus

, Van Swieten

, Seelaar

, Dopper

EGP

, Onyike

, Hillis

, Josephs

, Boeve

, Kertesz

, Seeley

, Rankin

, Johnson

, Gorno-Tempini

, Rosen

, Prioleau-Latham

, Lee

, Kipps

, Lillo

, Piguet

, Rohrer

, Rossor

, Warren

, Fox

, Galasko

, Salmon

, Black

, Mesulam

, Weintraub

, Dickerson

, Diehl-Schmid

, Pasquier

, Deramecourt

, Lebert

, Pijnenburg

, Chow

, Manes

, Grafman

, Cappa

, Freedman

, Grossman

, Miller

(2011) Sensitivity of revised diagnostic criteria for the behavioural variant of frontotemporal dementia. Brain 134, 2456–2477.

32.

Winblad

, Palmer

, Kivipelto

, Jelic

, Fratiglioni

, Wahlund

L-O

, Nordberg

, Bäckman

, Albert

, Almkvist

, Arai

, Basun

, Blennow

, De Leon

, Decarli

, Erkinjuntti

, Giacobini

, Graff

, Hardy

, Jack

, Jorm

, Ritchie

, Van Duijn

, Visser

, Petersen

(2004) Mild cognitive impairment-beyond controversies, towards a consensus: Report of the International Working Group on Mild Cognitive Impairment. J Intern Med 256, 240–246.

33.

Gorno-Tempini

, Hillis

, Weintraub

, Kertesz

, Mendez

, Cappa

, Ogar

, Rohrer

, Black

, Boeve

, Manes

, Dronkers

, Vandenberghe

, Rascovsky

, Patterson

, Miller

, Knopman

, Hodges

, Mesulam

, Grossman

(2011) Classification of primary progressive aphasia and its variants. Neurology 76, 1006–1014.

34.

Mckeith

, Boeve

, Dickson

, Halliday

, Taylor

J-P

, Weintraub

, Aarsland

, Galvin

, Attems

, Ballard

, Bayston

, Beach

, Blanc

, Bohnen

, Bonanni

, Bras

, Brundin

, Burn

, Chen-Plotkin

, Duda

, El-Agnaf

, Feldman

, Ferman

, Ffytche

, Fujishiro

, Galasko

, Goldman

, Gomperts

, Graff-Radford

, Honig

, Iranzo

, Kantarci

, Kaufer

, Kukull

, Lee

VMY

, Leverenz

, Lewis

, Lippa

, Lunde

, Masellis

, Masliah

, Mclean

, Mollenhauer

, Montine

, Moreno

, Mori

, Murray

, O Brien

, Orimo

, Postuma

, Ramaswamy

, Ross

, Salmon

, Singleton

, Taylor

, Thomas

, Tiraboschi

, Toledo

, Trojanowski

, Tsuang

, Walker

, Yamada

, Kosaka

(2017) Diagnosis and management of dementia with Lewy bodies. Neurology 89, 88–100.

35.

Jacova

, Kertesz

, Blair

, Fisk

, Feldman

(2007) Neuropsychological testing and assessment for dementia. Alzheimers Dement 3, 299–317.

36.

Weintraub

(2022) Neuropsychological assessment in dementia diagnosis. Continuum (Minneap Minn) 28, 781–799.

37.

Chen

, Sillaire

, Dallongeville

, Skrobala

, Wallon

, Dubois

, Hannequin

, Pasquierthe

, Bombois

, Boutantin

, Cassagnaud

, Delbeuck

, Delmaire

, Deramecourt

, Gele

, Houssein-Foucher

, Jacquemont

, Lebert

, Lebouvier

, Lopez

, Mackowiak

M-A

, Maureille

, Pasquier

, Petyt

, Pollet

, Rollin-Sillaire

, Schraen

, Semah

, Vanhoutte

, Lille YOD study group (2017) Low prevalence and clinical effect of vascular risk factors in early-onset Alzheimer’s disease. J Alzheimers Dis 60, 1045–1054.

38.

Falgàs

, Tort-Merino

, Balasa

, Borrego-Écija

, Castellví

, Olives

, Bosch

, Férnandez-Villullas

, Antonell

, Augé

, Lomeña

, Perissinotti

, Bargalló

, Sánchez-Valle

, Lladó

(2019) Clinical applicability of diagnostic biomarkers in early-onset cognitive impairment. Eur J Neurol 26, 1098–1104.

39.

Baptista

MAT

, Santos

, Kimura

, Marinho

, Simões

, Laks

, Johannenssen

, Barca

, Engedal

, Dourado

MCN

(2019) Differences in awareness of disease between young-onset and late-onset dementia. Alzheimer Dis Assoc Disord 33, 129–135.

40.

Wiels

, Wittens

MMJ

, Zeeuws

, Baeken

, Engelborghs

(2021) Neuropsychiatric symptoms in mild cognitive impairment and dementia due to AD: Relation with disease stage and cognitive deficits. Front Psychiatry 12, 707580.

41.

Cedres

, Machado

, Molina

, Diaz-Galvan

, Hernández-Cabrera

, Barroso

, Westman

, Ferreira

(2019) Subjective cognitive decline below and above the age of 60: A multivariate study on neuroimaging, cognitive, clinical, and demographic measures. J Alzheimers Dis 68, 295–309.

42.

Loreto

, Fitzgerald

, Golemme

, Gunning

, Win

, Patel

, Carswell

, Perry

, Kennedy

, Edison

, Malhotra

(2022) Prevalence of depressive symptoms in a memory clinic cohort: A retrospective study. J Alzheimers Dis 88, 1179–1187.

43.

Perrotin

, La Joie

, de La Sayette

, Barré

, Mézenge

, Mutlu

, Guilloteau

, Egret

, Eustache

, Chételat

(2017) Subjective cognitive decline in cognitively normal elders from the community or from a memory clinic: Differential affective and imaging correlates. Alzheimers Dement 13, 550–560.

44.

Barrows

, Barsuglia

, Paholpak

, Eknoyan

, Sabodash

, Lee

, Mendez

(2015) Executive abilities as reflected by clock hand placement: Frontotemporal dementia versus early-onset Alzheimer disease. J Geriatr Psychiatry Neurol 28, 239–248.

45.

Economou

, Routsis

, Papageorgiou

(2016) Episodic memory in Alzheimer disease, frontotemporal dementia, and dementia with Lewy bodies/Parkinson disease dementia: Disentangling retrieval from consolidation. Alzheimer Dis Assoc Disord 30, 47–52.

46.

Stojkovic

, Stojmenovic

, Stefanova

, Kostic

(2020) Neuropsychiatric symptoms in early onset Alzheimer’s disease and frontotemporal dementia. Alzheimers Dement 16, e044068.

47.

Ritter

, Leger

, Miller

, Banks

(2017) Neuropsychological testing in pathologically verified Alzheimer disease and frontotemporal dementia: How well do the uniform data set measures differentiate between diseases? Alzheimer Dis Assoc Disord 31, 187–191.

48.

Suhonen

, Hallikainen

, Hanninen

, Jokelainen

, Kruger

, Hall

, Pikkarainen

, Soininen

, Remes

(2017) The Modified Frontal Behavioral Inventory (FBI-mod) for patients with frontotemporal lobar degeneration, Alzheimer’s disease, and mild cognitive impairment. J Alzheimers Dis 56, 1241–1251.

49.

Lanza

, Sejunaite

, Steindel

, Scholz

, Riepe

(2020) Cognitive profiles in persons with depressive disorder and Alzheimer’s disease. Brain Commun 2, fcaa206.

50.

Vijverberg

EGB

, Schouws

, Meesters

, Verwijk

, Comijs

, Koene

, Schreuder

, Beekman

, Scheltens

, Stek

, Pijnenburg

, Dols

(2017) Cognitive deficits in patients with neuropsychiatric symptoms: A comparative study between behavioral variant frontotemporal dementia and primary psychiatric disorders. J Clin Psychiatry 78, e940–e946.

51.

Lanza

, Sejunaite

, Steindel

, Scholz

, Riepe

(2020) On the conundrum of cognitive impairment due to depressive disorder in older patients. PLoS One 15, e0231111.

52.

Braaten

, Parsons

, McCue

, Sellers

, Burns

(2006) Neurocognitive differential diagnosis of dementing diseases: Alzheimer’s dementia, vascular dementia, frontotemporal dementia, and major depressive disorder. Int J Neurosci 11, 1271–1293.

53.

Doubleday

, Snowden

, Varma

(2002) Qualitative performance characteristics differentiate dementia with Lewy bodies and Alzheimer’s disease. J Neurol Neurosurg Psychiatry 72, 602–607.

54.

Thompson

, Stopford

, Snowden

, Thompson

(2005) Qualitative neuropsychological performance characteristics in frontotemporal dementia and Alzheimer’s disease. J Neurol Neurosurg Psychiatry 76, 920–927.

55.

Sitek

, Barczak

, Harciarek

(2015) Neuropsychological assessment and differential diagnosis in young-onset dementias. Psychiatr Clin North Am 38, 265–279.

56.

Wechsler

(2008) Wechsler Memory Scale – Third Edition: Finnish Manual, Psykologien Kustannus Oy, Helsinki.

57.

Wechsler

(2012) Wechsler Adult Intelligence Scale – Fourth Edition: Finnish Manual, Psykologien Kustannus Oy, Helsinki.

58.

Lezak

, Howieson

, Bigler

, Tranel

(2012), Neuropsychological Assessment (5th ed.), Oxford University Press, New York.

59.

Reitan

(1958) Validity of the Trail Making Test as an indication of organic brain damage. Perceptual Motor Skills 8, 271–276.

60.

Golden

(1978) Stroop Color and Word Test, Stoelting Company, Chicago.

61.

Morris

, Heyman

, Mohs

, Hughes

, van Belle

, Fillenbaum

, Mellits

, Clark

(1989) The Consortium to Establish a Registry for Alzheimer’s Disease (CERAD). Part I. Clinical and neuropsychological assessment of Alzheimer’s disease. Neurology 39, 1159–1165.

62.

Heidler-Gary

, Gottesman

, Newhart

, Chang

, Ken

, Hillis

(2007) Utility of behavioral versus cognitive measures in differentiating between subtypes of frontotemporal lobar degeneration and Alzheimer’s disease. Dement Geriatr Cogn Disord 23, 184–193.

63.

Kroenke

, Spitzer

, Williams

JBW

(2001) The PHQ-9: Validity of a brief depression severity measure. J Gen Intern Med 16, 606–613.