Basic Neurosciences · Paper A
Dementia genetics
Because inheritance pattern and age of onset point to a different causal gene each time, dementia genetics only clicks once symptoms are matched to genotype systematically. Late-onset sporadic Alzheimer's disease usually reflects the ApoE ε4 risk allele, while early-onset disease running through generations points toward a deterministic single-gene mutation instead: e.g. a 40-year-old with several affected relatives across three generations should raise suspicion of a dominantly inherited gene, not the common sporadic form. Clinically, family history and age of onset together determine which genetic test is requested.
Late-onset, sporadic Alzheimer's disease is linked to the ApoE ε4 allele, a dose-dependent susceptibility (risk) gene, meaning more copies raise the risk further. The ε2 allele is protective, and the common ε3 allele is the neutral baseline against which ε2 and ε4 are judged, carrying neither raised nor lowered risk. Early-onset, autosomal-dominant Alzheimer's disease is caused by deterministic mutations, meaning inheriting the gene guarantees the disease, in APP (on chromosome 21, which is why Down syndrome, an extra copy of chromosome 21, causes early Alzheimer's), Presenilin-1 (chromosome 14, the commonest cause), and Presenilin-2. SORL1 is a fourth established autosomal-dominant familial Alzheimer's gene alongside these three: it normally shunts APP away from the amyloidogenic pathway, so a loss-of-function mutation lets more APP be processed into amyloid-β. In Down syndrome, the earliest change is often a personality or behavioural shift (apathy, frontal-type disinhibition) rather than the memory-led onset typical of sporadic Alzheimer's disease, because pre-existing intellectual disability makes early memory loss harder to detect clinically. Frontotemporal dementia is linked to MAPT (the tau gene), progranulin (GRN), and C9orf72. Huntington's disease is caused by a CAG trinucleotide repeat expansion in the HTT gene, inherited as autosomal dominant with anticipation (the repeat lengthens and the disease worsens or starts earlier across generations). For example, a patient with Down syndrome who develops new cognitive decline in their 40s reflects the extra APP gene copy on chromosome 21, not the more common ApoE-related sporadic disease. In practice, a young patient with Down syndrome and new cognitive decline should be assessed for Alzheimer's disease, not dismissed as behavioural change.
A fresh doctor might assume dementia genetics is just extra trivia layered on top of a clinical diagnosis. It isn't: matching the RIGHT gene to the RIGHT clinical pattern changes genetic counselling, family risk, and sometimes what a clinician screens for. Hold the phrase FAMILY PATTERN through every section below, because the age a patient's symptoms start and how many relatives are affected is the single biggest clue steering which gene to suspect.
Dementia genetics covers the inherited and genetic-risk contributors to progressive cognitive decline (a gradual loss of memory, thinking, and daily function). Some genes are DETERMINISTIC: inheriting the mutated copy guarantees the disease, following an autosomal dominant pattern (a single copy from one parent is enough, and each child of an affected parent has a 50% chance of inheriting it). Other genes are SUSCEPTIBILITY or RISK genes: they raise or lower the probability of disease without guaranteeing anything, and most people who develop dementia carry no single causal mutation at all.
A common mistake is assuming any family history of dementia points to a deterministic single-gene cause. Most dementia, including most Alzheimer's disease, is sporadic and multifactorial: ApoE epsilon-4 (e4) raises risk without guaranteeing disease, and many people who carry two copies of e4 never develop dementia at all, while many people with no e4 allele still do. Deterministic single-gene mutations are rare and should specifically be suspected when onset is unusually young (often before 65, sometimes before 50) combined with a clear autosomal-dominant family pattern across generations, not from family history alone.
Imagine two patients with Alzheimer's disease: one developed symptoms at 78 with no strong family history, the other developed symptoms at 38 with three generations of relatives affected. The first pattern points toward the common, sporadic form of Alzheimer's disease, driven mainly by the ApoE e4 allele: a dose-dependent susceptibility gene, meaning inheriting more copies raises risk further, while the epsilon-2 allele is protective instead. The second pattern, early onset with a strong multi-generation family history, points toward a rare but deterministic, autosomal dominant mutation instead. This is the single most exam-relevant discrimination in the whole topic.
Early-onset, autosomal-dominant Alzheimer's disease is caused by mutations in three genes: APP (amyloid precursor protein, on chromosome 21: which is why people with Down syndrome, who carry an extra copy of chromosome 21, are at markedly increased risk of early Alzheimer's pathology), PSEN1 (Presenilin-1, on chromosome 14, the commonest cause of familial early-onset disease), and PSEN2 (Presenilin-2, the rarest of the three). All three genes sit in the pathway that produces amyloid-beta, the protein that forms the amyloid plaques characteristic of Alzheimer's disease on investigation. Frontotemporal dementia (FTD), which presents earlier than typical Alzheimer's and disrupts personality, behaviour, or language before memory, is linked to three genes: MAPT (the gene coding for tau protein), GRN (progranulin), and C9orf72 (a repeat-expansion gene that is also the commonest genetic cause of motor neurone disease, useful because FTD and motor neurone disease can overlap in the same family). Huntington's disease is caused by a CAG trinucleotide repeat expansion in the HTT (huntingtin) gene, inherited as autosomal dominant, and shows ANTICIPATION: the repeat can lengthen when passed to the next generation, so children can develop symptoms earlier and more severely than their affected parent, particularly with paternal inheritance.
Sporadic late-onset Alzheimer's disease, modified by ApoE e4, should not be confused with familial early-onset Alzheimer's caused by APP, PSEN1, or PSEN2 mutations: the former is a risk modifier, the latter is deterministic. Down syndrome-associated early Alzheimer's, driven by an extra copy of the APP gene itself, is a distinct mechanism from both. Huntington's disease, with its CAG repeat expansion and characteristic chorea (involuntary jerking movements) alongside cognitive decline, should not be confused with any of the dementia genes above, since its inheritance pattern (with anticipation) and its motor phenotype are both distinctive.
Suspicion of a genetic dementia is raised clinically first: by age of onset, the shape of the family tree across generations, and any accompanying features such as chorea in Huntington's disease or early behavioural change in frontotemporal dementia: before any genetic test is ordered. Confirmatory diagnosis is then made by targeted genetic testing for the specific mutation suspected (for example, CAG repeat sizing for HTT, or sequencing of APP, PSEN1, or PSEN2), carried out through specialist clinical genetics services rather than as a routine dementia screen. ApoE genotyping is not used as a diagnostic test in the same way, because it only shifts probability rather than confirming or excluding disease.
Genetic testing and counselling are considered when the family pattern and age of onset suggest a deterministic mutation, guided by clinical genetics services and informed by NICE dementia assessment and diagnosis guidance alongside specialist neurogenetics input. A young patient with Down syndrome who develops new cognitive decline in their 40s should be actively assessed for Alzheimer's disease using standard cognitive screening and appropriate imaging, not dismissed as behavioural change. Management of the dementia itself, once diagnosed, still follows standard subtype-based treatment (for example, cholinesterase inhibitors for Alzheimer's disease) but genetic counselling additionally informs family members of their own risk and reproductive choices, which a purely sporadic diagnosis does not require.
Questions often describe an early age of onset with a strong family history and expect the candidate to name PSEN1 specifically, since it is the commonest cause of early-onset familial disease, rather than defaulting to ApoE e4, which only applies to sporadic, later-onset disease. Another recurring trap places a patient with Down syndrome and expects recognition that their raised Alzheimer's risk comes from an extra APP gene copy on chromosome 21, not from ApoE. A further trap tests whether candidates can distinguish Huntington's autosomal-dominant, anticipation-showing inheritance from the risk-only inheritance of sporadic Alzheimer's disease.
Match age of onset and family pattern to the gene: ApoE e4 is a risk-only, dose-dependent allele behind common sporadic late-onset Alzheimer's disease; APP, PSEN1 (the commonest cause), and PSEN2 are deterministic, autosomal-dominant genes behind early-onset familial Alzheimer's disease; Down syndrome causes early Alzheimer's pathology through an extra APP copy on chromosome 21; MAPT, GRN, and C9orf72 underlie frontotemporal dementia; and a CAG-repeat expansion in HTT, showing anticipation, causes Huntington's disease. Young onset plus a strong multi-generation family tree means think deterministic gene and refer for testing: old age with no family history means think ApoE risk, not a single mutation.