Genetic Screening of Patients with Sporadic Alzheimer’s Disease and Frontotemporal Lobar Degeneration in the Chinese Population

Abstract

Background:

Alzheimer’s disease (AD) and frontotemporal lobar degeneration (FTLD) account for the vast majority of neurodegenerative dementias. AD and FTLD have different clinical phenotypes with a genetic overlap between them and other dementias.

Objective:

This study aimed to identify the genetic spectrum of sporadic AD and FTLD in the Chinese population.

Methods:

A total of 74 sporadic AD and 29 sporadic FTLD participants were recruited. All participants underwent whole-exome sequencing (WES) and testing for a hexanucleotide expansion in C9orf72 was additionally performed for participants with negative WES results.

Results:

Four known pathogenic or likely pathogenic variants, including PSEN1 (p.G206D), MAPT (p.R5H), LRRK2 (p.W1434*), and CFAP43 (p.C934*), were identified in AD participants, and 1 novel pathogenic variant of ANXA11 (p.D40G) and two known likely pathogenic variants of MAPT (p.D177V) and TARDBP (p.I383V) were identified in FTLD participants. Twenty-four variants of uncertain significance as well as rare variants in risk genes for dementia, such as ABCA7, SORL1, TRPM7, NOS3, MPO, and DCTN1, were also found. Interestingly, several variants in participants with semantic variant primary progressive aphasia were detected. However, no participants with C9orf72 gene variants were found in the FTLD cohort.

Conclusions:

There was a high frequency of genetic variants in Chinese participants with sporadic AD and FTLD and a complex genetic overlap between these two types of dementia and other neurodegenerative diseases.

Keywords

Alzheimer’s disease frontotemporal lobar degeneration variant whole-exome sequencing

INTRODUCTION

Neurodegenerative dementias are a group of clinically heterogeneous disorders with frequently overlapping symptoms, and Alzheimer’s disease (AD) and frontotemporal lobar degeneration (FTLD) are two of the most common causes, especially in patients with early-onset dementia [1, 2]. Apart from a very small proportion of AD cases (less than 5%) and approximately 10–30% of FTLD cases having an autosomal-dominant inheritance pattern, it has been demonstrated that genetic factors are also involved in sporadic cases [3, 4].

In addition to the causal mutations that inevitably lead to the development of AD, including APP, PSEN1, and PSEN2 mutations [5], numerous genetic mutations have been recognized to highly (e.g., APOE genotype) or modestly increase the risk of AD [6]. These susceptibility loci, if alone, tend to only slightly increase the risk of AD but they can predict a diagnosis of AD more precisely when combined with environmental or demographic factors [7]. FTLD is an umbrella term encompassing a genetically and pathologically heterogeneous group of disorders with a higher hereditability than AD. At present, mutations in three genes have been found to cause familial FTLD, including MAPT, GRN, and C9orf72 [8]. Although no definite associations between genotype and phenotype have been clarified, some distinctive characteristics can raise suspicion for these mutations. For example, GRN mutations lead to poor and rapidly worsening attention, MAPT mutations are associated with more severely impaired memory and C9orf72 gene mutations suggest global but relatively stable cognitive impairment [2]. Mutations in several other genes have also been recently reported to cause FTLD in very few families worldwide, such as TARDBP, VCP, CHMP2B, SQSTM1, TBK1, and CHCHD10 [4].

It is worth mentioning that there are potential genetic overlaps between AD and FTLD as well as some other neurodegenerative diseases. Mutations in genes, including MAPT, GRN, VCP, TARDBP, and C9orf72, were found in >30% of AD patients with typical episodic memory impairment in a previous study [9]. Similarly, mutations in genes such as PSEN1, LRRK2 [associated with Parkinson’s disease (PD)], and ANXA11 [associated with amyotrophic lateral sclerosis (ALS)], were also reported in patients with FTLD [10]. This genetic overlap has also been identified in the Chinese population, e.g., MAPT (p.Q230R, p.V48L) and TBK1 (p.D534H) in AD patients and APP (p.T297M), PSEN2 (p.V214L), and LRRK2 (p.I2012T) in FTLD patients [11 –13]. Nevertheless, previous studies showed variable results, probably because of differences in the genetic background, diagnostic criteria, and genetic testing methods (e.g., only a targeted gene panel was used in several studies).

In this study, we identified the mutation spectrum of sporadic AD and FTLD through whole-exome sequencing (WES) and testing for a hexanucleotide expansion in C9orf72 in a well-characterized cohort of the Chinese population, in which the diagnosis was supported by amyloid and fluorodeoxyglucose (FDG) positron emission tomography (PET). We further investigated genotype-phenotype correlations to better characterize and understand the molecular mechanisms of sporadic AD and FTLD.

METHODS

Patient recruitment

A total of 103 patients (74 AD patients and 29 FTLD patients) were recruited from the Memory Clinic, Tianjin Medical University General Hospital. All AD patients met the diagnostic criteria of the International Working Group-2 (IWG-2) for typical or atypical AD [14]. FTLD was diagnosed according to the consensus criteria of the International Behavioural Variant FTD Criteria Consortium and the clinical criteria for primary progressive aphasia (PPA) published in 2011 [15, 16]. All patients underwent detailed clinical information collection, personal and family history evaluation, physical and neuropsychological examinations, brain MRI and PET scans. All participants were defined as “sporadic” according to a previous publication [17] because there was no autosomal-dominant family history of AD or FTLD syndrome with modified Goldman scores of 3–4. The detailed modified Goldman scores were as follows: score 1, autosomal-dominant family history, at least three affected people in two generations with one person being a first-degree relative of the other two; score 2, familial aggregation, 3 or more family members with dementia but not meeting the criteria for 1; score 3, a single family member with early-onset dementia (before 65 years); score 3.5, one other affected family member with late-onset dementia; and score 4, no or unknown family history.

This study was approved by the Ethics Committee of Tianjin Medical University General Hospital. All participants volunteered to participate in the study and signed informed consent forms before entering the study.

Imaging assessments

All participants underwent a multimodal brain MRI scan, which was performed on a 3.0-Tesla MRI scanner (Discovery MR750, General Electric, Milwaukee, WI, USA) with a 64-channel phased array head coil, and cerebral ¹⁸F-FDG and ¹¹C-Pittsburgh compound B (PiB) PET scans. The results of the PET scan were confirmed by two experienced radiologists in nuclear medicine. The positivity or negativity of PiB PET was determined by the mean value of the target region to the cerebellum ratio with a cut-off value of 1.5 (the upper 95% confidence interval from a cluster analysis of healthy individuals) as described in our previous studies [18].

Mutation screening and analysis

WES was performed for all participants. Briefly, 300 ng of genomic DNA from each sample was used for library construction. Then, an exon capture kit (KAPA HyperExome) was applied for exome enrichment, and the captured libraries were sequenced on the MGISEQ-2000 platform (MGI, Wuhan, China). The average depth of coverage was 270 ×. Sequencing reads were aligned to the reference human genome (UCSC hg19) assembly using the Burrows-Wheeler Aligner (BWA, version 0.7.17) with default parameters. Single nucleotide variants (SNVs) and insertion-deletions (InDels) were called using the Genome Analysis Toolkit (GATK, version 4.1.9.0) and annotated by the in-house pipeline (version 1.0.0) in disease-causing and susceptible genes available on the Online Mendelian Inheritance in Man (OMIM, December 2021). The candidate causative SNVs/InDels were prioritized considering the following aspects: 1) absent or with a minor allele frequency ≤1% in the databases of the Exome Aggregation Consortium (ExAC) and Genome Aggregation Database (gnomAD); 2) matching an expected segregation pattern for genetic disease; 3) the variants were conservative and had deleterious effects by in silico prediction; 4) the OMIM disease phenotype overlapped with the patient’s clinical features; and 5) cases of this variant have been reported in the literature. All the selected variants were assessed for pathogenicity based on the adapted American College of Medical Genetics and Genomics (ACMG) guidelines and the ClinGen sequence variant interpretation working group per updated recommendations for the ACMG criteria [19 –22].

Patients were considered to have a definite genetic diagnosis if the pathogenic (P) or likely pathogenic (LP) variants identified could explain their phenotype. Otherwise, patients who carried variants of unknown significance (VUS), even in dementia-related causing genes, were finally considered to have genetically unsolved cases.

Testing for hexanucleotide expansion in C9orf72 was performed by repeat-primed PCR [23] and capillary electrophoresis in patients with negative WES results.

Statistical analysis

Qualitative and quantitative variables are presented as proportions (%) and means±standard deviations (SDs), respectively. Differences in continuous variables and categorical variables between AD and FTLD patients were analyzed using the two-sample t test and the chi-squared test, respectively. To explore the relationship between genes and family history, we divided AD and FTLD patients into two groups based on whether they carried dementia-related gene mutations. The difference in positive family history frequency between genetic mutation carriers and noncarriers was compared with the chi-squared test. All analyses were performed using the Statistical Package of the Social Sciences (SPSS) 26.0. All results of significance were determined by p values of 0.05 or below.

RESULTS

Demographic and clinical characteristics of the participants

Seventy-four AD patients, including 66 with typical AD and 8 with atypical AD [5 with posterior cortical atrophy (PCA), and 2 with the logopenic variant of PPA (lvPPA)], and 29 FTLD patients, including 7 with the behavioral variant of frontotemporal dementia (bvFTD), 15 with the semantic variant of PPA (svPPA), 6 with the nonfluent variant of PPA (nfvPPA), and 1 with corticobasal syndrome (CBS), were recruited (Fig. 1). The mean ages at symptom onset of the AD and FTLD groups were 63.57±7.52 and 62.52±7.24 years, respectively. A total of 59.46% (44 of 74) of AD and 55.17% (16 of 29) of FTLD patients had an early-onset (age at onset < 65 years) of dementia.

Among all participants, there was 1 patient with AD with a modified Goldman score of 3, whose father began experiencing cognitive decline at 45 years, and there were 11 (14.86%) AD and 9 (31.03%) FTLD patients with a modified Goldman score of 3.5 who had a positive family history but no incidence of early-onset dementia in the family. The other participants had no known family history of dementia. The demographic and clinical information of the AD and FTLD patients is shown in Table 1.

Fig. 1

Clinical phenotypes of participants. AD, Alzheimer’s disease; FTLD, frontotemporal lobar degeneration; PCA, posterior cortical atrophy; bvAD, behavioral variant of AD; lvPPA, logopenic variant of primary progressive aphasia; bvFTD, behavioral variant of frontotemporal dementia; svPPA, semantic variant of PPA; nfvPPA, nonfluent variant of PPA; CBS, corticobasal syndrome.

Table 1

Demographic and clinical characteristics of all participants

	AD (n = 74)	FTLD (n = 29)	p
Age, y	66.24±7.78	64.86±7.58	0.531
Age range, y	42–79	44–75	–
Sex, female, (%)	54 (72.97%)	17 (58.62%)	0.157
Education, y	10.56±3.41	10.79±4.20	0.112
Age at onset, y	63.57±7.52	62.52±7.24	0.695
< 65, n (%)	44 (59.46%)	16 (55.17%)	0.692
< 60, n (%)	21 (28.38%)	6 (20.69%)	0.425
Disease duration, y	2.73±2.18	3.28±2.14	0.879
Family history, n (%)	12 (16.22%)	9 (31.03%)	0.093
Modified Goldman score
1–2	0	0	0.093
3	1 (1.35%)	0
3.5	11 (14.86%)	9 (31.03%)
4	62 (83.78%)	20 (68.97%)
MMSE	18.30±5.10	19.03±6.80	0.017
APOE ɛ4 allele frequency	31.76%	6.90%	< 0.001

Data are presented as the mean±SD or n (%) as indicated. Continuous variables and categorical variables were analyzed using the two-sample t test and the chi-squared test, respectively. AD, Alzheimer’s disease; FTLD, frontotemporal lobar degeneration; MMSE, Mini-Mental State Examination.

Frequencies of variants in AD and FTLD patients

In AD patients, 4 carriers of P/LP variants (5.4%), 15 carriers of VUS (20.3%), and 16 carriers of risk genes (21.6%) were found (Fig. 2a). There was 1 patient with both a VUS and a risk gene variant. Compared with that in AD patients, the prevalence of genetic variants was higher in FTLD patients (Fig. 2b), with 3 LP variants (10.3%), 10 VUS (34.5%) and 6 risk gene variants (20.7%).

Fig. 2

Frequencies of the variants in all participants. a) Proportions of dementia-related gene mutation carriers among AD patients (n = 74). b) Proportions of dementia-related gene mutation carriers among FTLD patients (n = 29). c) Family history frequency in patients with AD. No significant difference was found between genetic mutation carriers (+) and noncarriers (–) (p > 0.05). d) Family history frequency in patients with FTLD. No significant difference was found between genetic mutation carriers (+) and noncarriers (–) (p > 0.05). AD, Alzheimer’s disease; FTLD, frontotemporal lobar degeneration; P, pathogenic; LP, likely pathogenic; VUS, variants of unknown significance.

As shown in Fig. 2c and 2d, no significant differences in family history frequency were found between genetic mutation carriers and noncarriers in either AD patients or FTLD patients (p > 0.05).

3.3 Genetic and clinical features

Mutation information and the major phenotypic features of AD and FTLD patients with mutations (P/LP or VUS) are summarized in Tables 2 and 3, respectively. The mutation and clinical information of patients with variants in risk genes are presented in Table 4. One novel LP variant in the ANXA11 gene (p.D40G) and three novel ABCA7 loss-of-function (LOF) variants were detected. No hexanucleotide expansion in C9orf72 was found in the participants with negative WES results.

Table 2

Clinical features of patients with AD carrying P/LP variants or VUS

Case No.	Genes	Mutation (CDS)	Mutation (protein)	rs ID	Mutation class	ACMG class	Reported	GnomAD MAF	CP	Initial and main symptoms	AO	MMSE
AD36	PSEN1	c.617G>A	p.G206D	NA	Missense	P	Yes	NA	AD	Memory loss, Language disorder	41	21
AD23	MAPT	c.14G>A	p.R5H	rs63750959	Missense	LP	Yes	0.0000597	AD	Memory loss, Irritability	71	17
AD29	CFAP43	c.2802T>A	p.C934*	NA	Nonsense	LP	Yes	NA	AD	Memory loss, Depression, Language disorder	58	13
AD67	LRRK2	c.4302G>A	p.W1434*	NA	Nonsense	LP	NA	0.0000039	AD	Memory loss, Depression, Visuospatial problem	55	19
AD73	LRRK2	c.2829A>C	p.E943D	NA	Missense	VUS	NA	NA	AD	Memory loss, Depression	63	19
AD18	PSEN2	c.640G>T	p.V214L	rs574125890	Missense	VUS	Yes	0.0002426	AD	Memory loss, Apathy, Difficulties in language comprehension	58	11
AD76	MAPT	c.418C>T	p.P140S	rs151115928	Missense	VUS	Yes	0.0005896	AD	Memory loss, Tremor, Bradykinesia	63	18
AD88	MAPT	c.418C>T	p.P140S	rs151115928	Missense	VUS	Yes	0.0005896	AD	Memory loss	62	19
AD64	APOE	c.886G>A	p.G296R	rs757764781	Missense	VUS	NA	0.0000225	AD	Memory loss, Loss of initiative	68	20
AD3	APP	c.614_622delACTCGGATG	p.D205_D207del	NA	Cds-del	VUS	Yes	NA	AD	Memory loss, Visuospatial deficits, Difficulties in language comprehension	72	24
AD33	CSF1R	c.1771G>C	p.G591R	NA	Missense	VUS	NA	NA	AD	Memory loss	63	24
AD65	CSF1R	c.1606C>G	p.L536V	rs55942044	Missense	VUS	Yes	0.0001214	AD	Memory loss	65	28
AD17	NOTCH3	c.4444G>A	p.G1482S	NA	Missense	VUS	NA	0.000000	AD	Memory loss, Visuospatial deficits, Cataphasia	49	17
AD11	GIGYF2	c.3463C>A	p.P1155T	rs200216092	Missense	VUS	NA	0.0002903	AD	Memory loss	74	21
AD87	GIGYF2	c.3649_3650 insACC	p.Q1216_P1217insH	NA	Cds-ins	VUS	NA	NA	AD	Memory loss	54	19
AD8	DAO	c.308C>T	p.P103L	rs200127576	Missense	VUS	Yes	0.0003539	AD	Memory loss, Illusion, Delusions	63	16
AD25	ITM2B	c.622C>T	p.R208C	rs762725137	Missense	VUS	NA	0.0000120	AD	Memory loss, Delusions, Difficulties in language comprehension	70	12
AD60	SPTBN2	c.2459C>T	p.T820M	rs548188891	Missense	VUS	Yes	0.0002263	AD	Memory loss	70	18
AD57	ALDH18A1	c.1448G>A	p.R483H	rs756168752	Missense	VUS	NA	0.0000278	AD	Memory loss	71	25

AD, Alzheimer’s disease; P, pathogenic; LP, likely pathogenic; VUS, variants of unknown significance; CDS, coding sequence; ACMG, American College of Medical Genetics and Genomics; GnomAD, Genome Aggregation Database; MAF, minor allele frequency; CP, clinical phenotype; AO, age at onset; MMSE, Mini-Mental State Examination; NA, not available; Cds-del, coding sequence deletion; Cds-ins, coding sequence insertion.

Table 3

Clinical features of patients with FTLD carrying P/LP variants or VUS

Case No.	Genes	Mutation (CDS)	Mutation (protein)	rs ID	Mutation class	ACMG class	Reported	GnomAD MAF	CP	Initial and main symptoms	AO	MMSE
BV9	MAPT	c.530A>T	p.D177V	rs533610448	Missense	LP	Yes	0.0000796	bvFTD	Behavioral disinhibition, Personality changes, Language disorder	67	27
SV6	TARDBP	c.1147A>G	p.I383V	rs80356740	Missense	LP	Yes	0.0000173	svPPA	Anomia, Impaired single-word comprehension, Memory loss, Irritability	51	27
SV12	ANXA11	c.119A>G	p.D40G	NA	Missense	LP	NA	0.0000114	svPPA	Language disorder (anomia, comprehension, hyperlogia)	65	28
SV9	GRN	c.1625C>T	p.A542V	NA	Missense	VUS	NA	NA	svPPA	Anomia, Memory loss, Impaired object knowledge	61	9
SV5	MAPT	c.1507 + 2367C>G	NA	rs267604921	Intron	VUS	Yes	0.0002469	svPPA	Language disorder (anomia, alexia), Memory loss, Irritability	70	26
SV10	LRRK2	c.1096G>A	p.V366M	rs113065049	Missense	VUS	Yes	0.0000159	svPPA	Language disorder (anomia, alexia), Memory loss, Indifferent	64	21
NV1	PSEN1	c.792G>T	p.(P264=)	rs150301281	Coding-synon	VUS	NA	0.0000239	nfvPPA	Progressive reduction in speech production, Word retrieval difficulties	61	20
NV3	APOE	c.192G>C	p.Q64H	rs370594287	Missense	VUS	NA	0.0001476	nfvPPA	Nonfluent speech, Irritability, Dietary changes	61	23
NV7+	PLD3	c.851A>G	p.N284S	rs200274020	Missense	VUS	Yes	0.0000839	nfvPPA	Language disorder (grammatical mistake, comprehension, poor substantive words), Apraxia, Visuospatial deficits	54	7
BV3	SPTBN2	c.2459C>T	p.T820M	rs548188891	Missense	VUS	Yes	0.0002263	bvFTD	Disinhibition, Language disorder, Irritability	65	8
SV13	SPTBN2	c.4009G>A	p.D1337N	NA	Missense	VUS	NA	NA	svPPA	Language disorder (anomia, comprehension), Memory loss, Disinhibition, Apathy	73	28
NV4	SETX	c.431A>G	p.N144S	rs767453182	Missense	VUS	Yes	0.0002467	nfvPPA	Phonological and grammatical errors, Word retrieval difficulties, Memory loss	71	17
SV14	EEF2	c.1025G>A	p.R342H	rs532030743	Missense	VUS	NA	0.0000054	svPPA	Language disorder (anomia, comprehension), Dietary changes	62	13

FTLD, frontotemporal lobar degeneration; bvFTD, behavioral variant of frontotemporal dementia; svPPA, semantic variant of primary progressive aphasia; nfvPPA, nonfluent variant of PPA; P, pathogenic; LP, likely pathogenic; VUS, variants of unknown significance; CDS, coding sequence; ACMG, American College of Medical Genetics and Genomics; GnomAD, Genome Aggregation Database; MAF, minor allele frequency; CP, clinical phenotype; AO, age at onset; MMSE, Mini-Mental State Examination; NA, not available; Coding-synon, coding synonymous.

Table 4

Genetic variants found in risk genes for AD and FTLD

Genes	Case No.	Mutation (CDS)	Mutation (protein)	Mutation class	rs ID	Reported	GnomAD MAF	APOE	CP	Initial and main symptoms	AO	MMSE
ABCA7	AD16	c.5787_5788insG	p.1930Efs*55	Frameshift	rs758488225	NA	0.0000364	3 3	AD	Memory loss	73	21
	AD30	c.2041_2050delCTGCCCGCGG	p.681Vfs*113	Frameshift	NA	NA	NA	3 4	AD	Memory loss	72	23
	BV2	c.5260C>T	p.R1754*	Nonsense	rs556286113	NA	0.0000438	3 3	bvFTD	Behavioral changes, Memory loss	59	17
	AD40	c.5963G>T	p.C1988F	Missense	rs142573667	Yes	0.0003432	3 4	AD	Memory loss	66	25
	AD41	c.5963G>T	p.C1988F	Missense	rs142573667	Yes	0.0003432	3 4	AD	Memory loss	78	26
	AD38	c.5069T>C	p.I1690T	Missense	rs184218896	Yes	0.0002309	3 3	AD	Memory loss, Difficulties in language comprehension	73	21
	AD35	c.1832T>G	p.V611G	Missense	rs529414938	NA	0.0000596	3 4	AD	Memory loss	73	18
	AD18	c.2926C>T	p.R976C	Missense	rs373667015	NA	0.0000441	3 3	AD	Memory loss, Apathy, Difficulties in language comprehension	58	11
	SV1	c.2926C>T	p.R976C	Missense	rs373667015	NA	0.0000441	3 4	svPPA	Language disorder (anomia, comprehension) Memory loss, Irritability	65	24
SORL1	AD44	c.4570G>A	p.G1524R	Missense	rs201415809	Yes	0.0001989	3 4	AD	Memory loss	64	19
	AD51	c.4570G>A	p.G1524R	Missense	rs201415809	Yes	0.0001989	3 3	AD	Memory loss	53	16
	AD74	c.6289G>A	p.V2097I	Missense	rs74642146	NA	0.0012374	3 3	AD*	Visuospatial deficits, Memory loss	69	13
	SV4	c.4360C>T	p.P1454S	Missense	rs201304369	NA	0.0002944	3 3	svPPA	Language disorder (anomia, comprehension), Memory loss	60	8
	NV2	c.2771A>G	p.N924S	Missense	rs377498269	Yes	0.0000398	3 3	nfvPPA	Nonfluent language, Mutism	66	18
TRPM7	AD21	c.5489C>T	p.T1830M	Missense	NA	NA	0.0000364	3 4	AD	Memory loss	59	21
	AD78	c.581G>C	p.R194T	Missense	rs150262564	NA	0.0006423	3 4	AD	Memory loss	75	11
	BV1	c.5493T>G	p.(P1831=)	Coding-synon	NA	NA	NA	3 3	bvFTD	Abnormal behaviors, Bradykinesia	70	23
NOS3	AD20	c.2984 + 4A>G	NA	Splice+10	rs201229125	NA	0.0000326	4 4	AD	Memory loss, Delusions, Depression	62	22
	AD27	c.814G>A	p.E272K	Missense	NA	Yes	0.0000175	3 4	AD	Memory loss, Irritability, Depression	60	24
	SV11	c.3139G>A	p.G1047S	Missense	NA	NA	NA	3 3	svPPA	Language disorder (anomia, comprehension), Memory loss, Indifference	62	15
MPO	AD55	c.1484C>T	p.T495I	Missense	rs150426727	NA	0.0000636	3 4	AD*	Visuospatial deficits, Memory loss, Illusion	54	13
DCTN1	AD39	c.1505G>T	p.R502L	Missense	NA	NA	NA	2 3	AD	Memory loss	63	24

NOS3: NM_000603.4; MPO: NM_000250.1; DCTN1: NM_004082.4. AD, Alzheimer’s disease; PCA, posterior cortical atrophy; FTLD, frontotemporal lobar degeneration; bvFTD, behavioral variant of frontotemporal dementia; svPPA, semantic variant of primary progressive aphasia; nfvPPA, nonfluent variant of PPA; CDS, coding sequence; GnomAD, Genome Aggregation Database; MAF, minor allele frequency; CP, clinical phenotype; AO, age at onset; MMSE, Mini-Mental State Examination; NA, not available; Coding-synon, coding synonymous. AD*: posterior cortical atrophy (PCA).

Patients with AD carrying P/LP variants

There was one carrier (AD36) of a P variant of PSEN1 (p.G206D) who had her first symptom of memory loss at age 41. Gradually, there was a lack of verbal fluency and word retrieval, a slight decrease in comprehension, and irritability within two years. Her father presented cognitive decline at age 45 and died of a cerebral hemorrhage at age 52. No other dementia patients were recorded in three generations of her family. MRI demonstrated slight atrophy of the bilateral medial temporal lobe. WES revealed that this variant was a heterozygous missense variant in PSEN1 and was classified as P according to ACMG.

Three LP variants in the MAPT, LRRK2, and CFAP43 genes were found in 3 typical AD patients. The MAPT (p.R5H) variant, a heterozygous missense variant, was found in a patient (AD23) with an age of onset at 71 years who presented her first symptoms of memory loss and subsequent personality changes (such as stubbornness and irritability) during the follow-up. Her mother had suspected dementia around the age of 70 years. Mild atrophy of the whole brain and bilateral hippocampus was observed on MRI. A nonsense variant in the LRRK2 gene (p.W1434*) was detected in a patient with early-onset AD (AD67). She developed depression at age 55 with progressive memory impairment and irritability. Visuospatial problems and numeracy disability then developed. Neurological examination revealed no parkinsonism or motor symptoms. There was no dementia in other members of her family. MRI demonstrated no clinically significant atrophy. This variant has not previously been reported in the literature. Another nonsense variant in the CFAP43 gene (p.C934*) was detected in a 60-year-old female (AD29). Her symptoms started at the age of 58 years with memory impairment and depression, followed by language disability during the disease course. There was no family history of dementia. MRI showed moderate atrophy of the bilateral precuneus and medial temporal lobe, which was more prominent on the left.

Patients with AD carrying VUS

Another 15 carriers of VUS in genes related to cognitive impairment or neurodegenerative diseases were identified in typical AD patients (Table 2). A PSEN2 (p.V214L) mutation was found in a patient with an age of onset of 58 years who also had a missense variant in the risk gene of ABCA7 (p.R976C). The APP mutation (p.D205_D207del) carrier presented with memory loss, visuospatial deficits, and language disorder at 72 years. His mother had dementia at the age of 65 years. WES revealed that the variant was an in-frame deletion variant (c.614_622delACTCGGATG). One VUS in MAPT (c.418C>T) was detected in two patients with early-onset AD. One of the patients developed parkinsonism 3 years after disease onset. One APOE (p.G296R) and 2 CSF1R carriers were found. They all had early-onset AD. A NOTCH3 variant (p.G1482S) was detected in a 49-year-old male. He subsequently developed visuospatial deficits, personality changes and cataphasia within 3 years. This variant has not been previously reported in the literature. An additional 6 variants were identified in DAO, GIGYF2, ITM2B, SPTBN2, and ALDH18A1 in 6 AD patients.

Patients with FTLD carrying P/LP variants

Three LP variants in the MAPT, TARDBP, and ANXA11 genes were identified in our FTLD cohort. The MAPT variant (p.D177V) was identified in a bvFTD patient (BV9). The main clinical manifestations were behavioral disinhibition (such as impulsive actions and a loss of manners) and personality changes (such as apathy), which started at the age of 67 years. He subsequently developed difficulties in language comprehension with relatively preserved memory ability. MRI demonstrated mild atrophy of the left lateral temporal lobe. WES revealed that this variant was a heterozygous variant, which had been reported in several cases. A variant in the TARDBP gene (p.I383V) was detected in a svPPA patient (SV6) with onset at age 51 years. He presented with anomia, an impairment of single-word comprehension and mild memory decline at onset and then developed irritability and anxiety. In three generations of his family, his grandfather had cognitive impairment. MRI demonstrated moderate atrophy of the bilateral temporal lobes, predominantly on the right side. The carrier of an ANXA11 variant (p.D40G) was a svPPA patient (SV12) with an age of onset of 65 years. He also showed hyperlogia and inappropriate language during conversation. MRI demonstrated bilateral anterior temporal lobe atrophy, prominently on the left side. This variant had not been reported in svPPA patients.

Patients with FTLD carrying VUS

Ten VUS in FTLD patients were identified. MA PT (c.1507 + 2367C > G), GRN (p.A542V), and LRRK2 (p.V366M) variants were found in 3 svPPA patients, with typical symptoms of language disorder (anomia, an impairment of single-word comprehension, and hyperlogia) and impaired object knowledge, particularly for low frequency items. Unlike the GRN and LRRK2 variants, the MA PT variant was found to be located in the intron. It was a deleterious splicing variant resulting in acceptor gain as assessed by SpliceAI. The PSEN1 variant p.(P264=) was detected in a nfvPPA patient with a progressive reduction in speech production and word retrieval difficulties at the age of 61 years, whose diagnosis was supported by PET scans showing a negative result on PiB. This variant was a synonymous mutation and was also a deleterious splicing variant that could affect the splicing process as assessed by SpliceAI. The APOE (p.Q64H) carrier was also a nfvPPA patient with an age of onset of 61 years who was homozygous for the ɛ3/ɛ3 genotype of the APOE gene. A PLD3 (p.N284S) mutation was found in another nfvPPA patient, whose main symptoms were effortful speech, verbal apraxia, and difficulties in the comprehension of syntactically complex sentences at the age of 54 years. In particular, she developed significant visuospatial impairment within one year. In addition, some variants associated with other neurodegenerative diseases were identified, such as SPTBN (p.T820M) in bvFTD, SETX (p.N144S) in nfvPPA, and SPTBN (p.D1337N), and EEF2 (p.R342H) in svPPA (Table 3).

Genetic variants in risk genes for AD and FTLD

Nineteen susceptibility loci were identified in the ABCA7 , SORL1, TRPM7, NOS3, MPO, and DCTN1 genes in all participants (Table 4). Seven different loci were detected in the ABCA7 gene, including 4 missense, 2 frameshift, and 1 nonsense variants. Specifically, the 2 frameshift (p.1930Efs*55, p.681Vfs*113) variants in typical AD patients and 1 nonsense (p.R1754*) variant in a bvFTD patient were responsible for a LOF and were novel. For the SORL1 gene, 4 different missense variants were detected in 5 patients. One of the variants (p.G1524R) was found in 2 patients with typical AD. The p.V2097I variant was found in a patient with the PCA variant of AD. Another two variants (p.P1454S and p.N924S) were found in 2 PPA patients (svPPA and nfvPPA, respectively). For the TRPM7 gene, 2 missense variants were detected in AD patients. One synonymous mutation affecting the splicing process was found in a bvFTD patient. For the NOS3 gene, 2 missense mutations and 1 intron mutation were found in 2 AD patients and 1 svPPA patient. One variant in MPO was found in an atypical AD patient with PCA. A missense variant in the DCTN1 gene, which could affect susceptibility to ALS, was found in a patient with typical AD without motor symptoms.

DISCUSSION

In the current study, we identified a high frequency of P/LP variants in Chinese patients with sporadic AD and FTLD. A novel variant in ANXA11 (p.D40G) was found in a svPPA patient, and 3 novel LOF mutations in ABCA7 were found in patients with AD or FTLD. However, no C9orf72 gene mutations were found in patients in our FTLD cohort. Interestingly, a high frequency of gene mutations was also observed in patients with svPPA, which was previously considered rarely heritable.

In total, 4 P/LP variants (5.4%) in AD patients and 3 LP variants (10.3%) in FTLD patients were identified. Our study showed a higher frequency of P/LP variants than previously reported in AD (3.6%) [10] or FTD (4.9–7.7%) [24, 25] cohorts from the Chinese population. In addition, a recent genetic screening of sporadic FTD patients in North America showed a total frequency of pathogenic variants of 5.3% [26]. Compared with these studies, more early-onset patients were included in our study. No associated variants were found in a few patients (4 AD patients and 6 FTLD patients) who had a family history, suggesting that there is still a large amount of “missing heritability” in neurodegenerative dementia genetics.

In AD patients, 1 pathogenic variant (1.4%) in PSEN1 (p.G206D) was detected, which has been previously reported as a causal mutation in patients with autosomal-dominant AD in an Iranian family [27]. Although most patients with PSEN1 mutations present with typical amnestic syndrome, carriers can also exhibit atypical manifestations, such as behavioral changes and language impairment [28]. In our study, a synonymous PSEN1 variant, p.(P264=), was also detected and classified as a VUS in a nfvPPA patient. This variant and its clinical association have not been reported, expanding the mutation spectrum of PSEN1-associated disease. MAPT mutations, which were identified as causative for FTLD, were also found in our AD patients, including 1 LP variant (p.R5H), which has also been identified in a patient with PD in a large Chinese cohort [29], and 1 VUS (p.P140S), of which one carrier developed parkinsonism 3 years after disease onset. Although the most common clinical phenotype of MAPT mutations is bvFTD, with possible development of parkinsonism and/or aphasia over time [30], MAPT mutations have also been implicated in multiple neurodegenerative diseases [31]. In addition, one LP variant in LRRK2 (p.W1434*) was identified in an AD patient, which has not been reported. LRRK2 mutations are the most common genetic cause of sporadic PD. However, growing evidence indicates that they are also associated with an AD-like pathology [32] and are related to AD susceptibility in studies of the Chinese population [33]. Another novel finding is that a nonsense variant in the CFAP43 gene (p.C934*), which was reported in patients with hydrocephalus-related cognitive impairment [34], was identified in an AD patient. Consistently, it has been reported that mutations in genes associated with other neurodegenerative diseases, such as FTLD-associated MAPT and PD-associated LRRK2 mutations, could be found in AD patients [35]. Our results support that different dementia disorders can be caused by or associated with overlapping genetic factors, suggesting the complexity of genotype–phenotype correlation.

LP variants in MAPT (p.D177V) and TARDBP (p.I383V), which have been reported [26, 36], were found in a bvFTD patient and a svPPA patient, respectively. We also detected 2 VUS in MA PT (c.1507 + 2367C > G) and GRN (p.A542V) in svPPA patients. However, no patients with C9orf72 gene mutations were found in our FTLD cohort, which is consistent with previous reports that C9orf72 mutations were rare in Asian populations compared with Caucasian populations [37]. Moreover, an LP variant in the ANXA11 gene (p.D40G) that was previously reported in patients with ALS in Europe [38] was identified for the first time in a svPPA patient without any motor symptoms 2 years after initial symptom onset. Previous studies showed a lower frequency of p.D40G in Chinese patients with sporadic ALS than in Caucasian patients with ALS [10, 39]. It was also reported that Caucasian ALS patients with ANXA11 variants were more likely to have cognitive impairment than Asian patients.

We also found 15 (20.3%) VUS in AD patients and 10 (34.5%) VUS in FTLD patients, which are higher frequencies than that reported in a study of a Spanish population of similar size (12.62%) [40]. That study focused on genes with mutations that are associated with autosomal-dominant neurodegenerative dementias or an increased risk of AD or FTLD; additional genes related to neurodevelopment and various neurodegenerative diseases were included and interpreted in our study. PSEN2 (p.V214L) was found in an AD patient with memory loss and language disorder, consistent with presentations previously described in Chinese and Korean patients [41, 42]. However, a missense variant in ABCA7 (p.R976C) was also detected in this patient, which might have an interactive effect on the pathogenesis of AD. Mutations in APP (p.D205_D207del) and APOE (p.G296R) were also found in AD patients, although there was not enough evidence of pathogenicity. Interestingly, some mutations that could cause other types of dementia were found in our AD patients, including a CADASIL-causing variant of the NOTCH3 gene and two CSF1R mutations related to hereditary diffuse leukoencephalopathy with spheroids. Notably, the CSF1R variant p.L536V has been previously identified in a patient with early-onset AD [32]. Although the role of VUS in genes in the pathogenesis of AD and FTLD remains unclear, it is possible that some of these variants might be reclassified in the future based on more genetic research and functional studies to explain their pathophysiological and pathological contributions.

In previous studies, svPPA was generally sporadic and the least heritable among FTLD subtypes [17]. However, the frequency of svPPA-associated variants in our study was higher than that in previous studies [43]. Apart from 2 LP variants (13.37%) and 5 VUS (33.33%), including FTLD causal genes, e.g., MA PT (c.1507 + 2367C > G) and GRN (p.A542V), an LRRK2 variant (p.V366M) was found in our svPPA patients. Pathogenic variants of LRRK2 have been reported in patients with sporadic early-onset FTLD [44] and are correlated with TDP-43-related pathology [45, 46]. However, whether LRRK2 variants have a pathogenic role in svPPA is still unclear. Further studies will be needed to clarify the complex etiology and the genetic spectrum of svPPA.

Another 17 susceptibility loci were identified in the ABCA7, SORL1, TRPM7, NOS3, MPO, and DCTN1 genes in our study. In the ABCA7 gene, 3 novel LOF variants were detected. Although memory symptoms and AD pathology are the most predominant features of ABCA7 mutation carriers, other neuropathologies and presentations can also be exhibited, including PD and FTLD [47]. Apart from typical AD patients, we also observed an LOF variant in a bvFTD patient and a missense variant in a svPPA patient. Similarly, missense variants of SORL1, which have been identified to be associated with both familial and sporadic forms of AD [48], were detected in 3 AD patients and 2 FTLD patients (1 svPPA patient and 1 nfvPPA patient). Moreover, several other susceptibility loci were identified in genes related to various neurodegenerative diseases, including TRPM7 (previously reported in AD, PD, and ALS versus this study in AD and bvFTD), NOS3 (PD and AD versus AD and svPPA), MPO (typical AD versus the PCA variant of AD), and DCTN1 (FTD and ALS versus AD). All these findings indicate a genetic overlap between AD and FTLD and other neurodegenerative diseases. Although these mutations are unlikely to have an independent effect on AD or FTLD pathology, they might increase the risk or accelerate disease onset via potential molecular mechanisms and interactions with known risk genes, such as APOE.

Our findings were based on a cohort with amyloid and FDG PET-supported AD and FTLD diagnoses. However, there are still several limitations. First, the AD patients were relatively young, with approximately half having early-onset AD. Thus, these patients were not representative of the real-world sporadic AD population, for which the prevalence increases with age. Second, we did not perform family co-segregation analysis to better validate the novel variants and VUS as well as the genotype-phenotype relationship, since samples were not obtained from the patients’ family members. Finally, further functional studies are needed to confirm our findings.

Conclusions

Our findings expand the mutation spectrum of neurodegenerative dementias in the Chinese population. There were large genetic overlaps between AD and FTLD as well as other neurodegenerative diseases and cognitive disorders, suggesting genetic pleiotropy in the process of neurodegeneration and cognitive impairment.

AUTHOR CONTRIBUTIONS

Yaoru Li (Conceptualization; Data curation; Investigation; Methodology; Writing – original draft; Writing – review & editing); Ziying Yang (Conceptualization; Data curation; Methodology; Writing – original draft); Yanxin Zhang (Data curation; Investigation; Validation); Fang Liu (Conceptualization; Data curation; Investigation); Jing Xu (Conceptualization; Validation; Visualization); Yaping Meng (Data curation; Formal analysis; Investigation); Gebeili Xing (Conceptualization; Data curation; Formal analysis; Visualization); Xuqin Ruan (Data curation; Formal analysis; Methodology; Software); Jun Sun (Data curation; Formal analysis; Software; Visualization); Nan Zhang (Conceptualization; Data curation; Methodology; Supervision; Writing – original draft; Writing – review & editing).

Footnotes

ACKNOWLEDGMENTS

The authors are grateful to the patients and their relatives for their participation in this research.

FUNDING

This study was supported by the Science and Technology Innovation 2030–Major Project (2021ZD0201805) and the Tianjin Key Medical Discipline (Specialty) Construction Project.

CONFLICT OF INTEREST

The authors have no conflict of interest to report.

DATA AVAILABILITY

The datasets generated and analyzed during the current study are available from the corresponding author on reasonable request.

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